The growing need for oligonucleotide therapeutics aimed at larger patient populations has driven the demand for high-quality nucleoside phosphoramidites – the building blocks for oligonucleotide therapeutics. To support the emergence of synthetic oligonucleotide therapeutics, the Food and Drug Administration (FDA) and European Medicines Agency (EMA) have recently provided more clarity in regulatory expectations. In 2024, the FDA published a guidance that described the clinical pharmacology requirements while the EMA’s guidance focused on manufacturing and control of synthetic oligonucleotides. The recent EMA guidance reiterated the principles per International Conference on Harmonisation (ICH). This guidance reinforces the regulatory expectations of analytical rigor and process robustness needed for starting material by highlighting ICH Q9 Quality risk management and ICH Q11 Guideline on development and manufacture of drug substances. ICH Q11 is referenced in the context of starting materials selection, and Q9 is referenced to highlight how the benchmarking of certain impurities (referred to as “critical impurities” in the guidance) impacts process development. The guidance went on to list the specific analytical considerations, including impurity characterization, control of raw material quality, and batch-to-batch consistency. Per EMA’s guidance, “particular attention should be paid to differences in levels of critical impurities compared to pre-clinical batches” in the regulatory filing. The guidance went on to list the specific analytical considerations, including impurity characterization, control of raw material quality, and batch-to-batch consistency.
Without clearly defined impurity profiles, drug developers face increased scrutiny by health authorities as the clinical program advances. This is particularly important for regulatory starting materials, where data transparency is often lacking. The lack of consistent impurity profiling and data transparency complicates the assessment of product quality. These uncertainties in the lack of impurity data can lead to variability in the final oligonucleotide DS, increasing the complexity of managing process development and ensuring compliance with regulatory expectations.
WuXi TIDES has developed precise, data-driven analytical methods that enable reliable impurity identification, control, and documentation, providing drug developers with the essential tools to navigate regulatory requirements and progress confidently from development to market. By thoroughly analyzing impurity sources and implementing rigorous quality assessments and manufacturing processes, we ensure that materials consistently meet the high standards required for both clinical and commercial production.
Supporting Development Pipelines through Data Transparency
For oligonucleotide therapeutics, critical impurities are key impurities that can impact the final drug substance (DS) by interfering with synthesis, leading to variations in mass and/or structure. The levels of starting material-derived impurities are determined by both critical impurity levels and the frequency with which product-related impurities are incorporated. While some critical impurities can be detected based on mass deviations from the DS molecular weight, others introduce structural impurities with identical molecular weights to the DS.
Our extensive and in-depth analytical data set allows us to develop robust manufacturing processes that ensure batch-to-batch consistency and scalability for clinical and commercial applications. Taking the 2’-OMe amidite series as an example, an essential modification in all FDA-approved small interfering RNA (siRNA) drugs, we applied our analytical methods to benchmark impurity profiles from commercially available products sourced from two leading suppliers in comparison to our own product. Examining 2’-OMe C(Ac) amidite (CAS No. 199593-09-4), we identified and quantified critical impurities present and matched them to the corresponding impurities found in the synthesized oligonucleotide product. The results from our analysis revealed that both external vendor products each respectively contain three critical impurities above our limit of detection (less than 0.02%), whereas the WuXi TIDES product is absent of impurities that transfer to the final oligonucleotide product above the limit of detection. Additionally, the purity of our product was the highest among the tested samples, achieving 99.5% across three reproducible batches.
A Trusted Partner for Oligonucleotide Discovery, Development, and Manufacturing
As oligonucleotide therapeutics expand into broader clinical applications, maintaining stringent quality, impurity control, and regulatory compliance is essential. WuXi TIDES simplifies regulatory submissions for our customers by documenting select amidite products and PMO monomers in Drug Master Files (DMFs)— comprehensive FDA filings that provide detailed records of our manufacturing and quality control processes.
In addition, our quality standards ensure that drug developers meet the regulatory requirements not only for US markets, but for successful therapeutic development across global markets.
Moreover, access to modifications beyond the traditional building blocks used in FDA-approved oligonucleotide therapeutics is paving the way for the discovery of new candidates targeting underrepresented indications. WuXi TIDES Catalog Products now offers over 600 amidite products, available for direct purchase online, with select amidites stocked globally in the US and Europe. By offering a broad portfolio of high-quality building blocks, WuXi TIDES Catalog Products enables drug developers a seamless progression from discovery research to commercial manufacturing. With WuXi TIDES, every step of the oligonucleotide drug development process is backed by the expertise and resources needed to bring innovative therapies to market efficiently and confidently.
Table 1. Critical impurities in 2′-OMe C(Ac) amidite samples and their corresponding impurity in the final oligonucleotide.
Figure 1. Three reproducible batches of STA-AM10015 (2′-OMe C(Ac) amidite) at multi-kg scale with labeled non-critical impurities above detection limit.
About WuXi TIDES
WuXi TIDES, part of WuXi AppTec, is a unique Contract Research, Development and Manufacturing platform. WuXi TIDES offers our partners efficient, flexible, and high-quality solutions from discovery through the commercial supply of oligonucleotides, peptides and related synthetic conjugates (“TIDES” drugs).
WuXi TIDES has more than 1,000 scientists across 10 R&D and manufacturing sites, offering discovery synthesis, process development and manufacturing of novel monomers, linkers and ligands, oligonucleotides, peptides and complex synthetic conjugates at any scale. Beyond chemistry, we offer formulation development, manufacturing, packaging, labeling and distribution in a variety of oral & injectable dosage forms and filling formats. Our comprehensive analytical method development, validation and testing platform supports TIDES drug development from discovery through clinical to commercial for both drug substance and drug product. Moreover, our regulatory dossier preparation teams are experienced in global fillings of TIDES molecules with all major regulatory agencies.
Visit our website – tides.wuxiapptec.com
This advertorial includes internal data and analyses for informational purposes only. It is provided “as is” without any express or implied warranties. WuXi TIDES does not guarantee the accuracy, completeness, or suitability of the information contained within.
