Conduct commercial-scale production.
Provided that the feed material is available, a process can be developed from method screening to commercial quantities in
a mater of months. SMB as a unit operation to produce an API has been approved by FDA. For example, Escitalopram, an antidepressant
developed by Lundbeck (Copenhagen, Denmark), was one of the first drugs to be approved using an SMB step. Since then, additional
drugs have been approved, and a lot more are in the pipeline.
At this stage, this process, like any other process, must be well defined and ready for validation. The definition of the
batch for a continuous process is based on time in the unit. This time can be the time required to process enough material
to fill a dryer or fill the reactor for the next chemistry step. This must be defined clearly so that the pedigree of the
product can be traced.
The stability and robustness as well as the cost of the chiral stationary phase are always a concern when a new SMB process
is discussed. AMPAC Fine Chemicals (AFC) has been producing several hundred metric tons of an API with SMB as the penultimate
step of manufacturing using the same packing material for the past eight years. Unpacking the columns every 12 or 18 months
is sometimes required to remove the fines that accumulate as a result of slow attrition of the packing. Thus, for a commercial-scale
project involving the separation of hundreds of metric tons per year over several years, the cost of the packing material
amortized during three years is in the range of $5–10 per kilogram of product manufactured.
The cost of operating an SMB unit is not as expensive as it is commonly believed. Most of the solvent used for the process
is recycled at three levels. The first level is internal to the SMB. The second level is at the falling films used on each
outlet to preconcentrate the product. At this point 75–85% of the solvent is recycled. Finally, the solvent removed from the
drying step can be recycled to achieve a total greater than 99%. AFC received an award from the Department of Toxic Substance
Control (DTSC) and the Chemical Industry Council of California (CICC) for the implementation of the solvent recycling on the
large-scale manufacturing using SMB. Several thousands of gallons of solvent are recycled instead of being wasted, thereby
making SMB a green technology. Currently, the overall solvent usage at AFC for commercial-scale units (6 X 800 mm and 5 X
1000 mm) is less than a few drums of solvents per month.
The labor required for the operation of an SMB unit is also relatively low. A single operator can monitor the unit, and from
time to time, a second operator is required for preparing the feed or for recovering the product from the dryer.
The cost of equipment installation is still relatively high mostly because of the cost of the unit and the amount of ancillary
tanks required to operate the system. Nonetheless, this cost will eventually decrease as more units are sold around the world.
It is quite possible that for a separation with a decent productivity (2 kg of feed/day/kg of CSP or better) and relatively
high annual volumes, the price of the product falls into the range of $75–150/kg — all included.
SMB is not limited to chiral separations. Any separation that can be turned into a binary separation is potentially an excellent
candidate for SMB. Removal of troublesome impurities by SMB is a good example. Troublesome impurities are closely related
to the main product or are dimers or trimers of the product and are very difficult to remove. Sometimes multiple crystallizations
are required to meet the final product specifications.
As an example, at AFC we purify a natural product by SMB. There are numerous impurities in the natural product, but one in
particular that is very difficult to remove by traditional purification processes. Removal of this impurity by crystallization
would result in a substantial loss of the expensive natural product to the mother liquor, which in turn makes crystallization
a very expensive technique. Work was undertaken at AFC to develop a commercially viable SMB process to achieve high purity
and high recovery of the natural product. The chromatogram of the feed analyzed under the SMB conditions shows only two peaks,
but each peak represents the combination of several species. The SMB not only removes the troublesome impurity but it also
removes a significant portion of the other impurities, thereby bringing the product total purity from ~75% to >96%.