Process Simulation Widens The Appeal Of Batch Chromatography
Batch chromatography has selective value for purifying or recovering certain high-value biomolecules, and in processing fine chemicals and foodstuffs. Developing optimal processing schemes, however, tends to be timely and expensive because elaborate pilot testing is necessary. Process simulation technology is now available to significantly expedite the development of new applications, or the optimization of existing ones.
I Background
II Industry Challenges
III Addressing the Challenges
IV Customer Success Stories
I Background
What are Batch Chromatographic Processes?
A batch chromatographic process is an adsorption-based separation process used for the high-purity separation and purification of components in the liquid phase. It is applied extensively in the pharmaceutical, biotechnology, fine chemical and food processing industries (see Section II for a summary of target applications).
It consists of injection of the feed mixture to be separated into a packed column of adsorbent particles, through which there is a continuous flow of a mobile phase (Fig.1.1). The choice of the type of stationary and mobile phase depends on the type of application and the properties of the mixture to be separated. Frequently, batchwise chromatographic separation operations involve alternate injection of the feed mixture and a desorbent solvent. The different adsorption affinity of the feed components results in different migration rates of the components in the column.
Chromatographic separation methods involve a lower use of energy than other separation techniques, such as distillation. Furthermore, liquid chromatography is often performed at room temperature; thus preventing loss of activity of heat-sensitive components such as occurs in the industries mentioned above.
Batch chromatographic processes fall into three categories, depending on the scale of the process:
Analytical chromatography (feed volumes characterized by microliters) is used routinely as a powerful analytical tool and in the appropriate form is used for the quality control of raw materials, intermediates and products as well as for process control purposes.
Preparative-elution chromatography processes (feed volumes characterized by liters) are used increasingly, and are considered to be among the most efficient fractionation processes. Most of the important applications are in the liquid phase, including Low-Pressure Chromatography (LC), and High Performance (or Pressure) Liquid Chromatography (HPLC). Preparative Supercritical Chromatography is also undergoing commercialization.
Production-scale batch chromatography processes (feed quantities characterized by cubic meters/tonnes) are used mainly for sugar production and to some extent in hydrocarbon processing. They are generally less common than the other two types of process.
The separations carried out by preparative- and production-scale batch chromatography can also be performed using a Simulated Moving Bed Process. These processes are referred to below as chromatographic SMB processes.
What are True Moving Bed and Simulated Moving Bed (SMB) Processes?
Although batch chromatographic techniques have many merits, they suffer from the following drawbacks:
- Not all the adsorbent in the column is used efficiently.
- A large amount of eluent is needed to elute the separated components, resulting in dilution of the products.
- Highly purified products are not obtained whenever the differences in adsorption affinities of the two components for the adsorbent (i.e. selectivity) are small (unless exceptionally long columns are employed).
- The operation is discontinuous.
A 'true moving bed' system allows these drawbacks to be overcome (Fig.1.2). In these systems, the 'stationary' (solid) phase flows in a countercurrent direction to the mobile-phase stream. When the feed mixture is introduced into the column (usually in the middle), the most strongly adsorbed component is carried with the packing and is stripped at the column outlet, while the least adsorbed component is carried with the mobile-phase.
For example, in a binary TMB separation system, a feed consisting of two components A and B is introduced, where A is the more strongly adsorbed species. Through the countercurrent operation, concentration peaks of A and B will develop along the bed. When the peaks have fully resolved, the extract stream will be enriched in species A and the raffinate will be enriched in B.
However, TMB systems suffer from the following:
- The difficulties in controlling the flow of the adsorbent (solid phase).
- Low mass-transfer efficiencies because of the unevenness of the adsorbent in the bed.
- Increased attrition of the solid particles due to shear forces and entrainment in the adsorbent recycling system.
- Relatively low mobile phase velocities are required to prevent fluidization of the bed.
These problems are overcome with the Simulated Moving Bed (SMB) system. In particular, SMB technology is used where continuous countercurrent operation is required because the selectivity of the adsorbent is poor. The SMB concept allows a fixed bed to be used in place of a True Moving Bed (TMB) (Fig.1.3), for countercurrent adsorption/desorption.
A number of static columns or compartments, containing a fixed adsorbent, are interlinked and the countercurrent movement is effectively simulated by periodically shifting the positions at which material is fed and recovered. In an SMB process, a unit such as a multi-port rotary valve is often used to shift the relative positions of the material streams. Electronic on-off valves are also used.
II Industry Challenges
Batch Chromatographic and SMB technology is used for the high-purity separation and purification of products in the following industries:
- High-purity pharmaceuticals and biotechnology products
- Fine chemicals and their intermediates
- Foodstuffs
Pharmaceuticals & Biotechnology applications
Drug Purification
Pharmaceutical and Biotech companies use batch chromatography and/or SMB technology in their R&D and drug production plants for drug purification. Drugs are often produced in the form of enantiomers (optical isomers); these have molecular structures that are mirror images of each other and cannot reasonably be separated using distillation. SMB chromatography technology is employed as the only reliable means to obtain optically pure products.
Food & other applications
SMB technology is used extensively for separations in the food industry, the most important applications being in sugar processing. SMB chromatography systems are also employed for drink formulations, food flavorings, and in separating fine fragrances.
The table below lists the most important target markets for Aspen Chromatography, classified according to industrial sector.
| Industrial Sector | Process Applications |
|---|---|
| Pharmaceuticals and Biotechnology |
High purity separation and purification of optical isomer (enantiomer) drugs with different therapeutic effects: SMB offers an economically attractive method. Seperation of amino acids. Protein (monoclonal antibodies) purification |
| Food Processing | Desugarization of sugar beet molasses Separation of fructose from glucose by batch chromatography. Recovery of fatty acids from fish oil and from rosin acids produced in the pulp and paper industry |
| Others | Separation of fine fragrances |
Both batch chromatography and chromatographic SMB processes are often complex and highly interactive. They are difficult to design and operate systematically. Engineers and operators thus face many business and technical challenges.
The following lists the key challenges for each industry.
Pharmaceutical and Biotechnology Processes
Pharmaceutical companies are generally under pressure to reduce time to market, produce optically purer drugs, reduce the amount of off-specification products, and comply with strict FDA, health and safety regulations. According to one leading manufacturer, too much money and time is spent on R&D and pilot plant experiments. Simulation provides a cost-effective and time-efficient solution.
Following summarizes the business and technical challenges in the pharmaceutical and biotechnology industries:
- Reducing the time to market for a new drug product
- Reducing the cost of production, including research and development
- Producing higher quality drugs for clinical trials
- Complying with regulatory bodies, for example the FDA, and the EPA
- Reducing and eliminating off-spec products (with potential disposal problems)
Food Processing
The main efforts are concentrated on the profitability of sugar processing plants, particularly the desugarization of beet molasses, such as:
- Debottlenecking plants
- Increasing sucrose recoveries over the separation and crystallization stages
- Separating useful side products like betaine
- Cleaning the sucrose fraction, and removing its color
III Addressing the Challenges
Modeling products such as Aspen Chromatography by Aspen Technology offer a solution. Aspen Chromatography is a comprehensive simulation tool with full engineering functionality, flexibility, and ease-of-use. It is used for the modeling, simulation, design and optimization of industrial batch chromatography processes and chromatographic SMB processes. Aspen Chromatography provides an open, flexible and easy-to-use simulation environment. It is applied to the broad range of applications involving the separation of high purity pharmaceutical, biotechnology and fine chemical products.
The rigorous Aspen Chromatography simulator allows engineers and scientists to develop and design more efficient batch chromatographic and SMB processes. The models and flowsheets produced using this flexible and user-friendly tool have been used to reap benefits at all stages of the process life-cycle, including research, product development, pilot plant and design, plant commissioning, and production.
Pharmaceutical and Biotechnology Processes
Such a tool can help engineers complete simulations that will accomplish the following:
Research and Development
- Quickly examine the viability of separating a given drug enantiomer mixture
- Evaluate and screen process alternatives for multiple drug mixtures quickly and efficiently
- Reduce the number of pilot plant and laboratory trials, thereby saving development time and cost
- Determine alternative methods of process operation to achieve higher purities
- Compare the performance of a traditional batch chromatography process with an equivalent SMB process
Pilot plant studies and design work
- Perform operational studies beyond the original scope of the design and examine the effects of scale-up of bench design
- Quickly improve knowledge of the process
- Achieve the correct equipment size, such as bed length, or size of adsorbent chamber and the correct number of SMB ports to achieve a given separation.
- Examine the feasibility of revamping existing processes or redesigning new processes
- Determine a given adsorbent's characteristics and performance, and aid in the selection of the one with the most favorable attributes for the process
Production
- Launch new products onto the market-place through improved product quality for use in clinical trials and earlier compliance with regulations
- Optimize the process to achieve required product purity and yield. Variables include feed pulse volume and loading/elution time for batch chromatography; port-switch time and zone flowrates for chromatographic SMB
- For analytical chromatography, maximize resolution of the feed components subject to a maximum resolution time
- For preparative chromatography and SMB, maximize production rate at minimum capital and operating costs for a given separation efficiency
- Minimize the consumption of energy and raw materials in SMB through choice of recycle rate
- Improve knowledge and understanding of the process, such as in operator training
Food Processing
Typically a 90% sucrose purity is produced with a 75% overall recovery. The best way to increase recovery (up to say to 81%) is by increasing the purity of the sucrose fraction (up to say 94%); this requires optimization of the process, which is best carried out by direct simulation. The relative advantage of the sequential SMB process over the continuous SMB process to achieve this can also be demonstrated. Both these improvements require more separation capacity and more water removal capacity.
IV Customer Success Stories
Batch Chromatographic Application Simulation
This application, for a US pharmaceutical company, involves the separation of some drug enantiomer mixtures during the production of new high quality drugs.
Opportunity
Prior to using Aspen Chromatography, the company had invested a lot of time and effort in both laboratory and pilot plant trials at increasing cost. The level and quality of purification achieved by the trial and error runs were very poor, and a significant amount of waste due to off-spec product had been generated. Because of a delayed product launch, there was also the risk of losing the potentially lucrative market to competitors developing a very similar product.
Application of the Aspen Chromatography simulation tool was therefore seen as a solution to overcome these problems.
Approach
In applying Aspen Chromatography, the steps taken included the following. Rigorous models, which were pre-built and available within Aspen Chromatography, were made use of. The models were readily fitted to and validated against analytical data already available.
Benefits
The validated models were then employed to predict column behavior and drug purities under varying loads and conditions. Optimum operational and performance characteristics were identified. The results were confirmed by comparison with laboratory and pilot plant tests before being put to use in the plant.
Results
For each loading/elution level and operating strategy, Aspen Chromatography was applied to screen and predict separation and product quality including purity, recovery and yield levels. The resulting chromatograms for each elution load levels are also predicted, such as that shown in Figure 3-1.
Continuous SMB Chromatography Process
This application involved a continuous Simulated Moving Bed (SMB) pilot plant consisting of 12 columns. The unit was configured for the separation of chiral enantiomers as part of production of new drugs.
Opportunity
Prior to application of Aspen Chromatography, about 12 months had been spent on laboratory and pilot plant trials as well as laboratory work. This had failed to produce the desired optimum level. The improve purity and recovery levels were consistently low and needed to be improved significantly.
Approach
The approach in the application of Aspen Chromatography included the use of rigorous continuous (SMB) chromatographic models and facilities available within Aspen Chromatography. From the operating data provided, the first base-case simulation was set up in Aspen Chromatography to validate the models, and the results compared with the actual current process performance. Aspen Chromatography was then employed to optimize the operating conditions, including the switch time and zonal flowrates.
Benefits
A comparison between the base-case and the optimized process conditions using Aspen Chromatography is described below.
Base-case result
For the base-case, the extract yielded a product of 99.9% purity but a very poor recovery of 60%. Similarly, the raffinate yielded a recovery of 70%, but a correspondingly poor purity of 98.0%. Both of these needed to be improved.
Optimized result
Through the application of Aspen Chromatography, the switch time and zonal flowrates were optimized to achieve an optimum. The extract then had a product purity of 99.9% and yielded a recovery of 99.98%, while the raffinate had a purity of 99.99% and yielded a recovery of 99.99%.
Much higher purity and recovery levels were thus achieved. The simulation and optimization of the process by Aspen Chromatography took just two days compared to the 12-months of trial and errors work in the laboratory and pilot plant. At the same time, significant reduction (about 25%) in the size of the recycle stream was achieved, cutting the operating cost.
About the Author: Dr. Felix Jegede is product manager for Aspen Chromatography at its Cambridge, England offices.
For more information: Aspen Technology, Inc., 10 Canal Park, Cambridge, MA 02141, USA. Telephone: 617-949-1000. Fax: 617-949-1030.