Industrial scale center-cut purification: innovating TIDE production with continuous chromatography

Purification is often a bottleneck in the peptide and oligonucleotide (TIDES) production process, but after the establishment of the first industrial scale continuous chromatography system for center-cut purification, TIDES manufacturing is entering a new era of seamless large-scale production.

In a recent webinar, co-founders of ChromaCon AG Dr. Ralf Eisenhuth, Professor Massimo Morbidelli, and Dr. Thomas Müller-Späth shed light on the evolution of multicolumn countercurrent solvent gradient purification (MCSGP) technology. Working alongside Bachem,  a global leader in oligonucleotide and peptide production, their collaboration has proved successful in accelerating purification innovation. The advancements now allow for purification of up to two tons of crude peptides and kilograms of oligonucleotides, while meeting Good Manufacturing Practice (GMP) standards.

How does MCSGP work?

MCSGP operates via a fully automated system, which utilises two columns operating in counter current mode. This process allows for the continuous purification of product fractions while internally re-purifying side-fractions, and separates weak and strong impurities during gradient purification.

Following elution from column 1, the weak adsorbing side-cut fractions are diluted and transferred onto column 2. Simultaneously, a new crude solution is fed onto column 2. Following elution and collection of the product, the late eluting side-cut fractions are diluted and transferred onto column 2. The same elution process is then repeated with column 2. 

What are the benefits?

MCSGP offers a number of advantages compared to other methods of purification. It’s a scalable process that boasts superior efficiency, which is particularly desirable in large-scale production processes. Furthermore, being fully automated, cycles can be run 24/7, allowing for quicker turnarounds and greater capacity.  Such efficiencies create a more sustainable and reliable process, both beneficial to the environment and CDMOs themselves. 

Industry transitions from batch mode in favour of continuous production

The shift from batch to continuous processing is a trend that can be observed across the industry, motivated by improved sustainability and a reduction of solvents and process mass intensity (PMI). Since Bachem’s installation of their MCSGP systems in 2020, production of one molecule has seen a 21% increase in overall yield coupled with a 75% reduction in solvent consumption. 

This transition is not only endorsed by experts but also supported by regulatory bodies, such as the Food and Drug Administration (FDA).

Sustainable, economical TIDE production on an industrial scale

Dr. Eisenhuth emphasises the versatility of MCSGP in overcoming batch mode limitations, citing its robust operation and minimal supervision requirements thanks to UV-based process control. Additionally, Dr. Müller-Späth highlights the role of UV-based process control in maintaining consistent column bed height.

However, they advise to evaluate the performance of MCSGP systems early on in production stages, suggesting mechanistic modelling to streamline process optimization.

With one production line nearing an maximum output of two tons per year, Bachem's Bubendorf site is poised to become a cornerstone in large-scale TIDES purification. The new building will allow for purification of more than three tons per line, according to Dr Eisenuth. With consistent innovation from industry leaders such as Bachem, we can expect TIDE production to improve further in the coming years as technological advances continue.