Instrumental aspects of Simulated Moving Bed chromatography

G Model

ARTICLE IN PRESS

CHROMA-356796; No. of Pages 21

Journal of Chromatography A, xxx (2015) xxx–xxx

Contents lists available at ScienceDirect

Journal of Chromatography A journal homepage: www.elsevier.com/locate/chroma

Review article

Instrumental aspects of Simulated Moving Bed chromatography Rui P.V. Faria, Alírio E. Rodrigues ∗ Laboratory of Separation and Reaction Engineering, Department of Chemical Engineering, Faculty of Engineering of University of Porto, 4200-465 Porto, Portugal

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Article history: Received 16 June 2015 Received in revised form 22 August 2015 Accepted 24 August 2015 Available online xxx Keywords: Multicolumn counter-current chromatographic processes Chromatographic separation Simulated Moving Bed Equipment design

a b s t r a c t The Simulated Moving Bed (SMB) is one of the greatest illustrations of the potential of continuous multicolumn counter-current chromatographic processes. Although it was initially developed for the purification of petrochemicals, the advances that this technology has experienced during more than 50 years of existence were at the basis of its successful expansion into the food and pharmaceuticals industries. In this context, the present work provides an overview of the evolution of SMB focused on the most relevant instrumental aspects related with this technology. For that purpose, the details of the design and construction of this equipment will be reviewed, with special attention to the valves design. Due to its increasing interest, the technical requirements imposed by unconventional operating modes will be addressed together with the design adaptations that allow the operation of SMB units with compressible fluids and the implementation of Hybrid-SMB processes. Finally, as SMB technology has been unable to meet all the process specifications within the growing biopharmaceuticals industry, the development of alternative multicolumn counter-current units has intensified over the last few years. Hence, examples of the design and application of these new units will be provided. © 2015 Elsevier B.V. All rights reserved.

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Operating modes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Dynamic configuration variations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.1. 2.1.1. Varicol® . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Pseudo-SMB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.1.2. 2.2. Flow rate modulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.2.1. Power Feed . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.2.2. Improved-SMB® . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.2.3. Partial-Feed . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.2.4. Partial-Discard and Partial-Withdrawal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.2.5. Outlet Swing Stream. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .00 2.3. Concentration modulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.3.1. ModiCon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.3.2. Enriched Extract SMB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.4. Gradient operation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.4.1. Solvent Gradient SMB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.4.2. Temperature Gradient SMB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.5. Alternative SMB configuration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.5.1. SMB with reduced number of sections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.5.2. SMB with extended number of sections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.5.3. SMB cascades . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

∗ Corresponding author. E-mail address: [email protected] (A.E. Rodrigues). http://dx.doi.org/10.1016/j.chroma.2015.08.045 0021-9673/© 2015 Elsevier B.V. All rights reserved.

Please cite this article in press as: R.P.V. Faria, A.E. Rodrigues, Instrumental aspects of Simulated Moving Bed chromatography, J. Chromatogr. A (2015), http://dx.doi.org/10.1016/j.chroma.2015.08.045

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Design and construction details of SMB units . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.1. Valves and pumps design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.1.1. Central valves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.1.2. Distributed valves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.1.3. Summary of the different valves and pumps designs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.2. Considerations regarding the fluid transfer lines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.3. Design adaptations for special SMB units . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.3.1. Gas phase and supercritical SMB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.3.2. Hybrid SMB technologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Alternative multicolumn chromatographic units . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.1. Multicolumn solvent gradient purification (MCSGP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.2. Periodic counter-current packed bed chromatography (PCC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

Nomenclature 3C-PCC CIP MCSGP PCC SMB SMBR TMB

three column periodic counter-current packed bed chromatography cleaning in place multicolumn solvent gradient purification periodic counter-current packed bed chromatography Simulated Moving Bed Simulated Moving Bed Reactor True Moving Bed

1. Introduction Chromatography is a very effective purification technique with a wide range of industrial applications. The separation principle is based on the differences observed in the affinity of the species carried by a fluid mobile phase towards a solid stationary phase. Hence, as a multicomponent mixture is introduced and transported by the eluent along the column some of its components will establish more powerful interactions with the stationary phase than others generating concentration profiles that will percolate the chromatographic column at different velocities. The less retained species will elute earlier from the column than the most retained ones eventually allowing to collect the products of interest with a high purity degree. Single column batch elution is the simpler preparative chromatography process known. However, it presents very high eluent consumption values and its productivity is relatively limited [1,2]. To overcome these limitations the concept of counter-current movement of the solid and liquid streams was introduced in chromatographic processes through the development of the True Moving Bed (TMB) (Fig. 1). By employing a counter-current operation mode the separation is enhanced, through the maximization of the adsorption driving force, leading to the improvement of the overall performance of the chromatographic process and allowing to proceed to separations that otherwise would be too difficult. As the practical implementation of a TMB presents restraining technical issues mainly related with the motion of the solid, Broughton and Gerhold [3] from UOP, Inc. (United States of America), in 1961, developed and patented the first Simulated Moving Bed (SMB). This unit consists in a set of interconnected chromatographic columns with two inlet streams, feed and desorbent, and two outlet streams, extract and raffinate. The position of the streams at each moment divide the unit in four different sections according to their functions: section I, regeneration of the adsorbent; section II, adsorption of the most retained species so it can be collected at the extract

port and desorption of the least retained species to avoid contamination of the extract stream; section III adsorption of the most retained species to avoid the contamination of the raffinate and desorption of the least retained species so it can be collected at the extract port; and section IV regeneration of the eluent. Finally, the major feature of this unit is how it is able to simulate the solid movement of the TMB by a synchronous shift of all inlet and outlet streams position in the direction of the fluid flow. In Fig. 1 a schematic representation of the TMB and SMB units is provided. Over the years, this technology has been the scope of several research works that reviewed [4–8] alternative operation modes, design and optimization strategies among other technical aspects. An historical perspective of multicolumn counter-current chromatographic processes was provided by Sá Gomes et al. [5]. In this work, the authors identified two distinct periods on the evolution of this technology: a first period corresponding to its emergence and wide application to the purification of bulk chemicals, mainly focused on the petrochemical industry, and a second period associated with the introduction of these processes in the pharmaceutical industry. UOP, Inc. (United States of America) not only was responsible for the creation of the concept behind the SMB as it was the first company to accomplish a large-scale implementation of this technology in the Parex® process designed for the separation of p-xylene (with a purity of 99.8–99.9%) from o-, m- and p-xylene and ethylbenzene [9–11]. The purification of this aromatic compound is still one of the most important processes within the petrochemical industry, generally carried out at 180 ◦ C and using zeolites with a particle size distribution between 500 and 1000 ␮m as adsorbent. The SMB unit used in this process comprises 24 columns with an internal diameter of approximately 9 and 1 m height each. Other relevant processes within the petrochemical industry include the Molex® , for the purification of n-paraffins, the Olex® , for the separation of olefins from paraffins, both from UOP, Inc. (United States of America) and the Eluxyl® process from Axens/Institut Fracc¸ais du Petrole (France) also for the separation of p-xylene from the isomeric mixture of C8 compounds. Around 1970, still within the first period of the evolution of the SMB, another major industrial application was found for this technology, related with the purification of sugars. A particularly interesting case is the Sarex® process [12], also developed by UOP, Inc. (United States of America) through which fructose was separated from corn syrup using ion exchange resins with average particle diameters of 300–500 ␮m, at temperatures around 65 ◦ C. However, as in this case the purity specifications (approximately 90%) were much lower than those of the Parex® process a reduction of the size of the plants installed to 40% or 50% of the size of petrochemical units was verified.

Please cite this article in press as: R.P.V. Faria, A.E. Rodrigues, Instrumental aspects of Simulated Moving Bed chromatography, J. Chromatogr. A (2015), http://dx.doi.org/10.1016/j.chroma.2015.08.045

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Fig. 1. Representation of a TMB (a) and a SMB (b) unit and the corresponding internal concentration profiles.

The transition to the second period of the SMB process development was driven by the interest generated within the pharmaceutical industry in highly pure enantiomers [13]. The development of new and improved chiral stationary phases also played an important role. The average particle diameter of these materials dropped to values close to 20 ␮m and its efficiency increased significantly when compared with the stationary phases used in the first generation of SMBs. This resulted in a sharp decrease of the dimensions of the chromatographic columns used in pharmaceutical processes, to values as low as 10 cm, which was simultaneously impelled by the high cost of these materials. Nevertheless, despite the high purities achieved when performing the enantioseparation in the SMB, the limited adsorption capacity of the stationary phases leads to productivity values 1 order of magnitude lower than the values obtained in the petrochemical industry, for instance. Another noteworthy progress verified in this period was the intensification of the research regarding unconventional operating modes, including the Varicol® [14] and the Improved-SMB [15,16] processes. In a recent publication, Nicoud [17] corroborated the existence of the two periods previously proposed yet introduced a new one associated with the large number of multicolumn counter-current chromatographic processes developed and applied to biopharmaceuticals manufacturing in the last decade. However, most of these processes include the purification of intermediately eluting species from ternary or pseudo-ternary mixture which restrains the use of SMB. Although the separation could be accomplished in a cascade of SMB units the complexity of the system and the large quantities of the expensive stationary phases required would represent a significant drawback. Furthermore, the purification of biopharmaceuticals often include a complex series of sequential steps, namely,

loading (introduction of the feed), washing (removal of the least retained contaminants), elution (recovery of the target product), regeneration (removal of the most retained contaminants) and reequilibration (preparation of the column for the next load step) and in each of these a different solvent or solvent gradient might be used. SMB units are unable to meet all the requirements abovementioned. Therefore, several research studies led to the development of alternative units and processes that define this new era of multicolumn counter-current chromatography. The most prominent examples include the multicolumn solvent gradient purification (MCSGP) [18,19] and the periodic counter current packed bed chromatography (PCC) [20–22]. In the present work, the evolution of the SMB technology will be addressed under a different scope. Instead of analysing the evolution of the SMB in terms of the processes in which it has been applied, one will mainly focus on the technical specificities of the units developed throughout the years in order to achieve the expected performances for the said processes. For that purpose, primarily, a diversity of unconventional, yet increasingly important, operating modes will be reviewed taking into consideration its advantages, limitations and technical requirements. Subsequently, details regarding the construction of SMB units will be provided, centring the discussion in the most relevant valves and pumps design strategies reported. Furthermore, due to the growing industrial interest in SMB processes using compressible fluids, as the gas phase SMB and the supercritical SMB, and Hybrid-SMB processes, with emphasis on SMB reactors (SMBR), the particularities associated with its practical implementation will be addressed as well. Finally, this work will provide a description of some alternative multicolumn chromatographic processes recently developed that share some of the basic principles of the SMB but diverted into conceptually different technologies and equipment.

Please cite this article in press as: R.P.V. Faria, A.E. Rodrigues, Instrumental aspects of Simulated Moving Bed chromatography, J. Chromatogr. A (2015), http://dx.doi.org/10.1016/j.chroma.2015.08.045

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2. Operating modes The conventional SMB with four sections, two inlet and two outlet streams plus a recycling stream and synchronous shifts is unquestionably the SMB unit that has found a higher number of applications since it was first proposed in 1961. However, the development of alternative operating modes increased the efficiency of some of the existing processes and allowed to accomplish separations that would otherwise be impossible. In this work, the different operating modes will be classified considering the major modification by them induced in the classical SMB as follows: • Dynamic configuration variations: Varicol® , Pseudo-SMB. • Flow rate modulation: Power Feed, Improved-SMB® , PartialDiscard and Partial-Withdrawal, Outlet Swing Stream. • Concentration modulation: ModiCon, Enriched Extract SMB. • Gradient operation: solvent gradient, temperature gradient. • Alternative SMB configurations: SMB with reduced number of sections, SMB with extended number of sections, SMB cascades. Several advantages and limitations are associated to each of these unconventional operating modes. Furthermore, the technical requirements for their implementation diverge. Hence, all of these issues will be briefly addressed subsequently. 2.1. Dynamic configuration variations 2.1.1. Varicol® The Varicol® process, developed and commercialized by Novasep SAS SAS (France) [23,24], is probably the most commonly applied nonconventional SMB operating mode. It can be implemented through the asynchronous shift of the inlet and outlet ports, which promotes a variation of the number of columns per zone. This operating mode is particularly advantageous for units with a reduced number of columns having demonstrated the ability to increase of the productivity of the classical SMB for the same product purity requirements [25–27]. 2.1.2. Pseudo-SMB Japan Oregon Co. developed an alternative SMB operating mode for efficient ternary separation denominated Pseudo-SMB (also known as JO process) [28]. This process is implemented through an intermittent introduction of the feed stream in the unit and an intermittent withdrawal of both extract and raffinate. It comprises two main steps: initially the unit is operated as a series of fixed bed columns by feeding the ternary mixture at the beginning of section III and the eluent at the beginning of section I while the intermediately adsorbed specie is collected at the end of section II; in the second step the feed flow rate is suppressed (the eluent is the only inlet stream) and the unit is operated similarly to a conventional SMB for a complete cycle, in which the component with higher affinity towards the stationary phase in collected at the extract port and the component with lower affinity at the raffinate port. The momentarily elimination of the feed stream generates a zone of increased concentration of the intermediately adsorbed compound, simultaneously separating the other two species, which is responsible for the improved performance of this unit [29–31].Adaptations of this operating mode can also be found in the open literature [32–34]. 2.2. Flow rate modulation 2.2.1. Power Feed The Power Feed, or the time variable SMB operating mode, as originally denominated by Kearney and Hieb [35,36], is attained through the modulation of the section flow rates between two

consecutive switches. The possibility of changing the inlet and outlet streams flow rates considerably increases the number of degrees of freedom of the system and, therefore, conventional design approaches are unsuitable for the definition of the operating conditions. Instead, multi-objective optimization algorithms must be applied [36–38]. Nevertheless, the Power Feed SMB has demonstrated to be able to improve the classical SMB productivity and solvent consumption [38,39]. 2.2.2. Improved-SMB® The Improved-SMB® (also denominated Intermittent-SMB) has been largely applied in the sugar processing industry [40], however it has found other fields of applications [41]. Developed by Nippon Rensui Co. (Japan) this operating mode consists in the subdivision of the switching time into two different intervals: initially, the inlet and outlet streams are distributed through the unit, similarly to the classical SMB, however there is no flow rate in section IV and, consequently, no fluid is recycled into section I; in the second stage, all inlet and outlet streams are closed and the recycling is reestablished. The performance of the Improved-SMB® is comparable to the performance of the conventional SMB even if the number of columns per section is significantly reduced [7,15,16]. Furthermore, the Improved-SMB® is able to accomplish ternary separations [42]. 2.2.3. Partial-Feed The Partial-Feed operation mode [43,44] is achieved through a discontinuous introduction of the feed in the separation unit, compensating the variation of the inlet flow rates by changing the raffinate flow rate in order to keep the internal flow rates in sections I, II and IV constant. The moment at which the feed pulse occurs and its extent represent two specific process variables of Partial-Feed SMB, that increase the number of degrees of freedom of the conventional unit, resulting in a more efficient process, predominantly, for reduced number of columns per section [43,44]. Note that the Partial-Feed can be considered as a particular case of the PowerFeed mode in which the feed flow rate is set to zero in, at least, one of the time switch subintervals. 2.2.4. Partial-Discard and Partial-Withdrawal The Partial-Discard SMB process exploits the variation of the outlet concentration profiles throughout the switching interval, by selectively collecting the desired fraction of the extract and raffinate streams and discarding the remaining fractions [43,45]. Despite the undeniable benefits of this operation mode in terms of product purity, it is clear that, by rejecting part of the outlet streams, which might contain significant amounts of the target products, the productivity and recovery values are severely affected. However, several alternatives were promptly developed aiming the recovery of the product present in the discarded streams [46–49]. Additionally, this operation mode has also been implemented in combination with Partial-Feed, enhancing the overall process performance [50]. 2.2.5. Outlet Swing Stream A more complex modulation of the SMB outlet streams flow rate, entitled Outlet Swing Streams, has been proposed by Sá Gomes et al. [51]. The flow rates in sections I and IV can be dynamically adjusted, keeping a constant value in sections II and III, through the manipulation of the extract, raffinate and eluent flow rates. Thus, the product concentration fronts can be expanded or contracted in the vicinity of the withdrawal ports, consequently increasing the purity of the target species or decreasing the eluent consumption. An adaptation of this technique in which the outlet stream ports are completely closed for a fraction of the switching time has been

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reported in the open literature under the denomination of PartialPort-Closing [52].

2.3. Concentration modulation 2.3.1. ModiCon The possibility of performing a dynamic variation of the SMB feed concentration throughout a switching interval resulted from the development of the ModiCon concept [53]. Through a gradient mixing device located at the feed port (either a gradient pump or a valve circuit), the inlet stream concentration can be modulated and the process benefits from the influence of this parameter in the migration velocities of species that present nonlinear adsorption equilibrium isotherms. For instance, in the case of Langmuir adsorption isotherms, the increase of the feed concentration during the switching interval will improve the performance of the unit [54]. The major advantages of ModiCon are related with its ability to provide the target product with an increased purity value, preserving the productivity of the classical SMB [53,55]. Additionally, this technique can be combined with the Varicol® and/or Power Feed operating modes, overcoming the performances obtained when each of these strategies is applied independently [53,55].

2.3.2. Enriched Extract SMB The principle behind the Enriched Extract SMB is based on the effect of the increase of the extract concentration in the adsorption behaviour of the system species, that, for favourable adsorption equilibrium isotherms, can convert the dispersive desorption fronts within zone II into compressive fronts, enhancing the separation. This concept, developed by Novasep S.A.S. (France) [56], comprises an additional enrichment unit, responsible for concentrating the extract stream leaving section I. A fraction of the product stream of this parallel separation unit is collected and the remaining is reintroduced in the system at the same point. Consequently, the Enriched Extract SMB is able to overcome the classical SMB performance when operating under restrictive purity requirements for the more retained compound [57].

2.4. Gradient operation 2.4.1. Solvent Gradient SMB The first Solvent Gradient SMB process was implemented in a SMB unit working under supercritical conditions, in which the eluent strength was adjusted by controlling the pressure (and consequently its density) within the different sections [58,59]. For liquid phase SMB units, the Solvent Gradient operating mode can be accomplished by varying the composition of the solvent between the two inlet streams [60–63], which endows to the process two additional degrees of freedom. In fact, it was verified that the overall process performance would improve if the solvent introduced at the desorbent port presents lower affinity towards the stationary phase than the solvent introduced at the feed port. Under these conditions, it is possible to proceed to separations that would be extremely difficult in isocratic mode and the eluent consumption can be significantly reduced. Thus, the Solvent Gradient SMB was successfully applied to systems for which the adsorption equilibrium is strongly dependent on the solvent composition; however, when operating an SMB under solvent gradient conditions, attention must be drawn to the solubility of the solute over the entire range of solvent compositions within the unit. Most of the developments in Solvent Gradient SMB encompass the combination of this strategy with other operating modes, such as the Pseudo-SMB [64].

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2.4.2. Temperature Gradient SMB Temperature Gradient SMB follows the same basic principles than Solvent Gradient SMB; however, instead of varying the concentration of the solvent throughout the unit, its performance is improved by regulating the temperature in each section, in order to promote the required variations in the adsorption behaviour of the studied system [65]. As starting point for the design of a Temperature Gradient SMB one shall assume that the value of this process variable must decrease from section I to section IV, as a consequence of the exothermic character of the adsorption equilibrium established between the mobile and the stationary phase. The implementation of temperature gradients in the SMB has demonstrated to have a positive impact in the product purity, even for units with fewer columns than a conventional SMB [66]. It can be achieved by providing the inlet streams at different temperatures, by individually changing the operating temperature of all the columns (by means of a thermostatic jacket or another heating/cooling device) at each switch or by placing heat exchangers between each column (taking into consideration the resulting increase of the dead volumes). Hence, the practical application of this operating mode presents several limitations. On one hand, the rigorous control of the fluid temperature represents a complex task and, on the other hand, the variations be promoted by the designed temperature gradient must have a time constant in the same order of magnitude as the observed for the local adsorption phenomena.

2.5. Alternative SMB configuration 2.5.1. SMB with reduced number of sections The development of SMB processes with reduced number of sections was impelled by the advantages coming from the decrease of the complexity of the SMB unit, namely, the decrease of the hardware requirements (valves, chromatographic columns and pumps) and costs associated with the stationary phase. The most common implementation of this strategy is the three-zone open-loop SMB [67,68] in which the classical SMB configuration is changed through the elimination of section IV (or, alternatively, section I [69]) and the recycling stream. This principle has been further extended and separations carried out in SMB units with only two sections can be found in the open literature [70]. Regarding the overall process performance, it can be concluded that this operating mode is associated with a high eluent consumption and the product in the raffinate stream presents a high dilution factor; however, the process control is simplified, preventing extract contaminations through the recycling stream and increasing its purity. This class of SMB units is often combined with solvent gradients [71] and flow rate modulation strategies [70].

2.5.2. SMB with extended number of sections Several SMB units with extended number of sections (in certain cases referred to as Parallel SMB) have been developed over the last years as an alternative for the separation of ternary mixtures through continuous counter-current chromatographic processes. Five- [72], nine- [73–75] and even twelve-zone SMB [76] have been designed to achieve this goal. The increase in the number of sections results from the introduction of additional outlet streams, for withdrawal of the intermediately adsorbed species, and bypass streams between the sections of interest. Ternary separations might thus be accomplished with low eluent consumption; however, the existence of a unique switching time negatively affects its productivity. Furthermore, the complexity of the equipment required by this operating mode and the cost raise associated with the increase in the number of sections represent major drawbacks.

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2.5.3. SMB cascades The separations of multicomponent mixtures, containing three or more species, can be accomplished by multiple sequential SMB [77], in a process generally denominated SMB cascades or tandem SMB. The simpler application of this technology is the separation of a ternary mixture using two consecutive SMB units: in the first unit either the more or the least retained species is separated from the components present in the feed stream; the resulting binary mixture is then introduced in the second unit and the separation process is completed. In opposition to Parallel SMB processes, SMB cascades allow to independently adjust all the process parameters associated with the studied chromatographic separation (as the switching time, temperature or stationary phase used in each unit), attaining superior performances. On the other hand, the high desorbent amounts required to elute the target species impose an elevated dilution factor in the outlet streams, that increments after every additional separation step, leading to reduced productivity values. To minimize these effects, a strategy that involves the implementation of bypass streams between two SMB units has been proposed [78]. 3. Design and construction details of SMB units The design and construction of SMB units is a rather complex task. Depending on the separation to be carried out, one must be able to identify the most suitable configuration of the unit among a virtually infinite number of combinations of valves, pumps and their transfer lines. Throughout more than half of a century after the creation of this technology, many research groups have dedicated a lot of effort in the development of SMB units that are reliable and extremely efficient for a specific process while others have attempted to create flexible units that can adapt to a multiplicity of systems and operating modes. In this section, a technical description of the different design strategies implemented in some of the most relevant SMB units within the industrial and research fields will be performed focusing on the type of valves used, the problems associated with the selected configurations and the adjustments required to develop new SMB-based units. 3.1. Valves and pumps design As previously mentioned, the SMB unit was developed to overcome the practical limitations of the implementation of the TMB. The solution adopted was to simulate the counter-current by periodically shifting the streams from a column to another. Hence, a more or less complex valve scheme shall be responsible for displacing the external streams and promoting the internal recycling of the mobile phase. Moreover, depending on the SMB configuration, the recycling pump can operate either at constant or at variable flow rate. Certain valve designs associate the recycling pump to a specific section of the SMB, moving it along with the chromatographic columns during the port switching, which will enable it to operate at constant speed. However, the transfer lines must be adapted for this purpose, which may lead to the introduction of a significant dead volume that can adversely affect the separation, as discussed latter in Section 3.2. Alternatively, the recycling pump can be located in a fixed position between two consecutive chromatographic columns. In this case, the flow rate will have to be instantaneously adjusted every time the pump enters a different section during the SMB operation in order to keep the internal section flow rates within the defined values. Moreover, this design generally requires two outlet pump (for the raffinate and extract streams) and the development of a pressure control system to suppress the effects of the flow rates fluctuations experienced within the unit. The control of SMB units is a rather complex task due to the

inherent cyclic nature of the process and to the large time constants associated with its response to disturbances. As the recycling pump flow rate has a major impact in the internal flow rate ratios throughout all the SMB sections, the use of a constant speed pump generally provides a more robust operation. These facts undoubtedly expose the extreme relevance of the valves and pumps design on the SMB operation. An extensive review reported in the open literature over this topic [4], suggests that the valves designs can be classified in two major groups: central valves and distributed valves designs. SMB units in which a single valve is responsible for the “movement” of the streams are generally included in the first group while the units that have a plurality of valves associated to each stream or each column are framed under the second group. Since the concepts and the configurations inherent to central and distributed valves designs differ so significantly, these two strategies must be assessed independently. 3.1.1. Central valves Conventional central valves were large rotary valves that either allowed to periodically change the position of each stream in relation to static chromatographic columns or, oppositely, used a carrousel structure to periodically move the columns in relation to static transfer lines. Recently, small devices constituted by several valves assembled in a central block have been developed to perform the shift of the position of the streams required for SMB operation. Details regarding the specificities of each of these three types of central valves will be provided in the following subsections. 3.1.1.1. Central valves with static columns. According to the described in Section 1, Broughton and Gerhold [3] from UOP, Inc. (United Sates of America) developed and patented the first SMB process and, alongside, the first central rotary valve to perform the synchronous switch of the inlet and outlet streams required to implement the counter-current operating mode. One year later, in 1962, Carson and Purse [79] also from UOP, Inc. (United States of America) patented a rotary valve that was later used in the Parex® process. This company conducted a thorough research that led to several modifications in the design and functionality of the said valve that resulted in the reduction of its complexity, the minimization of cross-contamination problems, the improvement of its sealing system and mechanical resistance and the reduction of its cost [80–91]. In general terms, the central valves developed by UOP, Inc. (United States of America) are constituted by four main components: a lower stationary disc, called ducts plate, that contains several independent concentric channels in a central position to which the inlet and outlet streams of the unit are connected to and several ports in the periphery of the disc connected to tees at the inlet of the chromatographic columns; an upper rotary disc in which encompasses several fluid lines that connect the concentric channels of the ducts plate to its external fluid ports, called rotor plate; an elastomer seal sheet made of polyethylene, nylon or polyvinyl resins, placed in the middle of the two previous components and an external housing assembling all the components together. In its most advanced designs these valves include additional features such as the possibility of performing indexing movements and possess position sensors, that prevent misalignment problems, and pressure sensors, that allow a precise control of the seating force exerted by the housing in the valve components extending the life of the sealing system. A schematic representation of this rotary valve is presented in Fig. 2. All the chromatographic columns within SMB units with single central rotary valves are directly interconnected to each other by fixed fluid paths and possess three-way junctions at its inlet. According to the relative position of the rotor plate and the ducts plate, the feed, desorbent, raffinate and extract streams are driven

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Fig. 2. Central rotary valve with static columns from UOP, Inc. (1. fluid transfer lines; 2. concentric channels; 3. columns connection ports; 4. external streams connection ports; 5. external housing).

to a specific column junction depending on the configuration adopted. Hence, it becomes clear that the configurations reported for these central valves imply the use of a variable flow rate recycling pump positioned between two adjacent chromatographic columns. The pump must be able to promptly adjust its flow rate in accordance with the optimal set-point value required for the particular section in which it is incorporated at each moment. Besides UOP, many companies and institutes, including Institut Franc¸ais du Petrole (France) [92], Carbon Calgon Co. (United Sates of America) [93], Orochem Technologies, Inc. (United States of America) [94], Mitsubishi Petrochemical Co. (Japan) [95] and Toray Industries, Inc. (Japan) [96], among others, patented similar equipment. Even taking into account the different designs proposed and the number of improvements that central valves have been subjected to throughout the last five decades the fact is that these devices still present significant limitations inherent to its concept. The number of shared and unused fluid lines connected to the central valve causes cross-contamination issues with repercussions in the purity of the target products. The central valves design hinders the implementation of advanced SMB operating modes, including the use of extended and reduced number of sections, some concentration modulation strategies and dynamic configuration modifications. The final and, probably, the most important drawback of this equipment is its lack of flexibility, once it defines a unique configuration of the fluid lines for a specific number of chromatographic columns. Yet, this type of valves represents robust devices that completely fulfil the purposes for which they were designed with high reliability and effectiveness, requiring low maintenance and relatively simple control systems. These characteristics justify its extensive application at industrial scale. 3.1.1.2. Central valves with rotating columns. Among the central valves that promote the effective rotation of the columns to accomplish the counter-current movement of the stationary phase, the solution with greater acceptance at industrial level is the ISEP valve, commercialized by Carbon Calgon Co. (United Sates of America), which has been installed in over 300 units worldwide. Primarily developed by Advanced Separation Technology, Inc. (United Sates of America) in 1997 [97], this device comprises a double-disc valve and a rotary frame, attached to a rotor through a shaft, in which the

chromatographic columns are installed. The static upper section of the valve encloses the fluid lines that interconnect the columns and provides feed and withdrawal ports for the external SMB streams. All the columns inlet and outlet streams are connected to the rotating lower section of the valve. Lined up openings in both of these structures form ports that define the fluid path. A schematic representation of this type of valves is presented in Fig. 3. This configuration prevents cross-contamination and admixing phenomena, without the introduction of significant dead volumes. Furthermore, the solvent recycling from the last to the first section of the SMB can be performed through constant flow rate pumps, simplifying the control of the unit. Since the top section of the valve assembly can be designed with a virtually unlimited number of fluid path types, including zone bypassing and additional inlet or outlet ports, it can be easily foreseen that it enables the implementation of some unconventional SMB configurations and operation modes. Experimental demonstrations of the flexibility of this system were reported, for instance, for the separation of sugars (glucose and xylose) from a biomass hydrolysate in a nine-zone SMB unit [73] and for the separation of proteins [71] and enantiomers [98] in a three-zone SMB with solvent gradients. By using different materials in the construction of the two disks that form the valve, i.e., plastic and metal, the friction in the contact area is reduced and the sealing can be improved. This system also includes two independent co-axial rotors, one for the rotary section of the valve and another for the columns frame. The rotation movement coordination is assured by two optical sensors, located in a fixed position relative to each other, thus eliminating some of the alignment problems observed for other valves. Another relevant equipment is commercialized by SepTor Technologies B.V. (Netherlands; former part of the Outotec Oyj, Finland). Similarly to the ISEP valve, this system [99] has a double-disc valve with a moving and a stationary part, following the same basic concepts for providing the required liquid connections. However, the columns are installed in a turntable and the rotary movement is promoted by the action of an external servomotor connected to the columns frame by a driving chain. The inventors claim that this configuration is less prone to suffer from mechanical problems than the shaft-based configurations. Moreover, both the valve and the turntable are able to perform indexing movements if flexible connection lines are provided. The practical implementation

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Fig. 3. Central rotary valve with rotating columns from Calgon Carbon Co.: ISEP valve (1. intercolumn transfer lines; 2. external streams connection port; 3. chromatographic column inlet; 4. chromatographic column outlet; 5. shaft).

of this additional degree of freedom is easily achieved for laboratory units. Although it can also be implemented at industrial scale the inertia associated with the apparatus dimensions (particularly the columns) might lead to deformations that damage the rotary system at long term. Recently, the sealing system and the mechanical resistance of this device were improved by introducing minor changes in the valves construction [100]. As previously described, in its original design the valve assembly was constituted by a fixed metal disc and a plastic moving disc in order to accomplish an adequate sealing. However, when, for instance, stainless steel-PTFE valves were used, severe flaking of the PTFE material was observed, leading to leaking problems. To overcome this situation the valves were redesigned so that all the static and moving pieces in contact were made out of plastic materials (PEHD, PTFE or other material suitable for the intended operating conditions), supported in a metal structure. Despite the advantages demonstrated by this type of valves, some limitations still remain as the unfeasible implementation of important operating modes such as Varicol® and Pseudo-SMB. Furthermore, the number of columns is strictly conditioned by the number of connections of the central valve hindering the addition of columns to the unit. 3.1.1.3. Central valve blocks. The role of counter current chromatography in biopharmaceuticals manufacturing downstream processes has been progressively becoming more relevant over the last decades [101], marking the tendency of scaling down SMB processes and reinforcing the need of implementation of unconventional operating modes. In this scenario, Tarpon Biosystems (United Sates of America; former Xendo Holding B.V., Netherlands) developed a multicolumn chromatography system denominated BioSMB® [102]. This system comprises up to 240 individually addressable valves assembled in a single compact block presenting a noteworthy flexibility both in terms of the number of possible connections and in the number of columns within the unit. The BioSMB® valve block consists in several independent manifolds interconnected (in series or in parallel) each of which having a central duct and several branch ducts. The active fluid path inside the manifold is defined by the position of the diaphragm valves located in these ducts. To simplify the construction details of these

manifolds one can say that these components are essentially composed by four parts, namely, the base, central and cover parts of the duct layout and the valves assembly (Fig. 4). The in- and outlets of the chromatographic columns are connected to the central duct formed by channels longitudinally engraved in the cover and central parts of the duct layout. On the other hand, channels transversally engraved in the base and in the central parts of the duct layout form the branch ducts. The cover and the central parts of the duct layout have several through holes that allow the fluid to pass from the central duct to the chambers on the top of the cover part and from there to the branch ducts depending on the position of the diaphragm valves located above the cover part of the duct layout. A flexible membrane separates the valves actuators (that can be either electrical or pneumatic) from the flowing liquid and the action of these valves allows or hinders the flow of the liquid through the chambers towards the branch ducts. The central duct of the manifold also has a valve that can interrupt the flux between two consecutive columns and some of the branch ducts of a manifold directly connect it to adjacent manifolds. This arrangement allows, for instance, bypassing a column or proceed to a series of steps in an isolated column of the unit. These features represent a considerable improvement over the previously described central valve systems since it mitigates one of its major limitations, namely, the unfeasibility of implementing alternative operating modes. Moreover, although each manifold must be custom built for each particular application, the increment of the number of columns within the system is still possible by including additional manifolds in the valve block. Following an analogous concept, Semba Biosciences, Inc. (United States of America) developed an alternative valve block [103]. This device also consists on an assembly of structures, containing several channels and ports that interconnect them, in which the fluid paths can be dynamically adapted to the process requirements by independent diaphragm valves pneumatically actuated. The valves components are physically and thermally isolated from the fluid circulating in the block by a membrane and thermoplastic plate, respectively. The inventors claim that an enhanced sealing was accomplished through its design keeping the flexibility of the unit. However, contrarily to BioSMB® , in the Octave® SMB unit, commercialized by Semba Biosciences, Inc., a structure with two

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Fig. 4. Example of a manifold of the BioSMB® central valve block (1. chromatographic column connection port; 2. central duct diaphragm valve chamber; 3. central duct connection port; 4. branch duct diaphragm valve chamber; 5. branch duct connection port; 6. central duct; 7. branch duct).

main valves was adopted instead of the configuration comprising an assembly of independent manifolds. Thus it is not easy to increase the number of chromatographic columns beyond the eight columns for which the equipment was originally designed. Nevertheless, these valves still allow columns bypasses and dynamic configuration modifications, the basis of the flexibility of SMB. Additionally, it is also important to underline that both devices employ constant flow rate recycling pumps, with the benefits derived therefrom. As the BioSMB® and the Octave® SMB units were specifically conceptualized to meet the demanding hygienic and sanitary requirements of the biopharmaceuticals industry these equipment present the unique feature of being composed by disposable components. Its valve system designs aimed the minimization of dead volumes together with the minimization of the contact area between the fluid and the valve components. As result, only its interior duct structures and the membranes from the diaphragm valves are in direct contact with the fluid. These components can be easily disposed and replaced. Despite the enumerated advantages, central valve block technology has not reached the same level of maturity than the previously reported central valves systems and its implementation is more limited in terms of production scale than the former. Nonetheless, these devices have been progressively introduced in its target industries with a high success rate, finding particularly interesting applications for proteins processing [104–107], partially due to its ability to operate under different modes as standard SMB, three-zone SMB, Improved-SMB, Pseudo-SMB, Outlet Stream Swing and Partial-Feed mode among others [108,109]. 3.1.2. Distributed valves In opposition to central valve units in which all the fluid transfer lines are connected to a single valve or a valve assembly, in a distributed valves design, as the name suggests, these elements are scattered through the entire unit and the transfer lines connected them to each other, to the chromatographic columns and to the pumps that transport the fluid. A wide range of types of valves, with significantly different functions, is commercially available. If one combines this diversity of functions with the different possible configurations between them and the remaining components of an SMB a substantial number of designs can be proposed. An extensive review over this topic can be found in the open literature [4]. The authors divided the different design strategies according to the type of valves used, with particular focus in two-way valves, which allow or hinder the

flow through, or multiposition valves, as the so-called selecteddead-end valves, which direct the incoming fluid flow towards the selected port within its multitude of possible connections while closing the remaining. Other types of valves have also been considered as the select-common-outlet, select-flow-through and select-trapping; however, the number of practical implementations of these valves in SMB units does not have the same expression as the previous. When multiposition valves are the selected option, the possible configurations can be further subdivided in relation to the elements of the unit to which they are associated with, more specifically, if the number of multiposition valves is related to the total number of columns or to the existing external streams. In this work, the discussion of the technical details will be centred on two of the most common, and at certain extent, opposing, design strategies: two-position valves-to-column design and multiposition valves-to-stream design. 3.1.2.1. Two-position valves-to-column design. The Licosep, developed by Novasep S.A.S (France; former Separex, France), in a collaboration with the Institut Franc¸ais du Pétrole (France), represents the first SMB unit to implement two-position valves [110,111] that replaced the central rotary valves used in the pioneer designs. One of the most important features of these systems is its scalability, which is supported by its wide application both at laboratorial and industrial scale. For the particular case of enantiomers separation, for instance, these units have demonstrated to be able to achieve productivity values that go from a few grams per day to 50 tonnes per year [112]. Besides the separation of enantiomers [113–115], this unit has also found applications in the purification of sugars [116] and even Hybrid-SMB units as the SMBR [117–120] (approached in a following section). As it can be depicted from Fig. 5, the configuration of these units is quite simple. Basically, each external stream is connected to an individual manifold that distributes them by a number of valves equal to the number of chromatographic columns. These valves are connected by the unions to the transfer lines between every two adjacent columns. The last column of the unit is directly connected to the first and a variable flow rate recycling pump is inserted in this transfer line. The counter-current movement of the stationary phase within these units is simulated by independently opening and/or closing the valves associated to each stream and connected to every union between columns. Hence, the switching can be performed either in a synchronous or asynchronous way. Moreover, the unit presents a modular construction concept. Its elementary structures,

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Fig. 5. Schematic representation of a SMB unit with a two-position valves-to-column design.

that comprise one chromatographic column and a set of four valves connected to the external streams manifold, might be replicated or detached in order to change the total number of columns of the unit. These characteristics evidence the considerable flexibility of the two-position valves-to-column design. To further increase the number of possible operating modes some simple adaptations must be made, which for most of the cases comprises the introduction of intermediary valves in the transfer lines between two sequential columns. For instance, to operate the SMB under a reduced number of zones, a single two-position valve per column must be inserted in this position to suppress the recycling flow. To allow the implementation of a Pseudo-SMB process apart from these valves an additional two-position valve and the respective transfer lines for collecting the intermediately adsorbed component must be introduced at the outlet of each stream [121]. However, for the implementation of bypass lines a significantly larger number of valves must be added to the unit [4]. Although the flexibility of the unit can benefit from these adaptations the high number of valves required might compromise its reliability and increase the complexity of the control system. Another advantage of the two-position valves-to-column design is the reduced possibility of cross-contamination within the transfer lines due to the use of individual manifolds for each external stream and the low ratio between the volume of lines between adjacent columns and the volume of the columns itself. On the other hand the use of a recycling pump with flow rate modulation can represent an issue. As this configuration a priori leads to asymmetries within the unit, introduces dead volumes and might cause flow rate fluctuations, its substitution by a constant flow rate pump could be suggested. For that purpose, two additional twoposition valves per column would be required, one to prevent the flow between the last column of section III and the first of section IV, where the recycling pump must be placed, and the other to allow the re-introduction of the recycle stream in the first column of section IV after passing through the pump. However, this modification not only aggravates the cross-contamination problems, since it generates stagnant zones, but also increases the number of valves with all of the disadvantages associated with it. Considering this, the most effective strategy would be to keep the original design

and apply compensation measures (described in further detailed in Section 3.2) to overcome the asymmetry related issues. 3.1.2.2. Multiposition valves-to-stream design. In 1995, UOP, Inc. (United Sates of America) developed and patented a new design for small scale SMB units that used multiposition valves to inject and withdraw each of the external streams into the selected column of the SMB [122]. The feed and the desorbent stream were connected to four-way manifolds located at the inlet of the chromatographic columns while the raffinate and extract streams were connected to manifolds of the same type placed at its outlet. These manifolds were as well responsible for interconnecting the columns and the recycling stream was delivered by a variable flowrate pump. As this design strategy associates a single multiposition valve to each of the external streams, the total number of valves necessary to assemble an SMB is the lowest among distributed valves designs. Another interesting feature of such scheme is the possibility of extending the number of sections by simply providing additional multiposition valves. On the other hand, an immediate consequence of this design is the impossibility of increasing the number of columns beyond the number of ports available in the multiposition valves used. Moreover, admixing might occur at each manifold and contamination due to the use of common transfer lines is also possible. In addition to these disadvantages, the flexibility associated with this configuration is limited since operating modes that include columns bypass and open-loop cannot be accomplished. A major improvement on this design was accomplished by Daicel Chemical Industries Ltd. (Japan) for the industrial purification of high added value products [123,124] and this configuration was reproduced at smaller scale, leading to the development of one of the most interesting laboratorial SMB units reported, the FlexSMBLSRE® , which has presented particularly successful results for the separation of chiral mixtures [51,125–129]. Regarding the first multiposition valves-to-stream design addressed, the only differences are the introduction of two extra multiposition valves connected to the outlet streams and one two-position valve in the transfer lines between adjacent columns and the replacement of the four-way manifolds at the inlet of each chromatographic column by six-way

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Fig. 6. Improved multiposition valves-to-stream design, comprising two additional multiposition valves connected to the outlet streams and one two-position valve in the transfer lines between consecutive columns: the FlexSMB-LSRE® .

manifolds. A schematic representation of the unit is provided in Fig. 6. The main characteristic of this design strategy is related to its outstanding flexibility since, all unconventional operating modes previously addressed can be implemented. By adding two-position valves between two consecutive columns, the flow between them can be discontinued allowing, for instance, open-loop operation. Moreover, in this enhanced configuration both the extract and the raffinate pumps are connected to two multiposition valves with different functions: a first valve connected to the outlet of each chromatographic column is responsible for directing the fluid towards the product withdrawal ports where part off these streams is collected (similarly to the one multiposition valve-to-stream design previously reported) while the second valve offers the possibility of recycling the remaining part of these streams back to the unit at any desired location. Hence, in combination with the action of two-position valves column bypassing also becomes possible. This demonstrates how the minor adaptations to the valves design proposed by Daicel Chemical Industries Ltd. (Japan), enhanced the flexibility of its preceding units. The moderate number of valves used with this configuration also represents a major advantage both in terms of control and total cost of the equipment. Furthermore, the control system also benefits from the introduction of a constant flow rate pump. The few disadvantages of this design are related with the existence of considerable dead volumes. For instance, admixing phenomena is possible within the manifolds and crosscontaminations might occur when open-loop operating modes are implemented, since one or more of the two-position valves located between adjacent manifolds must be closed thus generating stagnant zones. However, the minimization of the volume of the transfer lines between columns and the implementation of some of the compensation strategies proposed in Section 3.2 are generally quite effective in the mitigation of these problems. Moreover, the apparent limitation imposed by the number of ports of the valves used, which might constrain the maximum number of columns, might not represent a real problem if, for instance, 26 position valves (commercially available) are included by default in the SMB unit design. This would allow to add or remove columns up to a maximum of 26 of these elements which encompasses

the majority of practical applications of the SMB. In fact, some authors suggest that the ideal configuration would only include 12 units [6,125]. Alternatively, a research group from Purdue University (United States of America) stated that if a completely different design strategy was used, comprising the use of select-trapping multiposition valves (instead of select-dead-end) associated with each columns (instead of each stream), these minor issues would be completely eliminated [4]. This lead to the development of the Versatile SMB unit [130]. Despite the advantages provided by the innovative design of this unit, as far as our knowledge goes, its application has been restricted to lab-scale processes [72,131–134]. Considering the discussion above, one is lead to conclude that, despite the specificities of each of the central and distributed valves design strategies assessed that make some of the units more suitable for a particular application, the design strategy developed by Daicel Chemical Industries Ltd. (Japan) and implemented in the FlexSMB-LSRE® , is probably the most effective solution in terms of the flexibility and scalability of a SMB unit. 3.1.3. Summary of the different valves and pumps designs The different valve systems addressed in this work significantly diverge in its design concept and fundamental technical details, thus representing the majority of the industrial, pilot and lab-scale SMB processes reported in the open literature. To establish a comparison between the different design strategies several parameters must be assessed including its flexibility, reliability and scale of operation. Distributed valves systems are intrinsically characterized by a remarkable flexibility. The design of units such as FlexSMBLSRE® allows to perform columns bypassing and independent port switching, enabling the implementation of virtually every unconventional operating mode. In some of these types of systems the number of valves is directly correlated with the number of columns. Hence, expanding the number of columns of the SMB can be easily accomplished by replicating the valve scheme of the existing columns and providing the adequate fluid transfer lines. On the other hand, the flexibility of SMB units with central rotary valves is much more limited. In fact, only the systems with moving columns can implement unconventional configurations; however, the Varicol® and the Pseudo-SMB operating conditions cannot be

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implemented. In recent years, a new trend has emerged regarding the central valves design through the incorporation of some concepts generally associated with distributed valves. Instead of the classical rotary valves, these systems encompass a matrix of individually addressable two-position valves assembled in a single block with a complex network of internal channels. Compared with the preceding central valves, these new devices provide the flexibility required for unconventional operating modes since columns bypass and asynchronous shift of the external streams becomes possible, features that were only available for distributed valves systems. Furthermore, some central valve blocks present a modular construction which enables the increment of the number of columns of the unit. As stated earlier, the appearance of the SMB technology is associated with the development of central rotary valves. Since then, this type of valves has suffered several improvements achieving an unprecedented maturity. The valve sealing mechanism is a key issue since the determination of the origin of leakages is nearly impossible and the maintenance associated with these devices is very expensive. Nevertheless, the reliability of central rotary valves is evidenced not only by its long-term use but also by the widespread industrial application of these devices in numerous SMB processes around the world [5,17]. The control required by these valves is also simpler than any other type of valve, since a single component must be actuated, and for systems with moving columns, inclusively, constant flow rate recycling pumps can be used. Distributed valves systems also provide similar levels of confidence for SMB operation; however, the large number of valves associated with these systems, particularly those using two-way valves, slightly increases the possibility of failure. The advantage of these systems relies on the easiness in overcoming this situation by the direct replacement of the elements that represent the source of the problem. The behaviour expected for central valve blocks is the same as for distributed valves but the information on this subject is rather scarce and does not allow to withdrawn trustworthy conclusions. Most of the practical implementations of rotary valve systems comprise large industrial-scale units, many of them dedicated to the purification of bulk petrochemicals. Although small pilot and lab-scale units have also been developed its application does not present the same projection of industrial processes. In opposition, central valves blocks were specifically designed to be implemented at pilot-scale since the complex configuration of the block assembly is not easy to reproduce at larger scales. These systems are particularly suited for the biopharmaceuticals industry and for the purification of other high added value chemicals for which, generally, extremely expensive stationary phases are required. The ability to work under strict purity requirements and the high productivities presented by SMB units with central valves blocks allow a reduction of the capital investment and operating costs of the corresponding processes. Finally, the simplicity of the scalingup and scaling-down procedures for SMB units with distributed valves creates the ideal conditions for the application of this design strategy to the research and development of new SMB processes and to an enormous variety of processes distributed by different industries. 3.2. Considerations regarding the fluid transfer lines The configuration of the fluid transfer lines in a SMB is fundamentally imposed by the valve system design adopted. However, the existence of dead volumes within the unit is inevitable due to the pumps, valves and tubing, required for transporting the fluid. Within the different valves designs assessed in this work, central valves with rotating columns present the most effective configuration for the minimization of the adverse effects of dead volumes

in the separation process since, in these units, all the internal and external fluid lines of the SMB unit are integrated in the static upper section of the valve. This specific characteristic is at the basis of the low dead volumes presented by these systems and allow the elimination of stagnant zones that could lead to cross-contamination. Typically, for industrial- or pilot-scale SMB, dead volumes represent approximately 3% of the total equipment volume [135]. This value significantly increases for lab-scale units, which generally account for over than 10% of dead volumes [125]. The transfer lines dead volume is known for producing a negative effect on the overall process performance. A classic case study is reported in the literature for the Parex® industrial unit that can see its extract purity reduced from 99.9% to 85% or 75% by the introduction of dead volumes fractions as low as 0.6% or 1%, respectively [136]. However, the impact of the dead volumes in the separation performance can slightly differ according to its location within the unit, which can generally be divided in two main cases: intercolumn dead volumes and external streams dead volumes [135]. In either, different compensation strategies may be suggested. Considering the case of intercolumn dead volumes, it can be easily understood that, for instance, the tubing connecting all the valves, columns and pumps induce a time delay in the internal concentrations fronts travelling throughout the unit. Nevertheless, as the flow within these transfer lines is, most often, appropriately described by a plug flow model, these effects might be included in the assumptions made by the triangle theory thus redefining the region of possible operating flow conditions within the required target product specifications [137,138]. On the other hand, if severe mixing occurs in the dead volume (usually in large local dead volumes created, for instance, by check valves) the correction provided will not be sufficient to overcome this problem. Another common issue related with intercolumn dead volumes is the asymmetry generated by the use of variable recycling pumps placed between the last and the first columns of the SMB (instead of the last and the first sections) and its connections, which might reduce the purity of the outlet streams. Here, a simpler empirical strategy has been proposed based on an asynchronous port shift [111]. The position of the injection and withdrawal ports that have passed the last column are shifted with a delay equal to the time required to elute the volume of the transfer line at the average zone flow rate conditions. This technique has demonstrated to be more effective and easier to implement than a priori account to the effect of these dead volumes in the model [125] once the unit will present a behaviour similar to a conventional synchronous SMB, despite its asynchronous operation. Dead volumes associated with the external streams also have a negative effect on the SMB performance. However, in opposition to the intercolumn dead volumes, the internal concentration profiles will not be significantly affected. Instead, a cross-contamination will arise due to the fact that both the inlet and the outlet streams, with considerably different compositions, will share the same transfer lines. Taking as example a classical four-zone configuration with two columns per section, it can be verified that the transfer line initially used for injecting the feed stream, after two consecutive switches, will be used to withdraw the extract. Hence, a certain volume of the feed trapped in the transfer lines will contaminate the extract. As consequence, the purity of the target products is reduced at some extent. This is a very common problem in SMB equipped with central valve systems, in particular, rotary valves. As a possible solution to overcome this problem several authors propose flushing of the shared transfer lines with pure product [135,136,139]. A flushing-in (between the extract and the feed) and a flushingout (between the desorbent and the extract) streams connected in a closed loop circuit must therefore be added to the original system, allowing to eliminate the volume of feed solution trapped in the transfer lines and replacing it by the extract product. Through

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this adaptation the purity of the extract stream can be preserved despite the limitations of the valve system used. During the development of new SMB processes, the above considerations regarding the disturbances introduced in the performance of the unit by the dead volumes should be taken into account. The mitigation of its consequences starts with the selection of a convenient valve system and must be complemented with the minimization of the overall dead volume and mixing zones, for instance, avoiding the introduction of check valves or intermediary pumps, together with the reduction of the number of shared transfer lines between the external streams. 3.3. Design adaptations for special SMB units The previous sections review important instrumental aspects related with liquid phase SMB units. However, if one intends to extend this discussion to units operating with compressible fluids, as the gas phase SMB or supercritical SMB, or to integrated SMB processes, which include additional unit operations performed in parallel or within the SMB, the necessity of performing specific adaptations for each case arises. Due to the growing interest of the industries and the research community in such units, these issues will be analyzed in further detail. 3.3.1. Gas phase and supercritical SMB The SMB technology was initially developed and finds most of its application for liquid phase applications. Nevertheless, in the last few years the interest in the operation of SMB units using different fluids has been increasing. For instance, gas phase SMB processes have been suggested for the purification of propylene, one of the more important chemical commodities [140]. On the other hand, supercritical SMB [58,59] has been used to several added value products [141–143], including omega-3 unsaturated fatty acids [144]. So far, the description of the technical details of the different SMB units has been exclusively focused on liquid phase chromatography systems. To implement a gaseous or supercritical SMB process, it might be necessary to perform some adaptations in the previous SMB designs due to the differences between the physicochemical properties of these fluids and those of the liquids. The major challenge in operating a gas phase or a supercritical SMB is that these are compressible fluids and, consequently, must be handled with special care to avoid, for instance, backmixing problems [2]. In this situation the use of check valves, advisable for liquid phase SMBs, becomes mandatory, especially for designs that involve two-position valves and long transfer lines. Minor though important adaptations would be required to implement the one multiposition valve-to-stream design proposed for liquids in a gas phase SMB. Biressi et al. [145] suggested that a multiposition valve of the select-trapping/flow-through type should be used to connect the columns to each other instead of the previously proposed manifolds; however, the recycling stream should be suppressed. The pressure within this type of units must be carefully controlled. Hence, a back pressure regulator should be placed at the end of section four and pressure sensors distributed along the unit (preferably on per column). Mass flow controllers should be used to define the external streams flow rate. Note that no pumps are used in the gas phase SMB. One of the most common supercritical SMB units design is also based on the one multiposition valve-to-stream strategy [141–143] but includes one additional two-position valve per column and an extra multiposition valve for the recycling stream. Similarly to liquid phase chromatography systems, the feed is introduced in the unit by a HPLC pump. Liquid carbon dioxide is delivered by air driven pump. After passing through a pressure regulating valve, the carbon dioxide is mixed with a modifier (controlled by an HPLC

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pump), heated up to the operating temperature and introduced in the system through the desorbent multiposition valve. The extract and raffinate flow rates are controlled by metering valves at the end of these streams. The target products are immediately separated from the desorbent in cyclones operated at controlled pressure and temperature. The carbon dioxide of the recycling stream must be separated from the modifier in a similar cyclone followed by an activated carbon filter. After being purified this stream is cooled down, condensed and then recycled. As it can be concluded the implementation of supercritical SMB process is much more complex than the liquid or even the gas phase processes. It requires more equipment besides the basic pumps and valves, since cyclones and heat exchangers must integrate the system, and is much more demanding in terms of the control of the unit, since the temperature and pressure must be accurately controlled not only at each section, but also at other points of the unit. 3.3.2. Hybrid SMB technologies Hybrid SMB units result from the combination of SMB with other physical–chemical processes in order to improve the overall process performance. A classical application of this concept, reported, for instance, for separation of enantiomeric mixtures [146,147] and for the purification of p-xylene [148], is the introduction of a crystallization unit in parallel with the SMB for processing the raffinate or extract stream that separates the products of interest from the desorbent that can be recycled back to the unit, therefore decreasing the total desorbent consumption of the process. One of the most interesting process intensification strategies was developed through the combination of chromatographic reactors with SMB separation units from which resulted the Simulated Moving Bed Reactor (SMBR) [149–151]. In a SMBR, the reactants are introduced in the unit through the feed stream while the most and least adsorbed products of the reaction are eluted by means of a desorbent and collected in the extract and raffinate ports, respectively, following the same basic operation principles as the conventional SMB process. In most of its applications, the SMBR presents a classical four-zone configuration in which the two central sections correspond to the reactive zone, while the first and the last section correspond to the adsorbent and desorbent regeneration zones, respectively. However, this can only be accomplished if each chromatographic column is packed with a homogeneous mixture of catalyst and adsorbent [152] or if the stationary phase presents a dual behaviour simultaneously being able to catalyze the reaction and selectively adsorb the species of the studied system (i.e., ion exchange resins present this ability and have been successfully applied in the synthesis of oxygenated compounds by SMBR [117–120,151,153–155]). If these conditions are met, the SMBR process can be implemented in any SMB unit without further modifications. A different configuration was proposed by Hashimoto et al. [156] for the production of higher fructose corn syrup and has been applied in a number of SMBR processes since then [155,157–159]. In this process reaction and adsorption take place in separate columns and the reactors are shifted together with the external streams in the direction of the liquid flow (Fig. 7) hence, the counter-current movement simulated by these periodical shifts is only experienced by the adsorbent. Furthermore, it becomes possible to restrict the reaction to specific zones of the SMBR, since reaction does not occur in the adsorbent beds, and the reaction and adsorption modules can be operated under different conditions, for instance, at different temperatures, which might enhance the unit performance. The instrumental implications of such process are evident: a specific number of reactors must be added in parallel with the SMB unit together with the required fluid lines. However, in terms of the design of the valves system, no significant changes are required,

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Fig. 7. SMBR following the configuration proposed by Hashimoto et al. [156], presenting separate reactive and adsorptive packed beds in the reactive zone (sections II and III) and a set of adsorptive columns in the adsorbent and desorbent regeneration zones (sections I and IV, respectively).

even for the less flexible options discussed earlier in Section 3.1. In fact, the original Hashimoto process was implemented using a central rotary valve unit. Among the different SMB based hybrid units developed in recent years, the PermSMB [160–163] stands out as one of the highest expressions of this concept, combining, in a single unit, the advantages of the SMB with chromatographic reactors and pervaporation membranes. In the PermSMBR, the fixed bed columns of the SMB are replaced by modules of membranes, packed with a mixture of catalyst and adsorbent or a solid that acts as both, either on the inside or on the outside of the membranes, depending on the location of its active layer. In its simpler configuration, the PermSMBR presents the same inlet and outlet liquid streams as the classical SMBR that divide the unit in similar zones and can accommodate any of the valve systems covered in this work. However, from each membrane module an additional gas stream is collected, the permeate, containing the permeable species according to the membranes selectivity. For that purpose it is necessary to supply vacuum or sweep gas flow to the membrane modules. It is important to notice that, the flux through the membrane can be controlled at every moment of the operation by manipulating the vacuum or sweep gas supply endowing an additional degree of freedom to this unit. An alternative PermSMBR configuration would consist in interchangeably positioning the chromatographic columns and the pervaporation modules [164]. The decoupling of the packed membrane modules initially proposed into two individual elements not only simplifies its maintenance and substitution but also, and most importantly, extends the membrane long-term stability since its mechanical and chemical resistances are no longer compromised by the contact with the catalyst/adsorbent. The only difference in the units operation mode introduced by this configuration is that, in this case, at each switching time, the streams must be shifted from

one column to the next column in the direction of the fluid flow disregarding the existence of the membrane modules in between them for this particular matter. The PermSMBR has been identified as one of the most efficient technologies for the synthesis of organic compounds, in particular, esters [163] and acetals [160,161,164]. As both esterification and acetalization reactions form water as by-products, hydrophilic silica membranes have been used for continuously removing this species from the reaction media. As the separation between the products is enhanced by combining pervaporation with adsorption, the reactive-separation region [165], which defines the unit operating conditions, is significantly increased leading to improved performances in terms of products specifications, productivity and desorbent consumption. This last parameter is precisely where the improvement is more evident once the unit is able to reduce it in the range 20–70% compared with the SMBR. From these studies another technology has emerged, the threezone PermSMBR. The authors were able to perceive that the extract stream could be eliminated without negatively affecting the productivity of the process, since water was being purged from the system through the permeate stream, thus creating this new unit (note that, if the membranes are selective to the less retained product the raffinate stream must be eliminated instead of the extract stream). The results obtained through this adaptation were even more impressive as the three-zone PermSMBR was able to reduce up to 85% the desorbent consumption of the classical four-zone SMBR process originally proposed, within similar productivity values. 4. Alternative multicolumn chromatographic units The potential of application of multicolumn counter-current chromatography to the downstream processes of biopharmaceuticals production is incontestable. However, many of these

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Fig. 8. Schematic representation of the process principle of the twin-column MCSGP (B is the target product, A and C are the least and the most retained impurities, respectively).

processes require the purification of intermediately adsorbed species from ternary or pseudo-ternary mixtures, solvent gradients and complex series of loading, washing, elution, regeneration and equilibration steps. Despite all the developments and improvements introduced in SMB units over the last decades, the challenges imposed by biopharmaceuticals industry exceed the capabilities of this technology. Therefore, according to some authors [17], a third generation of multicolumn counter-current chromatographic processes is arising with new designs and operating modes that will be able to accomplish these rather demanding separations in highly effective units with reduce capital costs and footprint. Some of these processes include the multicolumn solvent gradient purification (MCSGP) [18,19], the gradient with steady state recycle process (GSSR) [166], the periodic counter current packed bed chromatography (PCC) [167], the sequential multicolumn chromatography (SMCC) [168] and the capture SMB [169]. In this work, only the MCSGP and the PCC will be addressed due to their increased interest. 4.1. Multicolumn solvent gradient purification (MCSGP) The multicolumn solvent gradient purification (MCSGP) was first developed by Ströhlein et al. [19] and Aumann and Morbidelli [18] with the intention of overcoming some of the limitations presented by conventional SMB units in the purification of large biomolecules, such as the difficulty in the adequate implementation of solvent gradients and the impossibility of performing centre-cut separations of ternary mixtures in a single unit, essential features in most biopharmaceuticals production processes. Although it was originally designed as a fully continuous sixcolumn unit, the intensive research of the MCSGP led to successive improvements of this unit, mainly focused on the optimization of its operating mode [170–172] and the reduction of the number of chromatographic columns [172,173], resulting in a semi-continuous two-column unit [174,175]. Fig. 8 illustrates a schematic representation of the process principle of the twincolumn MCSGP for the separation of a ternary mixture of (A), (B) and (C) (in ascending order of affinity towards the stationary phase), where (B) is the target product and (A) and (C) are undesired impurities [176]. As it is a two-column unit, to complete a cycle in this optimized version of the MCSGP only two switches are required; however, in each switch four tasks take place. In an initial stage (task I1), a mixture containing the product (B) and the less retained impurity (A) is eluted from the column 2 and recycled to column 1, after being

diluted in the eluent (that contain the buffer or solvent). Hence, product (B) shall adsorb in column 1 while (A) leaves the system. At this point (task B1), pure product is eluted and withdrawn at the outlet of column 2 keeping all the impurity (C), the most adsorbed specie, in this column together with a fraction of (B). At the same time fresh feed is introduced in column 1. When this task is completed (task I2), a mixture containing (B) and (C) is eluted from column 2 and recycled to column 1, after being diluted in fresh eluent, assuring that (B) will adsorb in column 1 and only (A) leaves the system. This task proceeds until the impurity (C) becomes the only adsorbed species in column 2. To complete the cycle (task B2), impurity (C) is completely eluted from column 2, which is subsequently re-equilibrated, and product (A) is partially eluted from column 1. Then, the columns switch position the described tasks are sequentially repeated. Typically, the MCSGP reaches the cyclic steady state after only three cycles [176,177]. Through the continuous recycling of the overlapping fronts of (A)/(B) and (B)/(C) the MCSGP is able to maximize the yield, keeping the specified purity requirements. As previously stated, the ideal MCSGP setup comprises only two columns, simultaneously allowing to reduce the costs associated with the stationary phase and the hardware required for the complete flowsheet. The inlet and outlet stream of each column is connected to a six-way seven-port valve. Three gradient pumps are responsible for the introduction of the feed and the eluent in the system through two three-way six-port valves. All the multi-position valves of this unit are interconnected according to the configuration presented in Fig. 9. Through this complex scheme, it is possible to perform all the tasks required by the MCSGP on a cyclic base allowing to, simultaneously, integrate cleaning in place (CIP) procedures. Hence, a semi-continuous chromatographic process tailored for centre-cut purification is accomplished, benefiting from the advantages of counter-current operation mode and gradient chromatography. MCSGP has been applied in a variety of protein and peptide purifications such as the purification monoclonal antibodies from cell culture supernatant and charge isoform (Herceptin® ) isolation [178,179], bispecific antibody separation [180], PEGylated protein separation [176], peptide (calcitonin) purification [173], and even rare earth elements (cerium) separation [174]. One of the most interesting examples of application of the twin-column MCSGP was reported by Krättli et al. [175], in which a monoclonal antibody was separated from a clarified cell supernatant. The chromatographic columns used in this process were packed with Fractogel EMD SO3 resin (Merck, Darmstadt, Germany) and the monoclonal antibody

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Fig. 9. Twin-column MCSGP unit valves and pumps design.

concentration in the feedstock solution was 1 g/L. Three different buffers were used: A 25 mM phosphate solution with a pH of 6 was used as adsorbing buffer, a 25 mM phosphate solution with a linear gradient from 0 to 1 M sodium chloride was used as desorbing buffer, and a solution of 0.5 M sodium hydroxide was used for the cleaning in place. In order to optimize the performance of the unit the authors complemented the design strategies reported in the literature [170] with an innovative online control concept based on two independent PID controllers that continuously adjust the start and endpoint of the product elution window, achieving a purity above 90% with an yield of approximately 80%. To establish a basis for comparison it was demonstrated that through a conventional single-column batch process a yield as low as 30% would be attained to meet the same purity requirements. Alternatively, if the batch yield was increased to values similar to those presented by the MCSGP the purity of the target product would be approximately 80% (10% below the specification). Finally, no data is provided regarding the MCSGP productivity or desorbent consumption however, both were most probably improved comparing to the batch process due to the implementation of the countercurrent operation mode. 4.2. Periodic counter-current packed bed chromatography (PCC) The periodic counter-current packed bed chromatography (PCC) process from GE Healthcare (United Kingdom) [181] can be classified as a capture step among the downstream processes of biopharmaceuticals manufacturing, this meaning that, this technique will be used to remove impurities from a feed mixture, for instance, a harvest cell culture, in order to concentrate the product of interest. The large volumes and the characteristics of the feed suggest that the ideal stationary phase should have a high capacity

for the target species and a relatively large average particle size, to allow high throughputs at manageable pressure drops. Generally, for practical biopharmaceuticals separations by batch elution chromatography, the column loading (amount of solute retained by the column packing material, as a function of the fluid phase concentration, under flow conditions) shall not exceed 80–90% of its capacity (total amount of solute adsorbed in a stationary phase at equilibrium with a saturated solution) [176]. Hence, the productivity of the process is negatively affected. The use of multiple columns connected in series during the loading stage will provide a solution to overcome this limitation since the product of interest leaving the first column will be captured on the second, allowing to operate the first column up to 90% of its static binding capacity. This fact reveals the benefits of PCC in such processes. To better understand the PCC process, its operating principles for a three columns unit (3C-PCC) will be described hereinafter, according to Fig. 10. It is important to underline beforehand that the 3C-PCC is operated under a continuous feed while all the other streams are intermittent. Hence, in the first step, the feed stream is introduced in column 1 and its outlet is discarded. When the outlet stream of column 1 reaches 1% of the concentration of the feed stream in terms of the target products, column 1 is connected to column 2 until column 1 achieves the specified loading (for instance, 70% of the static binding capacity). At this moment, the feed stream is diverted to column 2. The washing buffer is added to column 1 and its outlet is connected to column 3 to assure that none of the product that might have remained in the first column is discarded. Similarly to what happened for column 1, when the concentration of the products of interest in the outlet stream of column 2 reach 1% of the concentration of the feed, this stream is connected to column 3. At this moment, the product is eluted from column 1 which is then subjected to a regeneration and a re-equilibration steps.

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Fig. 10. 3C-PCC unit: (a) operation principle; (b) valves and pumps design.

The subsequent steps follow the same logic and the unit completes a cycle after a number of feed stream switches equal to the number of columns. The PCC set up can comprise three to five chromatographic columns. Generally, each of this columns are connected to an eightport valve at its inlet and another at its outlet. These valves also connect the columns to each other. A feed pump and two gradient pumps are responsible for transporting the corresponding liquid streams. The pumps are connected to valves that distribute them for each column. Furthermore, one UV detector is placed at the outlet of each column and an additional UV detector is located in the feed line. A representation of the elements of the unit and its arrangement is provided in Fig. 10. Variants of this technique and equipment were proposed by ChromaCon A.G. (Switzerland) and Novasep S.A.S. (France) under the designations Capture SMB [169] and Bio-SC [168], respectively. The PCC process has successful applications, particularly, for the capture of monoclonal antibodies [20,22,167]. For instance, Mahajan et al. [21] used a 3C-PCC, for its purification from a harvest cell culture using two different stationary phases, MabSelect SuRe and ProSep® vA. The feed concentration varied between 1 and 4 g/L. The same equilibration, washing and elution buffers were used for both stationary phases: 25 mM Tris/25 mM sodium chloride, 0.4 M phosphoric acid and 0.1 N acetic acid. However, the regeneration buffer was 0.1 N sodium hydroxide for MabSelect SuRe and 0.1 M phosphoric acid for ProSep® . The results demonstrated that a

yield superior to 98% could be achieved for both stationary phases. Moreover, the authors indicated that the use of the 3C-PCC process, though more complex than the single-column batch elution, could lead to a potential reduction of 40% of the resin volume, buffer consumption and processing time. 5. Concluding remarks The relevance of SMB among multicolumn counter-current chromatographic processes is evidenced by the number of applications that it has found, distributed by a wide diversity of fields as the petrochemical or the pharmaceutical industries. However, to achieve this leading position, the SMB technology has experienced significant progresses over the last decades mainly focused in two closely related aspects: its operating mode and the units design. In fact, it is easy to perceive that, the implementation of unconventional operating modes that in so many cases led to significant improvements in the overall process performance, as the Varicol® process or the Improved-SMB® in the pharmaceuticals production, requires more or less extent adaptations on the design and the construction of the SMB. Furthermore, another important trend has been observed during the evolution of the SMB technology, namely, the attempt of simplifying the unit through the reduction of the total number of columns. The pioneer processes within the petrochemical industry presented more than 20 columns per unit. This number was significantly decreased within the pharmaceuticals

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industry to less than eight columns and the newest biopharmaceuticals processes report the application of units with only two or three columns. The valves design is one of the fundamental aspects of the construction and operation of the SMB and has been, alongside, complementing these developments. The valves design can be divided into two main groups, central and distributed valves systems, which present different practical realizations of each concept. Central valves systems, include, for instance, the rotary valves form the Parex® process or the ISEP carrousel-type valves, and have been used for a very long time in large-scale industrial processes. The main feature of these valves systems is its robustness and reliability. However, these advantages are attained at the cost of reduced flexibility. Recently, new central valves systems have been designed, mainly for application at pilot-scale pharmaceuticals and biopharmaceuticals production processes, which are able overcome this handicap through a complex combination of manifolds and small independent valves, assembled in a single valve block. Distributed valves systems comprise the second major concept of SMB valves design. Several strategies have been proposed with very distinct type, number and distribution of valves. Though, one of the most interesting strategies has been proposed by Daicel Chemical Industries Ltd. and implemented at lab-scale in the FlexSMB-LSRE® . These units are constituted by one multiposition valve per inlet stream and two multiposition valves per outlet stream, plus twoposition valves in each of the transfer lines between adjacent columns. The units adopting this valve design acquire an extraordinary flexibility without compromising its reliability due to the moderate number of valves installed. Nevertheless, despite the valve design implemented in the final SMB unit it is important to take into consideration that the operation with compressible fluids or the implementation of complex SMB-based processes might have a significant impact on the valve design that must be carefully analyzed. Despite all of the advantages of the SMB, this technology still presents some limitations, especially regarding centre-cut separations for ternary or pseudo-ternary mixtures and the accurate implementation of solvent gradients, which were predominantly exposed by the growing biopharmaceuticals industry. However, the SMB concepts are still at the basis of the development of alternative multicolumn counter-current chromatography units, as the PCC or the MCSGP designed for the capture and polishing of proteins, respectively. In the future, new challenges will be imposed to the industries for which chromatographic processes will represent an effective solution. Hence, it is expected that SMB pursues this continuous evolution and that new multicolumn counter-current chromatographic processes arise. Besides the development of new design strategies, the study and definition of its optimal operating modes and conditions shall also assume a primordial role. Acknowledgements This work was co-financed by FCT/MEC, FEDER under Programme PT2020 (Project UID/EQU/50020/2013). The authors also acknowledges the financing by QREN, ON2 and FEDER, under Programme COMPETE (Project NORTE-07-0124-FEDER-0000006 – Cyclic Adsorption Processes). References [1] A. Rajendran, Recent developments in preparative chromatographic processes, Curr. Opin. Chem. Eng. 2 (2013) 263–270. [2] R.M. Nicoud, Chromatographic Processes, Cambridge University Press, 2015. [3] D.B. Broughton, C.G. Gerhold, Continuous sorption process employing fixed bed of sorbent and moving inlets and outlets, US 2985589, 1961.

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