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    Bachem’s transformational oligonucleotide manufacturing innovations

    news-releasesBachem AG
    July 14th 2022

    Bubendorf, Switzerland: –Peptide and oligonucleotide technology specialist Bachem constantly advances its technologies and manufacturing processes as part of its mission to provide excellence to its customers and be a major player in their success.

    A cornerstone of Bachem’s success as a leading contract development and manufacturing company is innovation and over the years it has developed technical leadership in peptide and oligonucleotide manufacturing.

    Recently Bachem has successfully invested in capacity expansion for large-scale production of oligonucleotide active pharmaceutical ingredients (APIs) that includes innovative equipment designed with unique features.

    Tailor-made oligonucleotide synthesizer

    To provide the highest quality oligonucleotide to customers, Bachem has designed and customized a large-scale oligonucleotide synthesizer with innovations that improve and optimize the process of oligonucleotide synthesis. The synthesizer has been qualified for GMP batches from 0.2 moles (mol) to 2 mol scale.

    One of the novel engineering solutions for the synthesizer is in-line mixing of dichloroacetic acid (DCA) and toluene to produce a solution used as the first step for all coupling cycles of oligonucleotide synthesis, deprotecting the 5’-dimethoxytrityl (DMT) group and releasing the 5’-hydroxy group in order to perform the coupling reaction.

    While most synthesizers use a fixed DCA/toluene ratio, with Bachem’s skid the DCA proportion can be varied in-line from 3% to above 10%. Changing this concentration can be beneficial in reducing undesired side-reactions and securing API quality.

    In addition, Bachem introduced other customizations to further control and optimize oligonucleotide synthesis. A heat exchanger has been set up to ensure full temperature control to reach the optimum conditions for the deprotection and coupling steps. This temperature control will minimize side reactions and ultimately optimize the yield and quality of the crude oligonucleotide API. A third innovation is incorporation of dynamic axial columns (DACs) containing a piston that can move throughout each synthesis cycle of the process. The presence of an adaptable piston enables full control of the column’s volume, avoiding any dead volume and optimizing the amount and flow of solvent needed for the synthesis.

    Automated C&D

    After synthesis, an oligomer has to undergo cleaving and deprotection (C&D): being cleaved off from the solid support and decoupled from the protecting groups. Bachem has equipped its oligonucleotide production line with a unique streamlined and automated large-scale C&D system. This set-up delivers significant benefits in time optimization, cost-efficiency and lower solvent consumption.

    The large-scale 250 L pressure vessel automated C&D equipment uses a continuous two-step process. Once the synthesis is complete, the same column is moved and installed onto the C&D skid. The first step is to deprotect the cyanoethyl groups and then the cleavage of the oligonucleotide from its solid support. A solution of room temperature ammonia circulates through the column of a given volume. This solution carries the released oligonucleotide to the 250 L collector vessel, made from Hastelloy® to cope with highly corrosive solutions, such as fluoride-based reagents. The C&D system also includes a set of process control parameters such as temperature, UV, conductivity and volume.

    The second step is the deprotection of the protecting groups from the oligonucleotide. Once the ammonia solution has recirculated several times between the vessel and the column, all the oligonucleotide is cleaved from its support and eventually collected in the vessel. The vessel is then closed and heated under pressure with the ammonia solution with a further unique feature, an automated temperature program. The C&D machine is equipped with a multi-port inlet in case other deprotection solutions are required for the oligonucleotide. It enables delivery of the right reagents such as fluoride-based reagent for deprotection of silyl containing protection groups. After completing the C&D step, the oligonucleotide is free from the support and protecting groups. The crude API is now ready for the next steps: possible ultrafiltration followed by purification.

    Continuous Chromatography:

    Bachem has also set up the first continuous chromatography equipment for industrial scale (see Resources). Its innovative Multicolumn Countercurrent Solvent Gradient Purification (MCSGP) technology represents great progress in the downstream process for peptide and oligo manufacturing.

    Bachem first introduced this technology for peptide APIs and has now demonstrated its large-scale feasibility for oligonucleotides.

    Enabling continuous recycling of side-cuts (mixed fractions of impurities and API), can typically decrease solvent consumption by more than 30% compared to single-column batch purification. MCSGP thus improves sustainability during the purification step. Furthermore, this unique technology leads to attractive economic benefits due to automation. In regular batch processes, achieving target purity often comes with a decrease in yield and productivity. MCSGP runs 24/7 providing high product yield without a negative impact on purity, with potential for further savings in cycle time of up to 70%, compared with some batch chromatography methods.

    About Bachem

    Bachem is a leading, innovation-driven company specializing in the development and manufacture of peptides and oligonucleotides.

    With over 50 years of experience and expertise Bachem provides products for research, clinical development and commercial application to pharmaceutical and biotechnology companies worldwide and offers a comprehensive range of services.

    Bachem operates internationally with headquarters in Switzerland and locations in Europe, the US and Asia. The company is listed on the SIX Swiss Exchange.

    For further information, see


    Click on Innovation transforming Oligonucleotide Manufacturing to learn more.
    Click on Bachem continuous chromatography  to watch webinar.
    Click on Bachems News to see latest News & Events.


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    Bachem’s transformational oligonucleotide manufacturing innovations

    Bachem continuous chromatography equipment for API purification.

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