Loading study and simulation. Once the conditions are selected, the adsorption isotherm parameters must be determined to allow modeling. Several methods are available . The isotherm models should be verified and adjusted by comparing experimental and simulated overloaded chromatograms.
Modeling. A number of types of data — hydrodynamic (porosity, pressure drop) and chromatographic properties (retention times, column efficiency, tailing factor, isotherm data) — are required to accurately model the process. These data should be obtained on an analytical column filled with the same packing material. The parameters are entered in simulation software that, in turn, provides flow rates and switch time for the SMB unit [3,4]. The production rate is then calculated and the equipment can be sized for the desired annual production.
The scale up of a SMB process follows the same rules as those for batch chromatography. Providing that packing and eluent are kept identical, the scale up is the ratio of the column diameter squared. For example, if 1 kg of enantiomer can be produced on a SMB with 50-mm columns, 16 kg of the enantiomer can be produced using 200-mm columns under the same conditions.
Chromatographic processes are still considered as the last resort, to be selected only when everything else fails. Several hurdles remain to be overcome before this technology becomes widely used in a production environment.
Image. Chromatography is often considered expensive and not applicable at large scale. This misconception is based on chemists’ experience with low pressure columns, where separations can indeed be very slow and consume a lot of solvent. Modern batch chromatography and SMB are more efficient techniques. Large diameter columns (up to 1,000 mm) operating at 30-40 bars are in use in the industry for both batch and SMB. Several metric tons of API (enantiomers) are produced every year using SMB chromatography at a lower cost than traditional separation techniques.
Regulatory issues. The pharmaceutical industry is heavily regulated. All processes must be perfectly defined and validated. As a consequence, batch processes usually are favored because tracking of material is easier. SMB is a continuous process and, hence, raises many questions from quality groups. However, several processes for the manufacturing of APIs using SMB have been approved by the FDA and other regulatory agencies.
Reliability. A SMB unit is a complex assemblage of valves, pumps, pipes and columns. This complexity causes concerns about downtime, especially considering the continuous nature of the process. A good preventive-maintenance program can minimize downtime. Aerojet Fine Chemicals has achieved an on-stream factor of 95% over 15 months on its commercial-scale SMB unit, demonstrating the reliability of the technology.
Process robustness. Careful selection of various parameters is crucial. The pumps’ accuracy is essential for the robustness of the separation. A small change in the flow rate can have an impact on the final product purity and must be evaluated. The same type of evaluation should be conducted for variation of the eluent or the feed composition, the column performance  and the separation temperature. Assessment of these parameters should pinpoint a range of operating conditions that will ensure that product quality is maintained.
Packing material. The mechanical and chemical stability of the packing material during long campaigns is always an issue. If the material deteriorates over time then replacement will be required. Fortunately, the use of dynamic axial compression allows for long column lifetime. It is not uncommon, however, to see the performance degrade slowly over time, necessitating repacking of the columns with new material.
Sometimes trace-level impurities such as residual solvents or high-molecular-weight compounds are present in the feed material. These impurities can either slowly erode the packing material or be strongly absorbed onto it. Either results in a reduction of the separation performance. Eventually the separation will not be possible and regeneration or replacement of the packing will be necessary. The use of a pre-column can help increase column lifetime and, hence, reduce the cost associated with the packing. The packing replacement must be carefully evaluated and included in the cost of the final API.
SMB now should be considered for a number of applications:
Enantiomer purification. SMB is ideal for the separation of enantiomers. APIs purified by chromatography have been validated and approved by the FDA. Because SMB can provide high purity and high recovery in a very short time, it is an excellent way to reduce time to market.
The cost of the packing material used for chiral separations is often a hurdle in the early development phase. When the production reaches larger scale, the stationary phase can serve for several years and, hence, can be amortized over a longer period. Thus, its relative cost per kg of product becomes small.
Other applications. Any binary-like separation can be a good candidate for SMB.
Separation of diastereoismers sometimes can be achieved via SMB. This often can be economically attractive because cheap packing with high loading capacity can be used.
In the recent years, applications to remove a small amount of a single impurity have been developed. Bioxel Pharma has recently published information on the use of a new high-containment SMB unit at Aerojet Fine Chemicals (Figure 2) for the purification of Paclitaxel (Taxol) from its closely related impurities .