Manufacturing and Supply Chain

Upstream processing advances • Downstream processing and purification • Scalability • Integrated supply chain • Sustainable manufacturing

Scheduled: February, March, April, May, June, July, September, October, November, December  ·  10 issues

Cross-modality

• How can upstream synthesis and downstream purification be better integrated in parallel process development workflows, and can inline analytics compress the feedback loop between synthesis changes and their purification implications?
• Is lyophilization still a viable final step and what alternatives are emerging?
• How can AI accelerate supply chain management in nucleic acid manufacturing?
• How does the lack of cross-agency harmonization on starting material control and testing standards complicate supplier onboarding, and what would a workable international framework look like?

Oligonucleotides

• With oligonucleotide therapeutics advancing into obesity, diabetes, hypertension, dyslipidemia, MASH, and other large indications, at what scale does solid-phase synthesis become commercially unviable?
• Adopting liquid-phase, hybrid ligation, chemical ligation, and enzymatic synthesis platforms to achieve the scale, cost of goods, and sustainability profile required for large chronic indication programs.
• Can solvent recycling, downcycling, replacement, or in-process reuse strategies meaningfully reduce acetonitrile dependency, and at what volume threshold does recycling deliver a genuine net environmental benefit when full lifecycle costs including transport and energy are modeled?
• Addressing phosphoramidite supply concentration: with export controls and tariff uncertainty reshaping global trade, are vertical integration, onshoring, and dual sourcing realistic near-term responses?
• As enzymatic synthesis accelerates, shifting raw material dependency from phosphoramidites to NTPs, how will the sector scale enzyme supply, reduce costs, and address the limited sourcing options for newer chemistries?
• Will established purification platforms (ion-pairing, AEX, UFDF, lyophilization) retain their regulatory precedent and resolving power as programs scale toward commercial production of large-indication oligonucleotide drugs?
• Exploring the new generation downstream processing roadmap for oligonucleotides: multi-column continuous chromatography, solution API, and the prospect of a chromatography-free future.

mRNA

• What are the current upstream manufacturing challenges limiting the commercial scalability of mRNA therapeutics, and how are advances in cost of goods, sequence design, and molecular stability beginning to address them?
• Addressing dsRNA removal and resin binding capacity limitations as key downstream processing bottlenecks in mRNA manufacturing: what purification strategies are emerging to fill the gap at commercial scale?

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Analytics, AI, and Digital Tech

Process analytical technology • Impurity profiling • Regulatory CMC • AI and machine learning • Digital twins

Scheduled: February, March, April, May, June, July, September, October, November, December  ·  10 issues

Cross-modality

• From monitoring to control: moving PAT beyond passive observation toward active intervention in nucleic acid manufacturing, enabling early failure detection and real-time adjustment of critical quality attributes.
• Identifying rapid analytical techniques capable of providing near-real-time impurity characterization during chromatographic elution.
• What would a genuinely fit-for-purpose analytical validation framework look like for complex nucleic acid therapeutics?
• Applying AI across nucleic acid manufacturing and analytics: from process parameter optimization and reagent consumption prediction to sequence-process correlations, predictive maintenance, and extracting deeper insight from large-scale LC-MS datasets.
• AI digital twins for nucleic acid manufacturing: how far can model-driven process control extend beyond small molecules, and what would early adoption look like for complex oligonucleotide and mRNA processes?

Oligonucleotides

• Is IPRP LC-MS still adequate for purity assessment and identity confirmation, or are current separations fundamentally insufficient for the complex impurity profiles of modern oligonucleotide drug substances?
• Choosing the appropriate analytical strategy for duplex impurities and chemically modified oligonucleotides: when does single-dimension HPLC fail, and how are orthogonal methods, 2D-LC, HILIC, and ion mobility spectrometry filling the gap?
• Leveraging ML for impurity profiling: can AI identify the origins of process-related impurities and accelerate oligonucleotide optimization?
• How feasible is regulatory harmonization across US FDA, EMA, and APAC agencies on analytical expectations for oligonucleotide drug substances, and what would a jointly developed industry-regulator framework need to achieve?
• Characterizing extractables, leachables, and bioburden control during liquid storage as oligonucleotide programs mature toward commercial scale.

mRNA

• Establishing analytical standards for mRNA critical quality attributes as the therapeutic pipeline expands beyond vaccines into more complex applications.
• Can charge detection mass spectrometry advance mRNA characterization beyond the current limitation of RNase digestion, enabling intact molecule analysis of critical quality attributes?

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Formulation and Delivery

Extrahepatic delivery • LNP formulation • Conjugate-based delivery • Endosomal escape • Tissue-specific targeting

Scheduled: February, March, April, May, June, July, September, October, November, December  ·  10 issues

Cross-modality

• As programs expand into cardiovascular, oncology, respiratory, and immune disease indications, can advances in LNP composition and targeting achieve organ-specific delivery across nucleic acid modalities, or is a fundamentally new approach required?
• How are AI and ML tools reducing the experimental burden in LNP formulation design, and can predictive models replace empirical screening?

Oligonucleotides

• Beyond GalNAc: what progress is being made in systemic delivery of oligonucleotides to organs beyond the liver, and can AOCs and peptide conjugates deliver on their promise?
• Exploring strategies beyond transferrin receptor ligands and intrathecal delivery to achieve systemic CNS delivery.
• Assessing intranasal delivery as an underexplored route for CNS and pulmonary applications.
• Addressing endosomal escape: how close is the field to building delivery systems that can both reach the right cell and release their payload with full functionality?
• Addressing off-target effects in extrahepatic delivery: as non-liver programs advance toward clinical translation, how can the field develop consistent standards for characterizing and reporting delivery specificity?

mRNA

• Are LNPs the permanent default delivery system for mRNA therapeutics, or can next-generation lipid engineering and alternative carrier systems eventually enable tissue and cell-specific targeting beyond hepatocytes?

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New Chemistries, Conjugates, and Emerging Modalities

Backbone modifications • Conjugation strategies • Non-coding RNA • Synthetic DNA • Gene editing

Scheduled: February, March, April, May, June, July, September, October, November, December  ·  10 issues

Oligonucleotides: new chemistries and conjugates

• Exploiting new phosphorus chemistry and 2′ substituent modifications to alter oligonucleotide charge, functionality, and activity while avoiding innate immune sensors.
• How does IP-driven innovation in nucleoside chemistry, where competing modifications achieve the same biological effect, affect standardization and regulatory expectations?
• How do conjugation strategy choices between small molecule ligands, peptides, lipids, and antibodies shape synthesis routes, raw material supply chains, and long-term cost of goods?
• Addressing the compounding analytical and physicochemical challenges of characterizing peptide conjugates and AOCs as single entities.
• When does a fit-for-purpose potency assay for AOCs and oligonucleotide conjugates become a fully validated regulatory requirement, and what should it look like?

Emerging modalities

• Exploring non-coding RNA biology: how are advances in microRNA modulation, lncRNA targeting, and selective gene upregulation beginning to unlock this underexplored space?
• Circular RNAs, self-amplifying RNAs, and in vivo CRISPR editing as the next frontier: mapping the manufacturing, analytical, and regulatory challenges that must be resolved before these modalities reach the clinic.
• How does the length and secondary structure complexity of gRNAs complicate manufacturing relative to standard oligonucleotides?
• How are combination approaches pairing oligonucleotides with other modalities expanding the boundaries of what nucleic acid therapeutics can achieve?
• Addressing the regulatory and commercial challenges facing synthetic DNA: GMP classification, cost competitiveness against cell-based processes, and the path toward large-scale adoption.
• Personalized DNA cancer vaccines: what are the key manufacturing, delivery, and biological hurdles standing between current early-phase trials and routine clinical use?

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Preclinical, Translational, and Clinical Development

Preclinical models • Translational tools • Immunogenicity • Toxicology • Clinical updates

Scheduled: March, May, June, July, September, November  ·  6 issues

Cross-modality

• Selecting the most appropriate preclinical model for a given delivery system and route of administration.
• Addressing delivery vehicle accumulation at high dosages: as programs scale toward larger indications, what standardized approaches to characterizing pharmacological and toxicological profiles are needed?
• Assessing the implications of divergent species responses in preclinical models for predicting immune effects in humans.

Oligonucleotides

• How is the transition from non-human primate models toward ex vivo organoids and computational approaches improving the speed and translational relevance of oligonucleotide development?
• How can chemical modification strategies reduce oligonucleotide immunogenicity without compromising activity?
• Exploring advances in tools and approaches for understanding oligonucleotide distribution and clearance.

mRNA

• Positioning mRNA therapeutics for growth across cancer immunotherapy, rare genetic disorders, protein replacement, and regenerative medicine.
• Addressing the unresolved scientific risks in mRNA therapeutics: immunogenicity control, expression durability, and intracellular trafficking.
• Exploring how far post-transcriptional modification can advance mRNA stability to sustain protein expression for weeks or months, while maintaining activity and suppressing innate immune responses.

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