Biomagnetic Separation, Thinking Bigger Part I

Contrary to popular belief, biomagnetic separation is ready for large-scale processing

By Lluis M. Martinez, PhD. CSO, SEPMAG

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Separation is a key process used in life science. Cells, proteins and genetic material of interest for medical and pharmaceutical use are rarely obtained in a purified form. The molecules we are interested in are usually in a matrix that contains numerous other biological substances. We therefore need to extract/isolate these molecules from the supernatant before work can start. Even high-value pharma processes such as protein purification, the downstream process (i.e. purification) can lead to losses of 50-80 percent of the product. 

When working on a small scale, using magnetic beads or particles as solid support for separation has become increasingly popular, particularly when it involves immunocapture. Coated with the right antibody, magnetic carriers can capture the molecule of interest in seconds and retain this by magnetic force while washing out the supernatant. When the magnetic field is removed, the beads can then be re-suspended in a clean buffer.

With such obvious benefits, it makes sense to use this technology on a larger scale. It is commonly believed that biomagnetic separation is not suitable for large volumes, which may explain why people are so doggedly attached to centrifugation, filtration and packaged columns—even though the methodology is slow, complex, requires extremely expensive equipment and can be a cleaning nightmare.

One life science industry has already tackled these questions. Efficiency, rapidity and simplicity of biomagnetic separation are among the reasons behind the success of chemiluminescent immunoassays (CLIA). The rapid growth of this market has prompted In-Vitro Diagnostics (IVD) manufacturers to scale up magnetic-bead processes to cope with demand. The lessons learned by this industry can be very helpful in other life science companies and cell capture or protein purification may be of benefit to processes in the IVD industry for coping with volumes up to tens of liters.

At the beginning of the current century, the IVD industry had similar challenges to those now facing other life science companies. Attempts made to scale up biomagnetic separation processes beyond a few milliliters proved unsuccessful. The paradox was that the main cause of failure lay in its success with small volumes. Easy implementation of biomagnetic separation at milliliter scale had allowed researchers to focus on selecting the right magnetic beads and how to coat them with the antibody or biomolecule. Given that almost any magnetic separator (or even a simple magnet) would capture the beads in few seconds, little emphasis is placed on the workings of the process. Descriptions of the biomagnetic separation conditions were limited to a description of the magnet and, at most, the separation time. When the volume was scaled up, the initial attempts used a ‘larger magnet, usually with no more specification than the material (NdFeB magnet) or the required magnetic field on the surface. However, with this approach, the scaled-up biomagnetic separation process did not work as expected. Separation time increased exponentially, magnetic beads losses were significant and the beads became irreversibly aggregated. The process is no longer fast, reliable or consistent technology when the working volume is increased.

Around 2000, when my team and I were approaching the problem, IVD-manufacturers were considering several options. One was to replicate the small volume process. To increase production by a factor of 10 it was necessary to build 10 production lines. This option involved large-scale investment and proportionally increased labor costs with virtually no economy of scale. Worse still, a new problem arose: The need to guarantee batch-to-batch consistency between the different lines. As one of our customers said, “It is far simpler to validate one ten-liter batch than to guarantee that 10, one-liter batches are the same.”

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