October 2, 2018 PAP-Q3-18-CL-010
Preparative chromatography can be a highly effective method for the purification of pharmaceutical intermediates and active ingredients (APIs), particularly when the desired compound must be separated from a complex mixture of impurities with similar structures and properties.
Chromatography typically involves two phases — a stationary phase and a mobile phase. The mobile phase containing the target molecule and impurities flows through the stationary phase. The different interactions between the desired compound and impurities and the two phases leads to their separation. In some cases, the desired compound flows through the column and is collected directly. In others, the product binds to the stationary phase and is removed by treatment of the column with a solvent system.
Overall, the global market for preparative and process chromatography is estimated to be expanding at a compound annual growth rate of 7.5% from $5.79 billion in 2016 to $7.88 billion by 2021.1
While preparative chromatography can enable difficult separations, specialized equipment and expertise is required to implement these separation solutions. Servier has employed preparative chromatography for the purification of intermediates and APIs for 30 years. In 2018, we launched our InnoPreP™ preparative chromatography offering.
A new, dedicated 500-m2 development and production suite was constructed to house our preparative chromatography operations. The space includes a dedicated lab, our existing batch chromatography columns, new continuous simulated moving bed (SMB) technology, a falling film evaporator, supercritical fluid (supercritical CO2) chromatography equipment and a high containment area for processing highly potent compounds down to OEB5, the lowest current occupational exposure band.
For batch preparative chromatography, Servier has six columns (50 mm × 2, 110 mm × 2, 200 mm and 450 mm). Our intensified SMB technology for continuous chromatography is highly efficient at separating racemic mixtures and can afford measurable cost savings. Supercritical CO2 technology is an attractive green technology that complements the SMB technology. The falling film evaporator is attractive because it allows for recycling of up to 90% of the solvent used in a separation.
Capacities vary depending on the type of stationary phase required. For projects that require normal-phase separations, up to 50 kg of product can be purified per day (up to 20 tons/year). With reverse-phase systems, we can purify up to 40 kg/day of product (up to 16 tons/year). Chiral separations using chiral stationary phases are much more complex and often have lower throughputs. As a result, the capacities are less: up to 15 kg/day or 6 tons/year.
The new industrial preparative chromatography suite is located at our Normandy, France facility and allows Servier to support customer projects from development through manufacturing. The suite was completed in July 2018 and should be operational by September.
Preparative chromatography can be a highly effective method for the purification of pharmaceutical intermediates and active ingredients (APIs), particularly when the desired compound must be separated from a complex mixture of impurities with similar structures and properties.
The prefix “Inno” in InnoPreP™ is derived from the word “innovative.” This offering reflects our focus on development methods for the preparative chromatographic purification of small-molecule intermediates and APIs, isolating desired compounds in the highest possible yield at the required purity in the minimum amount of time. Our optimized processes provide our customers with lower manufacturing costs and reduced development times, allowing them to be the first in the clinic and therefore the first to market.
We have the ability to isolate impurities that are present even at less than 0.1% and can not only develop processes for new products, but save compromised batches and improve the quality of non-compliant chemical batches. For laboratory projects, critical process parameters are identified and then validated along with product specifications (i.e., yield and purity). The technical feasibility of processes is also confirmed. At the pilot scale, processes are implemented to produce small quantities for necessary toxicity and other testing. Process optimization is performed to develop highly robust and efficient processes that meet specifications while minimizing cost. At the manufacturing scale, processes are designed to provide fast delivery of intermediates and APIs (including highly potent APIs [HPAPIs]). Subsequently, process tuning and continuous improvement are ongoing.
Preparative chromatography is widely regarded as the best method for the purification of small-molecule APIs and intermediates. At Servier, the decades of experience we have developing preparative chromatography processes is applied to each new project. Upfront studies enable the development of an industrial manufacturing process for targeted molecule purification within one week. Overall, the time to market for client projects can be reduced by as much as three months. This allows clients to not only get to the market faster, but also realize significant financial gains.
Our approach ensures greater understanding of target molecules and impurities. Impurities present even at very low levels can be isolated in high purity, enabling easier identification. Information about the impurities formed in a process provides insight into the conditions present as the reaction proceeds. This information is used to develop improved processes, which can lead to higher purities and yields. Our equipment and know-how also lead to the development of optimized processes that can be readily scaled. Our process flexibility — batch and continuous, plus supercritical CO2 and falling film evaporation — allows us to develop the optimal process tailored to each client’s needs.
InnoPreP™ leverages the flexibility and responsiveness of Servier’s team of preparative chromatography experts in support of research and development projects in the lab through scale-up to pilot and commercial production — all in a unique workshop. Servier can help customers improve yields, develop more robust separations, separate racemic mixtures and isolate impurities — all with the goal of reducing their time to market.
In one example, an intermediate generated by the coupling of three different compounds needed to be purified before the final steps of the API synthesis could be completed. Servier optimized an internal existing preparative chromatography process on our 450-mm batch column by changing the mobile phase. The stationary phase and flow rate were maintained. The result: an increase in the productivity from 36 kg/day to 44 kg/day and an improved yield of 80% (compared with 70% for the initial process). In this case, even though the existing process was fairly efficient, our commitment to continuous improvement enabled us to further optimize the preparative chromatography step, providing time and cost savings.
In another example, a process exhibited a lack of robustness, leading to the potential for overlap of the desired product with the main impurity and prevention of their separation. This impurity was present at <2% in the crude, but failure to separate it from the product could lead to the production of a non-compliant batch. Servier modified the preparative chromatography step to provide a robust process that ensured separation of the main impurity from the product during each run.
We also employed preparative chromatography to help a client recover a noncompliant batch. An impurity was present at 0.55%, but the specification was 0.50%, and the client was unable to reduce the content of the impurity via recrystallization. Servier developed a process on our 450-mm column, successfully processing the 72 kg of non-compliant material in less than four days.
In a fourth example, Servier improved a preparative chromatography process designed to separate a mixture of racemic compounds before completing the synthesis of a chiral API. In this case, the separation was highly suited for continuous processing using SMB technology. The optimized process provided 4 kg/day of the desired racemate, with 172.5 kg of the product purified in just eight weeks. A total of 122 m3 of solvent was used, with 110 m3 recycled.
Servier’s expertise in preparative chromatography has also helped us to recover compromised batches. In one instance, 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 of the project. A preparative chromatography process was developed that enabled recovery of both compounds and savings of nearly $300,000.
Preparative chromatography also provides a rapid approach for isolating impurities that must be identified and recorded to meet regulatory requirements. In one example, after completion of a production run, the silica gel column was washed, and seven impurities in the obtained solution were isolated after just four chromatographies; structure determination was then completed.
Servier is a full-service partner to clients, and we can expand our support far beyond purification. The exceptional purification technology offered through the InnoPreP™ program is integrated within our full service contract development and manufacturing capabilities, allowing us to leverage our knowledge and network, centralizing the understanding of compounds. Tech transfer is also simplified and efficient, shortening project timelines and reducing costs.
Our Normandy facility is a full cGMP production site specializing in the development and manufacture of APIs, including HPAPIs. As a global pharmaceutical company, Servier offers a full suite of drug substance and drug product services from 16 sites worldwide. We can support all aspects of projects from proof of concept through development and manufacturing, further shortening time to the clinic and to the market. Customers have the option to advance their entire projects with Servier, protecting their IP, minimizing risk and ensuring rapid progress.
Both smaller companies that have limited, small-scale preparative chromatography capabilities and mid-sized pharmaceutical companies looking for an outsourcing partner that can help them move their projects forward quickly to get into clinical studies ahead of the competition benefit from Servier’s InnoPreP™ offering.
Christophe Berini received his Ph.D. in 2008 from the University of Grenoble (France) in organic chemistry. After working for two years in the United States as a postdoctoral research associate, he came back to France, growing his research background in several fields in diverse laboratories. In 2015, he joined Servier in the Innovative Technologies Department, where he focused his work, with Daniel Dron, on preparative chromatography for the development of methods to purify small molecules, intermediates and APIs in order to develop manufacturing processes for industrial cases.
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