Zürich, Switzerland
Zürich, Switzerland

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Grant
Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: NMP.2011.3.2-1 | Award Amount: 5.58M | Year: 2012

In response to world-wide changes in the chemical/biopharmaceutical industry, new market requirements for specific end-use product properties as well as to stricter energy, safety and environmental constraints a revolutionary approach is needed regarding equipment design, plant operation and new production paradigms that will result in better products and processes. Process intensification (PI) is the key technological pathway to drastically improve the sustainability of the chemical and biopharmaceutical processes by replacing the existing, inefficient plant equipment with new, intensified operations. PI comprises the development of novel equipment and production methods that can bring dramatic improvements in manufacturing and processing and lead to safer, cleaner, smaller and cheaper production routes. PI is expected to open up the way for the production of new products, unblock the potential for plant operation under less stable conditions and reform entire business models to foster just-in-time or distributed production. In a series of recent publications and roadmaps, PI has been identified as the path for sustainable development. The OPTICO project aims at overcoming the present limitations on implementing PI by establishing a new methodological design approach for sustainable, intensified chemical/biopharmaceutical plant design and operation through a flexible, integrated multi-scale modeling framework coupled with advanced process analytics tools and modern optimization/control techniques. It is envisaged that, within a 3 year time frame, the proposed work will enable the innovative process design and promote a substantial improvement in chemical/biopharmaceutical plant efficiency by reducing energy consumption, operating costs, handled volumes and generated wastes as well as by improving the process efficiency and safety.


Getaz D.,ETH Zurich | Stroehlein G.,ETH Zurich | Stroehlein G.,ChromaCon AG | Butte A.,Lonza Ltd. | Morbidelli M.,ETH Zurich
Journal of Chromatography A | Year: 2013

In this work we present a general procedure for the model-based optimization of a polypeptide crude mixture purification process through its application to a case of industrial relevance. This is done to show how much modeling can be beneficial to optimize complex chromatographic processes in the industrial environment. The target peptide elution profile was modeled with a two sites adsorption equilibrium isotherm exhibiting two inflection points. The variation of the isotherm parameters with the modifier concentration was accounted for. The adsorption isotherm parameters of the target peptide were obtained by the inverse method. The elution of the impurities was approximated by lumping them into pseudo-impurities and by regressing their adsorption isotherm parameters directly as a function of the corresponding parameters of the target peptide. After model calibration and validation by comparison with suitable experimental data, Pareto optimizations of the process were carried out so as to select the optimal batch process. © 2013 Elsevier B.V..


Voitl A.,ETH Zurich | Muller-Spath T.,ETH Zurich | Muller-Spath T.,Chromacon AG | Morbidelli M.,ETH Zurich
Journal of Chromatography A | Year: 2010

The downstream processing of monoclonal antibodies from cell culture supernatant is usually done by a number of chromatographic and non-chromatographic steps. Efforts are taken to reduce the costs associated to those steps, while maintaining a high product purity. A possibility to reach this goal is the reduction of the number of chromatographic steps using mixed mode resins that offer more than one functionality in one chromatographic step. In this work, a commercially available mixed mode resin was evaluated systematically with respect to the adsorption of proteins. The Henry coefficient, which quantifies the adsorption strength, was measured for the full working range of the stationary phase as a function of the salt concentration and the pH. The results were compared to a conventional anion exchange and a hydrophobic interaction resin. Furthermore, the resin was applied for the polishing step of an antibody from an industrial clarified cell culture supernatant. © 2010 Elsevier B.V.


Guelat B.,ETH Zurich | Strohlein G.,ETH Zurich | Strohlein G.,ChromaCon AG | Lattuada M.,ETH Zurich | Morbidelli M.,ETH Zurich
Journal of Chromatography A | Year: 2010

A model for the adsorption equilibrium of proteins in ion-exchange chromatography explicitly accounting for the effect of pH and salt concentration in the limit of highly diluted systems was developed. It is based on the use of DLVO theory to estimate the electrostatic interactions between the charged surface of the ion-exchanger and the proteins. The corresponding charge distributions were evaluated as a function of pH and salt concentration using a molecular approach. The model was verified for the adsorption equilibrium of lysozyme, chymotrypsinogen A and four industrial monoclonal antibodies on two strong cation-exchangers. The adsorption equilibrium constants of these proteins were determined experimentally at various pH values and salt concentrations and the model was fitted with a good agreement using three adjustable parameters for each protein in the whole range of experimental conditions. Despite the simplifications of the model regarding the geometry of the protein-ion-exchanger system, the physical meaning of the parameters was retained. © 2010 Elsevier B.V.


Krattli M.,ETH Zurich | Muller-Spath T.,ETH Zurich | Muller-Spath T.,ChromaCon AG | Morbidelli M.,ETH Zurich
Biotechnology and Bioengineering | Year: 2013

The multicolumn countercurrent solvent gradient purification (MCSGP) process is a continuous countercurrent multicolumn chromatography process capable of performing three fraction separations while applying a linear gradient of some modifier. This process can then be used either for the purification of a single species from a multicomponent mixture or to separate a three component mixture in one single operation. In this work, this process is extended to the separation of multifractions, in principle with no limitation. To achieve this goal the MCSGP standard process is extended by introducing one extra separation section per extra fraction to be isolated. Such an extra separation section is realized in this work through a single additional column, so that a n fraction MCSGP process can be realized using a minimum of n columns. Two separation processes were considered to experimentally demonstrate the possibility of realizing a four-fraction MCSGP unit able to purify two intermediate products in a given multicomponent mixture. The first one was a model mixture containing four different proteins. The two proteins eluting in the center of the chromatogram were purified with yields equal to 95% for the early eluting and 92% for the later eluting one. The corresponding purities were 94% and 97%, respectively. Such performance was well superior to that of the batch operation with the same modifier gradient which for the same purity values could not achieve yields larger than 67% and 81%, respectively. Similar performance improvements were found for the second separation where two out of seven charge variants which constitute the mAb Cetuximab currently available on the market have been purified in one single operation using a four-fraction MCSGP unit. In this case, yields of 81% and 65% were obtained with purities of 90% and 89%, respectively. These data compare well with the corresponding data from batch chromatography where with the same gradient and for the same purities, yield values not larger than 49% and 34%, respectively, could be achieved. Biotechnol. Bioeng. 2013; 110:2436-2444. © 2013 Wiley Periodicals, Inc.


Patent
ChromaCon AG | Date: 2014-09-03

A chromatographic process for the enrichment of at least one compound of interest (X) from a mixture (F) comprising said at least one compound of interest (X) as well as at least one further compound (W, C, S), which is not of interest, is proposed, using at least two chromatographic columns, wherein said process at least involves a sequence of the following steps:(i) a cyclic accumulation phase, in which the at least two chromatographic columns are alternatingly operated in an interconnected phase (IC), followed by a disconnected phase (B), wherein after these two phases the first and second column or group of columns exchange places; wherein said two phases are carried out sequentially M times with M > 1;(ii) a cyclic separation phase, in which the at least two chromatographic columns are alternatingly operated in an interconnected phase (IC), followed by a disconnected phase (B), wherein after these two phases the first and second column or group of columns exchange places to undergo the next interconnected (IC) and disconnected phases (B); wherein said two phases are carried out sequentially N times with N 0;(iii) an elution phase, in which from the column or group of columns, which at the end of phase (i) or, in case of N>0 at the end of phase (ii) contains the at least one compound of interest (X), said at least one compound of interest (X) is extracted via the outlet.


The document pertains to a method for the purification of a ternary mixture of dimeric antibodies of the type AA, AB, BB, characterised in that for the separation of the three components and in particular for the isolation of the multi-specific fraction AB multicolumn counter current solvent gradient purification chromatography with a stationary phase load of more than 1 mg antibody mixture per millilitre stationary phase is used. It furthermore relates to a method for the identification of in particular bispecific antibody systems, which are particularly suitable for the application of such a purification method.


The document pertains to a method for the purification of a ternary mixture of dimeric antibodies of the type AA, AB, BB, characterised in that for the separation of the three components and in particular for the isolation of the multi-specific fraction AB multicolumn counter current solvent gradient purification chromatography with a stationary phase load of more than 1 mg antibody mixture per millilitre stationary phase is used. It furthermore relates to a method for the identification of in particular bispecific antibody systems, which are particularly suitable for the application of such a purification method.


Patent
Chromacon Ag | Date: 2014-01-29

A chromatographic process for the enrichment of at least one compound of interest from a mixture is proposed, using chromatographic columns, wherein said process involves a sequence of the following steps: (i) a cyclic accumulation phase, in which the chromatographic columns are alternatingly operated in an interconnected phase, followed by a disconnected phase, wherein subsequently columns exchange places and wherein the phases are carried out sequentially; (ii) a cyclic separation phase, in which the chromatographic columns are alternatingly operated in an interconnected phase, followed by a disconnected phase, wherein after these phases columns exchange places to undergo the next interconnected and disconnected phases; and (iii) an elution phase, in which from the column, which at the end of phase (i) or at the end of phase (ii) contains the compound of interest, is extracted via the outlet.


Patent
ChromaCon AG | Date: 2014-01-31

A chromatographic purification method for the isolation of a desired product fraction from a mixture using 2 chromatographic columns, comprises, within one cycle to be carried out at least once, the following steps: a first batch step, wherein said columns are disconnected and a first column is loaded with feed and its outlet is directed to waste, and from a second column desired product is recovered and subsequently the second column is regenerated; a first interconnected step, wherein the outlet of the first column is connected to the inlet of the second column, the first column is loaded beyond its dynamic breakthrough capacity with feed, and the outlet of the second column is directed to waste, a second batch step analogous to the first batch step but with exchanged columns; and a second interconnected step, analogous to the first interconnected step but with exchanged columns.

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