5th mRNA Process Development & CMC Summit

• Investigating intrinsic yield loss mechanisms in linear DNA UF/DF that are not universally resolved by operational optimization alone
• Demonstrating plasmid-specific limitations of UF/DF through mechanistic analysis of flow-induced elongation and protein–DNA interactions
• Redesigning downstream processes by decoupling protein removal and buffer exchange, introducing HIC to improve robustness while enabling further optimization

Key questions include:

• What are the most persistent challenges you face in reducing dsRNA impurities, and where are current purification approaches falling short?
• How are you balancing regulatory expectations for low impurity levels with the technical limitations of existing purification technologies?
• Which purification strategies, platforms, or resins have shown the most promise, and where do gaps still remain?

• Establishing robust process characterization strategies for LNP formulation and fill-finish operations to enable consistent product quality through Phase II/III and commercial manufacturing
• Sharing approaches to scale microfluidic mixing and downstream purification workflows while maintaining critical quality attributes including particle size, encapsulation efficiency, and potency
• Aligning analytical methods, comparability packages, and control strategies with evolving global regulatory expectations for commercial mRNA therapeutics and vaccines

• Utilizing emerging single-particle analysis techniques to complement ensemble analysis and detect heterogeneity in mRNA loading into LNPs, mRNA-LNP size, and cell transfection efficiency
• Improving characterization to feedback into into mRNA-LNP manufacturing processes to optimize process conditions, reduce empty LNP populations and enhance overall product consistency
• Establishing characterization-based improvement of process consistency and product quality to reduce dose requirement and improve safety profile of enhanced mRNALNP potency, to inform more robust, scalable and purification-aware CMC strategies

• What are the most persistent challenges you face in reducing dsRNA impurities, and where are current purification approaches falling short?
• How are you balancing regulatory expectations for low impurity levels with the technical limitations of existing purification technologies?
• Which purification strategies, platforms, or resins have shown the most promise, and where do gaps still remain?

• Exploring how enzyme-free purification strategies can overcome key manufacturing bottlenecks in circular RNA development while improving scalability, recovery, and product purity
• Discussing the commercial and CMC implications of reducing purification complexity, lowering cost-per-dose, and minimizing supply chain dependency across clinical-tocommercial manufacturing
• Sharing early regulatory, process development, and scale-up considerations from advancing circular RNA therapeutics toward first-in-human studies

Key questions include:

• Are current circRNA purification strategies fundamentally overcomplicated – and where can we simplify without compromising quality?
• How do you balance purity, yield, and scalability when designing purification processes for clinical and commercial manufacturing?
• What will define a “fit-for-purpose” purification platform for circRNA as the field moves toward first-in-human and beyond?