Commentary pubs.acs.org/IECR
The Amazing Ability of Continuous Chromatography To Adapt to a Moving Environment ABSTRACT: While normally considered an expensive technology, chromatography has been used for very large-scale applications for ∼50 years. Main successes reported in the petrochemical or sugar industries are obtained with systems having the characteristics of being counter-current and continuous. These systems are the first generation of a lineage that has developed over the past decades to successfully address various purification needs including amino acid production, optical isomers separation, various biopharrmceuticals capture or polishing. The objective of the article is to show how continuous chromatography has adapted and continues to adapt to ever-changing purification needs.
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understand the details by reading the ∼2500 articles and 2500 patents published on the subject to date; therefore, I will avoid technical details and focus instead on principles, to help put things in perspective.
INTRODUCTION At the end of the 1980s, although the concept of continuous chromatography was already used for hydrocarbon and sugar separations for ∼30 years, it was totally ignored in the fine chemical, pharmaceutical, or biopharmaceutical industries. Discussions with Institut Français du Pétrole (IFP) made me realize the potential of continuous chromatography for these unexplored industries. After a first exhibition during Achema in 1991, I gave my first lecture that proposed using continuous chromatography for pharmaceutical applications during the Preparative Chromatography Symposium organized in Nancy, France, in 1992.1 At that time, only one presentation was devoted to that concept and the two subsequent remarks and questions that I got from the industry were “It is bright concept, but it will never work.” and “Do you believe that one day you will be able to purif y 1 kg of racemic mixture with this system?”. A year after, Sandoz gave me the chance to prove the concept and accepted to publish the results.2 This helped to raise the level of confidence of the industry, and a few additional years were needed before a company seriously invested in continuous chromatography for purifying industrial quantities of a commercial drug (UCB Pharma was the first company to do so). Twenty years later, the Preparative Chromatography Symposium that was organized in Boston, MA, in July 2013 (PREP 2013) offered 27 contributions devoted to the topic. In addition, eight chromatography suppliers have shown some involvement in the field, and optical isomers are produced annually at the multiple hundreds of tons level. The above numbers only show the visible part of the iceberg, with technical evolution being even deeper. Eric Valery from Novasep introduced the concept that continuous chromatography evolves under environmental pressure, somewhat similar to the way animals evolve according to Darwin’s law. I thought that this was an interesting way of presenting the evolution of this technology during the last decades and decided to elaborate on this concept. This document is a written version of a few short lectures that I gave on the subject in 2013. I used to start these lectures by saying that my goal was to convince the audience of this Darwinist evolution and that, to reach this objective, I would use no mathematics and no detailed flowsheets. By using this approach, my goal is to share a personal view on the evolution of this technique by trying to remove most of the technical difficulties. People have ample opportunity to © 2014 American Chemical Society
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GENERAL CONSIDERATIONS Modifying chromatographic processes compared to the initial batch implementation proposed by Tswett more than a century ago is driven by the legitimate desire to improve process performances. Even if, in all likelihood, parameters such as cost are going to play a major role at the end of the day, different technical parameters must be tuned to optimize the economical result. When developing a process, four main objectives are normally considered: (1) Minimizing system size: productivity, expressed in terms of kg/kg/day, is normally presented as the main objective function to be optimized. There is no question that this parameter is important, but a large low-pressure system can be much less expensive than a small high-pressure system. As a matter of illustration, a simple way to minimize system size consists of using smaller particle size. This reaches some limits, either due to the price or availability of small-particle-size materials and because using particles that are too small can lead to technical difficulties, making the system unsuitable and/or too expensive. (2) Minimizing eluent consumption: chromatography is an excellent diluting machine, so that eluent consumption, which is a parameter normally neglected and secondary on a small scale, becomes a major concern on a large scale. Let us notice that elution chromatography is especially diluting and that other modes (such as frontal analysis, displacement chromatography, and/or gradient elution (especially for biomolecules)) can simultaneously purify and concentrate. However, this concentration ability is normally and unfortunately “balanced” by a solvent-demanding regeneration step, so that chromatography remains overall diluting. Solvent recycling is mandatory for large and efficient processes, and as an illustration, during a highly educating lecture given during PREP 2013 in Boston, Dr. Veronique Pinilla from UCB Pharma mentioned a 99.99% solvent recovery on the Keppra industrial chromatography production unit. On a very large scale, even with optimized multiple effects recycling units, the energy associated with the solvent recycling becomes a significant cost factor so that minimizing the unquenchable thirst of chromatography is Published: February 18, 2014 3755
dx.doi.org/10.1021/ie5005866 | Ind. Eng. Chem. Res. 2014, 53, 3755−3765
Industrial & Engineering Chemistry Research
Commentary
behavior, the perception of continuity by the user may be broader. The problem is generally a problem of scale of observation and of averaging: a car moves continuously even if the explosions that occur in the cylinders are discontinuous. Similarly, a complex purification process including a few discontinuous steps may appear continuous depending on the needs of the user (and on the size of buffer tanks). Finally, operating a few identical but desynchronized batch systems in parallel would allow one to obtain quasi-continuous feeding and collection, but again, certainly not a counter-current contact. There is an obvious need to compare possible processes and many contributions have been proposed during the last years for comparing continuous and batch processes performances. These comparisons are typically expressed in terms of kilograms of purified product per kilogram of chromatographic media per day (kg/kg/day, or K/K/D for short). Taking some liberties with the literature details, one can state that when the batch system is associated with a productivity of 1 (arbitrary units), the proposed improved chromatographic process (let us call it “my clever continuous process”) is typically granted a productivity of 10. I had the chance to work with very strong batch chromatography developers, and my experience is that gaining a factor 2 or 3 with “my clever continuous process” is often exceedingly difficult. Comparing batch chromatography systems with “my clever continuous process” is a task presenting a real level of difficulty and requiring one to make many assumptions. As a matter of illustration, is the pressure drop limit the same for both processes ? If yes, in the case of multicolumn systems, is it the pressure drop limit taken for one column or for the set of columns connected in series? In addition, the optimum particle size, eluent composition, and temperature values are different for different processes. In many of the published comparisons, particle size and eluent composition are the same for both processes, which means that at least one of the two is penalized.
important. The biopharmaceutical industry is certainly less concerned with that aspect than other industries, possibly due to the difficulty of recycling buffers. Because of the solvent needs, ancillary equipment is normally more costly and spaceconsuming than chromatography itself. This ancillary equipment is also a good driver for difficulties with the relevant authorities. (3) Maximizing yield: nobody likes losing a material that could already come from several reaction/fermentation/ purification steps and can thus represent a significant value. Any chemist or chemical engineer knows that saving material and maximizing productivity are not easily compatible. (4) Ensuring operability: many different concepts are considered behind the wording “operability”, including the ability to control the unit, to accept parameters fluctuations (like feed composition), to offer long-term stability and thus to provide “robustness” and “reliability”. One could also mention the ability to clean the unit, to restart quickly after inevitable stops, the compatibility with the PAT (Process Analytical Technology) initiatives. Thinking that a chromatographic process, be it batch or continuous, could be able to optimize simultaneously the four above objectives is a chimera: life in always a matter of compromise! During the 20th century, chemical engineering transformed batch separation processes to continuous ones. Liquid−liquid extraction, gas−liquid absorption, and distillation are relevant examples and we know that counter-current processes can help to improve the first three objectives. There was no a priori reason for chromatography to be an exception, and the Nobel Lecture given on December 12, 1952, by Archer J. P. Martin (Martin and Richard L. M. Synge received the Nobel prize for their discovery of partition chromatography) looks unbelievably visionary: “Partition chromatography resulted from the marrying of two techniques, that of chromatography and that of countercurrent solvent extraction. All of the ideas are simple and had peoples’ minds been directed that way the method would have flourished perhaps a century earlier. In fact the minds of laboratory workers seem to have been closed to countercurrent procedures, which were adopted in industry, e.g., in distillation and lixiviation, long before they were generally used in the laboratory. In industry the use of the countercurrent principle led to great economies in heat and solvents, and its value was obvious.” There is not a lot to add 60 years later. Note that the Martin quote refers to counter-current processes, not continuous processes. Introducing continuous operations can certainly help to improve objective 4 above, by allowing possibly more stable and reproducible processes, but does not bring much improvement to objectives 1−3. Understanding the difference between counter-current and continuous processes is important to appreciate differences and possibilities of the numerous chromatographic designs proposed in the past decade. As an illustration, the Preparative Continuous Annular Chromatography system proposed a decade or two ago by a company called Prior Separation Technology3 is continuous but not counter-current. Alternatively, we will present a system called Varicol, which is counter-current and continuous, but never reaches steady state. It is probably worth commenting somewhat about the concept of continuous processes. While a strict definition would require constant inlet/outlet flow rates and steady-state
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THE FIRST GENERATION OF CONTINUOUS CHROMATOGRAPHIC ANIMALS As already mentioned, during the 20th century, chemical engineering transformed many batch separation processes into continuous processes. Chromatography, because of intrinsic complexities, resisted longer but industry needs finally imposed this evolution. The first noticeable generation of continuous chromatography animals arrived in the late 1950s. The underlying concept consists in promoting a counter-current contact between a chromatographic adsorbent and an eluent in the well-known four-zone true moving bed system presented in Figure 1 (left). The impracticality associated with the requirement of a solid motion pushed D. B. Broughton from UOP4 to propose certainly one of the cleverest inventions of the last few decades. Instead of moving the solid with respect to fixed inlet and outlet lines, he proposed moving inlet and outlet lines with respect to fixed chromatographic beds, as shown in Figure 1 (right). This process is the well-known simulated moving bed (SMB) process, which simulates the behavior of a true moving bed (TMB) process. The most visible characteristic of the SMB consists of its ability to separate, continuously, a feed mixture in two fractions. However, one must recall that its expected improved performance, compared to the batch, is connected with its counter-current nature. Chromatography not only became 3756
dx.doi.org/10.1021/ie5005866 | Ind. Eng. Chem. Res. 2014, 53, 3755−3765
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Commentary
of individual columns but of two towers of 12 elements each. The 12 elements are separated by distributors having the functions of keeping the beds in place, distributing the fluid between the different sections, and allowing for the inlet/outlet fluid connections (G. Hotier, Institut Français du Pétrole, personal communication). The demands on para-xylene are very large and, today, more than one hundred units are in operation, some of them with a production capacity of ∼1 000 000 Mt/yr. The technology has certainly evolved over the past years, but key features remain the same. The Eluxyl process, proposed by IFP (now Axens), is worthy of note; it takes advantage of a coupling between chromatography and crystallization (www.axens.net). The SMB concept has led to other applications aimed at producing small aromatic molecules, with ethylbenzene, nparaffins, olefins, and cresol being cited most frequently. Another major business pressure came in the 1970s from the growing needs for purified fructose and high-fructose syrup. The feed stream is a mixture of fructose and glucose typically coming from the hydrolysis of starch and isomerization of glucose, with production units being on the scale of 100 000 t fructose/yr. The separation is performed on ion-exchange resins, with the selectivity being ∼1.5. The particle size is typically in the range 300−500 μm and the temperature is ∼65 °C, to prevent bacterial growth and lower the viscosity. The target purity varies from one application to the other but is generally rather moderate (e.g., 90% or less, to chose a number). Even if the HETP is in the centimeter range, as in the para-xylene application, the limited purity requirement allows one to work with a shorter total bed length (for example, 8−12 m instead of 24 m). Very important constraints for this application are to minimize the water needs associated with the chromatographic step and to optimize multiple-effect evaporators to keep energy costs under control. As observed for the para-xylene application, columns are typically of a tower type made of different subsegments. Let us mention an alternative implementation of continuous counter-current chromatography represented by the commercial systems CSEP (Continuous Separator Technology) and ISEP (for i-ion-exchange) currently proposed by the Calgon Carbon Company (www.calgoncarbon.com). The columns are mounted on a turntable that rotates along with the distributor that connects these columns to process fluid streams. During a 360° rotation, each column is subjected to an entire sorption cycle that typically consists of adsorption, regeneration, or elution, and one or two rinse steps. The concept of using large beds of ion-exchange resins for continuously purifying different mixtures issued from biomass has been implemented for various applications, such as producing betaine as a side product from sugar obtained from beetroot molasses (the NS2P/FAST Process, from Novasep) or lysine from fermentation. The first continuous chromatographic systems were thus operating at low pressure (
