Felix Jegede

WHAT IS ASPEN CHROMATOGRAPHY? Aspen Chromatography is a comprehensive software tool for modeling, simulation, design, optimization and analysis of chromatographic processes. It is designed specifically for use in the pharmaceutical, biotechnology, fine chemicals and food industries. Aspen Chromatography is applicable to both batch & continuous (SMB) chromatographic processes. Batch Chromatographic applications include analytical chromatography, preparative elution chromatography as well as production scale batch chromatography. KEY FEATURES OF ASPEN CHROMATOGRAPHY Aspen Chromatography contains a number of power features that enables it to provide a complete environment for the evaluation and analysis of chromatographic operations. Aspen Chromatography includes: M M M M M rigorous chromatographic column models and a comprehensive library of other equipment models for chromatographic systems; flexible GUI Flowsheet building environment for batch and continuous SMB chromatographic applications; extensive isotherms and physical property facility; parameter estimation facility for fitting of model parameters; and extensive and interactive results saving and display facility.

Aspen Chromatography rigorously predicts product quality, including the purity, recovery and yield levels for different feed conditions and also enables quick comparisons of process alternatives, including performance between traditional batch method versus equivalent SMB column system. HOW IS ASPEN CHROMATOGRAPHY USED? Aspen Chromatography is a complete, easy-to-use tool for engineers and chemists who are involved in development, design or operation of chromatographic processes. In Research & Development stages, it is used as a tool to: M M M M M M quickly and effectively examine viability of separating given drug mixtures; evaluate and screen process alternatives for multiple drug mixtures quickly and efficiently; perform scale-up analysis for different feed conditions; improve process knowledge; reduce number of pilot plant & laboratory trials; and compare and evaluate relative performance between traditional batch versus SMB methods.

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In Design & Pilot Plant stages, it is used to: M M M M design most efficient and effective processes; perform operational studies beyond original scope of design; select the most effective (and economical) adsorbents for the processes; and select the correct equipment size to achieve the desired purification specification.

In Operation and Production stages, it is used to: M M M M optimize column loading and elution strategy for different purification and throughput levels; determine optimum zonal flowrates and switch times (in SMB system); improve reliability & flexibility of processes subject to disturbances such as changes in capacity, feedstocks and product purity demands; and investigate adsorption of impurities onto bed during loading and elution.

SUCCESS STORIES Application of Aspen Chromatography has resulted in a number of significant successes in both batch chromatography and continuous (SMB) chromatography. Two recent applications of Aspen Chromatography are presented below. 1. BATCH CHROMATOGRAPHIC APPLICATION SIMULATION This application, by a US pharmaceutical company, is based on a chromatographic column unit for the production of new high quality drugs and involves the separation of some drug enantiomer mixtures. OPPORTUNITY Prior to using Aspen Chromatography, M M M M the company had invested a lot of time and effort in both laboratory and pilot plant trials, with increasing cost; the level and quality of purification achieved by the trial and error runs were very poor; a significant amount of off-spec product wastes had been generated; and there was also the risk of losing the potentially lucrative market to competitors developing a very similar product through delayed launch.

The application of Aspen Chromatography simulation tool was therefore seen as a tool opportunity to overcome these problems. APPROACH In applying Aspen Chromatography, the steps taken included: M M M Use of rigorous models that were already pre-built and available within Aspen Chromatography. The models were readily fitted to the analytical data available and then validated against the data. The validated models were then employed to perform simulation and predict column behaviour and drug purities under varying loads and conditions and to identify overall operational and performance characteristics.

The results were then re-confirmed in the laboratory and pilot plant before acceptance and deployment 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 shown in Figures 1-3.

FIG 1: CHROMATOGRAM FOR 250MICRO-LITRE SAMPLE:

0.14 0.13 0.12 0.11 0.10 0.09 0.08 0.07 0.06 0.05 0.04 0.03 0.02 0.01 0.00 0 5 10 15 20 25 30 35 40 45 50 55 60

Concentration (g/litre)

Time (min) -TB +TB Total

FIG 2: CHROMATOGRAM FOR 4MILLI-LITRE SAMPLE:

2.0 1.8 1.6 concentration (g/litre) 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0 0 5 10 15 20 25 30 35 40 45 50 55 60 65 Time (min) -TB +TB Total

FIG 3: CHROMATOGRAM FOR 6MILLI-LITRE SAMPLE:

2.4 2.2 2.0 Concentration (g/litre) 1.8 1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0 0 5 10 15 20 25 30 35 40 45 50 55 60 65 Time (min) -TB +TB Total

2.

CONTINUOUS SMB CHROMATOGRAPHY PROCESS This application involved a continuous Simulated Moving Bed (SMB) pilot plant consisting of 12columns. The unit was set up for the production of new and other drugs and involves the separation of chiral enantiomers. OPPORTUNITY Prior to application of Aspen Chromatography, M M M about 12 months had been spent in several laboratory and pilot plant trials; trial and error laboratory work had failed to produce the desired optimum level; and the product purity and recovery levels were consistently low and would need to be improved significantly.

APPROACH The approach in the application of Aspen Chromatography included: M M M 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 and simulate the operating conditions, including the switch time and zonal flowrates.

BASE-CASE RESULT For the base-case, the extract yielded a product of 99.9% purity but very poor recovery of 56%. Similarly, the raffinate yielded a recovery of 69%, but a correspondingly poor purity of 98.0%. Both of these needed to be improved.
Concentration Profiles (base case)
25
Results for Last Cycle
Purity Recovery

Component B in Raffinate Feed

Raffinate :

68.9% 100%

98.3% 55.6%

20
Extract :

Concentration (g/l)

15

10

Component A in Extract

0 1 2 3 4 5 6 7 8 9 10 11 12 Port Position (-)

OPTIMIZED RESULT Through use of Aspen Chromatography, the switch time and zonal flowrates were optimized to achieve an optimum. The extract yielded a purity of 99.9% and recovery of 99.98% while the raffinate yielded a purity of 99.99% and recovery of 99.99%.

Profile Concentration at Steady State (Optimized Case)

25.0 Component B in Raffinate Results for Last Cycle
Purity Recovery

Feed

20.0

Raffinate : Extract :

100% 100%

100% 100%

Concentration (g/l)

15.0

10.0 Component A in Extract

5.0

0.0 1 2 3 4 5 6 7 8 9 10 11 12 Port Position (-)

In this application, dramatically improved purity and recovery levels were achieved. In addition, the simulation and optimization of the process by Aspen Chromatography took just 2-days compared to 12months of prior laboratory trial and error. Furthermore, a significant reduction (of about 25%) in the amount of recycle stream was achieved, which would significantly reduce the operating cost. BENEFITS OF APPLICATIONS OF ASPEN CHROMATOGRAPHY In both of the batch and SMB applications the customers derived dramatic benefits through the applications of batch chromatography, including the following: M M M M Significant reduction in R&D time and associated costs Reduction and elimination of off-spec products Higher and purer quality drugs for clinical trials Improved regulatory compliance

M M

Reduced time to market Improved yield and capacity

For further information on Aspen Chromatography please contact : Felix Jegede AspenTech UK Tel: (44) 1223 312220 Fax: e-mail: felix.jegede@aspentech.com

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