Main Conference Day 3Thursday, 5 November 2026 - Europe/Amsterdam

This presentation outlines a risk‑based downstream impurity control strategy for therapeutic oligonucleotides that integrates impurity assessment with process design. Clearance of oligonucleotide‑related impurities, small‑molecule and potentially carcinogenic byproducts, residual solvents, and endotoxin are demonstrated through two orthogonal chromatography steps and a UF/DF operation. Microbial control considerations for liquid drug substance, including endotoxin management and hold‑time strategies, are also addressed.

Recent clinical successes have established targeted covalent inhibitors as a viable strategy in drug discovery, demonstrating their ability to target the so-called ‘undruggable’ proteome where conventional non-covalent molecules often fail. However, the development of covalent ligands to new targets remains a significant challenge, primarily due to the lack of large, diverse, and ready-to-use covalent libraries, impeding the development of novel lead compounds. We addressed this bottleneck by developing a new method for high-throughput solid-phase synthesis of short peptidic compounds that all carry a covalent warhead. Towards this end, we established synthesis procedures compatible with the introduction of reactive electrophiles such as acrylamides, chloroacetamides, sulfonyl fluorides. The peptides are produced in 384-well plates and are released at high purity that omits throughput-limiting purification. Using a combination of non-natural amino acids and non-amino acid building blocks, we synthesized a diverse library of 85,000 sub-kDa peptidic covalent compounds. The library and screening approach was validated in high-throughput screens with the model target thrombin that identified several potent covalent inhibitors. Recently, we applied the strategy to the challenging protein-protein interaction (PPI) targets Keap1-NRF2 and -catenin-TCF that identified potent and selective covalent inhibitors based on the sulfonyl fluoride warhead.

AstraZeneca has set very ambitious climate change targets within Ambition Zero Carbon. Linear solid-phase peptide synthesis (SPPS) presents significant sustainability challenges for longer peptides, characterized by declining stepwise yields and substantial carbon footprints that scale unfavorably with sequence length. Fragment-based synthesis offers a compelling solution to these challenges, enabling improved yields and facilitating liquid-phase synthesis, which offers enhanced process efficiency and reduced environmental impact. However, unlike small-molecule synthesis, peptide route design lacks standardized methodologies for fragment selection. This presentation introduces a systematic route-design framework for peptide synthesis that addresses three selection parameters: condensation site selection, fragment length, and number of fragments. By applying computational screening criteria based on these parameters, we dramatically reduce the complexity of route evaluation. A case study will be shared to demonstrate the applicability of the approach.

Therapeutic peptides (<40 aa), including amylin analogues, are key for metabolic and weight management, improving post‑prandial glucose and regulating appetite. Regulators expect identity verification using multiple orthogonal tests, but extra tests increase burden. We present a risk-informed approach using cagrilintide (AM833) to rationalize a two-test scheme. Evaluating LC–MS, UPLC, NMR, bioactivity, and CD, we propose UPLC retention time plus LC–MS intact mass as sufficient identity assurance, enabling compliant quality control.

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For many years, SPPS has relied on highly swellable polystyrene resins, DMF as solvent, carbodiimides as coupling reagents, and TFA for global deprotection, making the process unsustainable. To address these, we propose developing novel resin architectures that enable reduced solvent consumption and/or facilitate the use of more readily recyclable solvents. Furthermore, alternative non-carbodiimide coupling reagents and non-polyfluoroalkyl (PFAS-free) acids for peptide cleavage are explored to improve sustainability. A comparison between SPPS and LPPS will also be discussed.

Multicolumn Countercurrent Solvent Gradient Purification (MCSGP) has emerged as a robust and highly efficient technology for peptide manufacturing. By leveraging automated side-cut recycling, MCSGP significantly minimizes the analytical workload and reduces process turnaround time. In this peptide purification example, development efforts prioritized optimizing process efficiency while ensuring operational robustness and seamless scale-up. To validate the robustness, an extensive multivariate characterization strategy was employed, correlating Critical Process Parameters (CPPs) with Critical Quality Attributes (CQAs) via the establishment of Proven Acceptable Ranges (PARs). Systematic analysis of both univariate process variations and complex multiparameter interactions facilitated the definition of Acceptable Ranges (ARs), thereby ensuring robust, reproducible, and high-purity yields at commercial manufacturing scale.

The implementation of a continuous downstream process presents several challenges. This work focuses on the drying process used to stabilize oligonucleotides through electrostatic drying. This technology was designed to ensure maximum API quality at low solid content in liquid feedstock, while enabling the management of various solvents, including water, with careful attention to utility consumption.

Amid the rapid expansion of RNA therapeutics, conventional solid-phase oligonucleotide synthesis increasingly falls short in scalability and the efficient production of long RNA species such as sgRNAs. Hongene addresses these challenges through a proprietary chemoenzymatic ligation platform, combining blockmer synthesis with engineered enzymes to enable high-purity, cost-efficient manufacturing of siRNAs and sgRNAs. This approach enhances API quality, improves scalability, and supports more sustainable, next-generation RNA therapeutic development.

Next-generation RNA medicines require effective and safe delivery technologies. This presentation will showcase Bayer’s LNP platform, highlighting proprietary ionizable lipids and their application across multiple modalities, including mRNA-based protein expression and in vivo genome editing.

Ensuring the therapeutic performance of phosphorothioate (PS)-modified oligonucleotides requires robust analytical and manufacturing approaches. The PS substitution, used to impart nuclease resistance and improve efficacy, generates a chiral phosphorus centre at each linkage and introduces added complexity to both analysis and control strategy, since clinical material is typically administered as a mixture of P-diastereomers. Because individual diastereomers may differ in pharmacology and biological activity, it is essential to maintain a consistent diastereomeric distribution across drug substance batches to underpin reproducible efficacy. Although maintaining a stable diastereomeric profile is often achieved by holding the coupling activator constant during solid-phase oligonucleotide synthesis (SPOS), it has been proposed that chromatographic purification of single-stranded siRNA can partially resolve diastereomers and risk changing the diastereomeric ratio. From a regulatory perspective, any process change requires an assessment and justification of comparability with respect to the diastereomeric profile. While developing liquid chromatography methods to resolve and quantify diastereomers, we observed that separation is highly sequence dependent, especially influenced by the tendency of single strands to adopt higher-order structures. At AstraZeneca, we demonstrated that substantial diastereomer resolution can occur during strong anion exchange (SAX) purification under specific conditions, creating a potential for altering diastereomer ratios. Our characterisation work connected features of oligonucleotide structure with an elevated risk of diastereomer separation during purification, and thus with a risk of changing the diastereomer distribution. Building on these findings, we outline key considerations for designing a robust, scalable manufacturing process for oligonucleotides and propose mitigations to minimise diastereomeric changes during purification, thereby supporting seamless clinical development without batch-to-batch changes in pharmacological properties. This study illustrates practical analytical and process approaches that enable sustainable scale-up of oligonucleotide therapeutics and streamline regulatory acceptance, ensuring consistent pharmacological behaviour throughout development and commercialisation.

Voxvoganan is a synthetic antimicrobial peptidomimetic designed by applying the principles of natural antimicrobial peptides sharing many of the attractive properties such as wide antimicrobial spectrum and fast antimicrobial action. In contrast to the natural peptides that typically consist of 15 – 25 residues, voxvoganan contains only three amino acids, comparable to a classical small molecule drug, and can be manufactured on an industrial scale using solution phase methods. The talk will highlight both the medicinal chemistry and the industrial production of voxvoganan.

Bicycle Therapeutics' platform leverages small, synthetic, constrained peptides for precision-guided medicine. This modular "plug-and-play" technology enables the creation of diverse therapeutics by attaching various payloads. These include Bicycle® Drug Conjugates (BDCs) like nuzefatide pevadotin, Bicycle® Radioconjugates targeting novel antigens such as MT1-MMP, and oligonucleotide conjugates for muscle and CNS delivery. The platform's versatility, combined with AI-enabled discovery, is rapidly advancing a robust pipeline of novel first in class and best in class treatments

Priavoid develops disease-modifying therapeutics for neurodegenerative diseases. Its all-D-peptide platform targets pathogenic protein aggregation by stabilizing monomeric proteins and detangling aggregates. Building on clinical-stage PRI-002 for Alzheimer’s disease, the platform has identified Parkinson’s disease candidates that reduce α- synuclein pathology and show brain penetration after oral administration in mice.

Characterizing low-abundance, equal-length impurities (e.g., deamination) in oligonucleotide therapeutics remains a significant analytical challenge due to co-elution and MS ion suppression. Here, we present a novel heart-cut 2DLC method, FOCUS (Flow-split Orthogonal Characterization of Unresolved Species) [1], which couples industry-standard IP-RPLC with IP-HILIC [2] to further resolve impurities from the main product peak. Simultaneous UV and HRMS detection is performed across both dimensions, achieving baseline resolution of overlapping species and facilitating quantification. The resolving-power selectivity offered by FOCUS analysis provides a powerful means to accelerate the development of complex oligonucleotide therapeutics and next-generation conjugated modalities.