By Bachem AG
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Bachem develops advanced oligonucleotide capabilities to serve future markets
Bubendorf, Switzerland: – Bachem AG is showing its prowess and agility as a leading CDMO provider of peptides and oligonucleotides by developing new oligomer chemistry and manufacturing capabilities that anticipate future market trends.
The therapeutic usage of oligonucleotide based drugs is growing and extending beyond rare diseases to chronic indications. As the market demand for oligonucleotide therapeutics keeps increasing, they raise challenges of scalability, sustainability and cost.
Recognizing these new realities, Bachem is driving innovation by investing in new oligo manufacturing capacities to meet future customer needs. With its GMP-qualified equipment, Bachem is able to develop and manufacture oligonucleotide-based API in partnership with customers, complemented by the support of exceptional analytical chemistry teams, and underpinned by Bachem’s well-established expertise in developing and validating test methods for large and structurally complicated molecules.
Industry challenges in oligonucleotide API development
As a new therapeutic modality, oligonucleotides present numbers of regulatory challenges for agencies and pharmaceutical companies. So far, neither the International Council for Harmonization (ICH) nor the U.S. Food and Drug Administration (FDA) have published guidelines for the specifications of oligonucleotides quality expectations. Nor has any consensus been reached on reporting thresholds for impurities identification and qualification.
This is partly because the nature of oligonucleotides makes them inherently complex to characterize, as well as the impurities that exist as mixtures of closely related molecules of the target API and become challenging to separate during chromatography purification. Furthermore, there is a lack of analytical methods to accurately resolve these impurities.
Bachem is aware of these challenges and anticipates an evolution of the quality expectations and standards. Based on its observations, it has put technologies in place to deliver improved impurity profiles accompanied with the required analytics:
Established expertise in peptides is a significant advantage because of the many similarities between oligonucleotides and peptides. Bachem’s world-class TIDES team is used to building in-depth know-how based on past experiences in the production of peptide-based commercial APIs.
Continuous chromatography benefits
Maximizing yield and quality in a sustainable, streamlined way has always been important for API production. Continuous processes are the perfect method to tackle these challenges in large-scale manufacturing.
Bachem has set up the first continuous chromatography system, a MCSGP (Multicolumn Countercurrent Solvent Gradient Purification) technology, for center-cut purification at industrial scale. The innovative MCSGP technology represents significant progress in the downstream processing for peptides and oligonucleotides, allowing higher capacity at typically 30% lower solvent consumption. It reaches the target purity of the product often with a higher yield, typically 10 % more, compared to a conventional single-column batch purification. It is a scalable, highly efficient and cost-effective process – particularly for large scale production. It is also an automated system, which can run 24/7, significant decreasing purification campaign cycle times.
An additional benefit is that MCSGP is a more sustainable process. It reduces solvent consumption and process mass intensity (PMI). Finally, MCSGP deploys standard chromatographic conditions, and API quality is not adversely affected by changing from batch to continuous mode. This technology increases capacity, quality and sustainability of the purification process.
Mass spectrometry (MS) characterization for accurate product identification
High-resolution MS is the most efficient method to analyze and identify modified or non-modified oligonucleotides. Our team of experts implemented ultra-high-resolution MS for peptides that we transferred for oligonucleotides analysis and characterization. With our powerful equipment and software, we are able to characterize complex oligonucleotides and collect the accurate mass of the molecule. Our system enables the identification and quantification of impurities.
Bachem has also successfully developed a very handy and precise method to help customers with their control over Chemistry, Manufacturing and Control (CMC) development. Based on its ultra-high-resolution electrospray ionization Mass Spectrometry (ESI-MS), Bachem has developed a direct infusion ESI-MS/MS for a robust and specific sequence confirmation method.
Bachem CMC risk mitigation
During drug development, it is crucial to ensure that the product is safe, effective and of consistent quality. CMC involves these activities by defining manufacturing practices and product specifications. Bachem can thus offer its partners, a clear plan for developing the CMC of peptide and oligonucleotide-based drug substances, offering its customers a risk-mitigated approach to any clinical and commercial milestones.
The Bachem drug development process for new chemical entities (NCEs) is based on interactions with regulatory authorities and sponsors around the world to provide a general plan that is adaptable and can be custom-tailored to every project.
Bachem accompanies its customers through all clinical phases up to market approval with an analytical approach tailored to individual needs. Its extensive analytical expertise is reflected in full portfolio of analytical services needed to ensure successful product development and extended life cycle, including:
- Method Development / Method Validation
- Stress Tests / Forced Degradation
- Stability Studies (Hold Time, Developmental, ICH, Follow UP Stability Studies (FUST))
- Impurity identification, characterization and profiling
- Characterization of aggregation / higher order structure
- Reference standard qualification
- Nitrosamine determination
- Genotoxic impurity assessment and analysis
Bachem offers various support solutions for the compilation of regulatory documentation for oligonucleotide APIs, based on its international experience and meeting customer needs at any stage of the product lifecycle.
Molecular Hiving™ technology
Bachem has signed an exclusive Licensing Agreement for Molecular Hiving™ technology from partner Jitsubo Co., Ltd.. Under the License agreement, Jitsubo transfers selected manufacturing processes using Molecular Hiving™ technology to Bachem, which then undertakes further optimization, scale up and production for commercial applications.
Bachem’s very broad analytical know-how has set industry standards for peptides, now being extended into oligonucleotides. This background in peptides is a key asset in innovating and transforming oligonucleotide manufacturing.
Over several decades, Bachem has implemented new, innovative engineering solutions to optimize the scalability, sustainability and cost-effectiveness of peptide manufacturing to provide the highest API quality. As a proof of quality and compliance, Bachem’s cGMP facilities are regularly inspected and approved by national and international regulatory authorities like FDA, Swissmedic and others.
Based on its world-leading know-how, Bachem can now offer a full range of CMC development services for oligonucleotide-based API starting with the establishment of scalable manufacturing processes and ending with IND and NDA applications supported by in-house regulatory affairs specialists.
Looking to the future, Bachem is constructing ultra-modern manufacturing plant for oligonucleotides that will expand its production capacities by 2024, making the company ready to address the capacity challenges revolving around oligos targeting large patients’ populations. Innovation in this field is one of our Bachem’s top priorities, enabling it to provide more complex molecules with superior quality and cost structures.
Bachem is a leading, innovation-driven company specializing in the development and manufacture of peptides and oligonucleotides. The company, which has over 50 years of experience and expertise, 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 www.bachem.com.
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