Effective and selective preparative chromatography purification can provide higher quality products and decrease time to market
Effective and selective purifications are essential to achieve product specifications. The purification step is particularly crucial when the target molecule has a similar structure and properties to the impurities generated during a reaction. A highly selective separation method is also necessary to avoid the loss of batches owing to potential non-compliance with specifications.
Preparative chromatography is both a highly selective and efficient purification method for challenging reaction mixtures, including those that contain racemic blends of chiral compounds. As such, demand for this technology is expected to increase. Research firm MarketsandMarkets predicts that the value of the global market for preparative and process chromatography will grow at a compound annual growth rate of 7.5% — from $5.79 billion in 2016 to $7.88 billion by 2021.1
Chromatography is widely used in analytical labs to separate complex mixtures. Preparative chromatography, however, is not as widely implemented in the pharmaceutical industry owing to inherent challenges at large scale. Specialised equipment and technical expertise are required to implement, operate and maintain preparative chromatography systems.
Although many companies operate smaller-scale versions, few have the capability to perform large-scale purifications for clinical and commercial manufacturing.
The introduction of Servier’s InnoPreP Preparative Chromatography addresses the need for preparative chromatography capacity in the small-molecule pharmaceutical segment. This new service builds on 30 years of experience employing preparative chromatography for the purification of intermediates and active pharmaceutical ingredients (APIs) at both small and large scale.
As part of their commitment to continuous investment and meeting market needs, in 2018 Servier built a dedicated 500 m2 development and production area for preparative chromatography at its Normandy facility in France. In addition to moving their existing batch chromatography columns to this space, they added a new dedicated lab, continuous simulated moving bed (SMB) technology, a falling film evaporator, supercritical fluid (supercritical CO2) chromatography equipment and a high containment area.
Batch preparative chromatography is performed on six columns ranging from 50–450 mm in diameter. SMB is an intensified preparative chromatography technology that reduces both the time and cost of complex purifications, including chiral separations. Both supercritical CO2 and falling film evaporation are preparative chromatography solutions with reduced environmental impacts.
The high containment area is used to process highly potent compounds down to OEB5, the lowest current occupational exposure band. Capacities for the different preparative chromatography solutions vary depending on the stationary phase in the columns; normal, reverse and chiral phase separations yield the desired product at up to 20, 16 and 6 tons/year, respectively.
Positioning for InnoPrep was developed after carefully observing market conditions. The offering is ideal for both smaller companies looking to scale-up their processes and mid-size companies looking for ways to decrease their time to market. The prefix “Inno” in InnoPrep is derived from the word “innovative.”
Says Christophe: “Our goal with InnoPreP is to focus on development methods for the preparative chromatographic purification of small-molecule intermediates and APIs, isolating desired compounds with the highest possible yield at the required purity in the minimum amount of time. We have the ability to isolate impurities that are present at less than 0.1%. We can also develop processes for new products, save compromised batches and improve the quality of non-compliant chemical batches.”
“InnoPreP brings together the flexibility and responsiveness of our team of preparative chromatography experts to support research and development projects through scale-up to pilot and commercial production –– all in a unique workshop. We are also able to help our customers improve yields, develop more robust separations, separate racemic mixtures and isolate impurities.”
An initial industrial manufacturing process for targeted molecule purification is generally developed within 1 week. The time to finalise an optimised preparative chromatography solution is often reduced by as much as 3 months compared with the industry standard, owing to Servier’s use of highly effective and selective preparative chromatography technologies.
As importantly, their approach ensures a greater understanding of target molecules and impurities. Rapid isolation and the identification of low-level impurities provides insight into reaction mechanisms and allows the development of improved processes, which can all be scaled. “Our process flexibility –– batch and continuous, plus supercritical CO2 and falling film evaporation –– allows us to develop the optimal process tailored for each client,” says Christophe.
Servier is a global pharmaceutical company that has commercialised more than 50 products in six decades of experience, producing therapies that have treated 94 million patients worldwide. “Our contract development and manufacturing services are embedded within this global pharma framework. ervier is a full-service partner, providing services well beyond the exceptional purification technology offered through the InnoPrep programme. The Normandy facility is a full cGMP production site, specialising in the development and manufacture of APIs, and is part of an extensive global network of drug substance and drug product facilities."
"We leverage our knowledge and global network to support all aspects of projects from proof of concept through development and manufacturing, simplifying tech transfer and thus further shortening project timelines and reducing costs. Customers have the option to advance their entire projects with Servier, protecting their IP, minimising risk and ensuring rapid progress,” concludes Christophe.
Case study one: continuous improvement: An intermediate generated by the coupling of three different compounds needed to be purified before the final steps of API synthesis. Servier optimised an internal existing preparative chromatography process using its 450 mm batch column. The same stationary phase and flow rate were used in the new process, with only the mobile phase changed.
As a result of the effort to identify more appropriate separation conditions, the productivity was increased from 36 to 44 kg/day; the yield increased from 70–80%. Even though the existing process was fairly efficient, Servier’s commitment to continuous improvement enabled further optimisation of the preparative chromatography step, providing time and cost savings.
Case study two: improving robustness: An existing preparative chromatography process exhibited a lack of robustness, leading to the potential for overlap of the desired product with the main impurity and preventing separation. This impurity was present at <2% in the crude, and failure to separate it from the product could lead to the production of non-compliant batches.
This situation was unacceptable and, therefore, Servier modified the preparative chromatography step to provide a robust process that ensured separation of the main impurity from the product during each run. Providing quality assurance and avoiding the production of non-compliant chemical batches eliminates unacceptable material and the need to repeat manufacturing runs.
Case study three: non-compliant batch recovery: Although preparative chromatography may not be the primary purification method, it can serve as an efficient solution when problems arise. As such, Servier helped a client to recover a non-compliant batch that was initially purified via crystallisation. An impurity in the batch was present at 0.55%, exceeding the specification of 0.50%.
The content of the impurity could not be reduced via recrystallisation. Servier developed a preparative chromatography process using a 450 mm column, successfully processing the 72 kg of non-compliant material in less than 4 days.
Chromatography is widely used in analytical labs to separate complex mixtures
Case study four: chiral separation: Servier improved a preparative chromatography process designed to separate a mixture of racemic compounds before completing the synthesis of a chiral API. The separation was highly suited for continuous processing using SMB technology. The optimised process permitted the purification of 4 kg/day of the racemate, yielding 172.5 kg of the product in just 8 weeks –– a total of 122 m3 of solvent was used, with 110 m3 being recycled.
Case study five: compromised batch recovery: A low yield of a desired product was obtained after a chemical reaction, leading to a mixture of the desired compound and unreacted starting material. Recovery of both molecules was essential to avoid significant cost and delay. A preparative chromatography process was developed that enabled the recovery of both compounds, saving nearly $300,000.
Case study six: impurity identification: Preparative chromatography provides a rapid approach to isolating impurities that must be identified and recorded to meet regulatory requirements. After completing a production run, the silica gel column used for the preparative chromatographic separation was washed; seven impurities were detected in the wash solution.
These compounds were isolated in high purities after just four additional chromatographic runs, after which structure determination was completed.