The therapeutic horizon for genetic medicines is rapidly expanding through next-generation RNA modalities, such as self-amplifying RNA (saRNA), trans-amplifying RNA (transRNA), and circular RNA (circRNA). These RNA modalities offer potential for the development of a broad range of transformative products, from gene, base, or prime editing to immunology and immuno-oncology therapeutics. This session focuses on the Chemistry, Manufacturing, and Controls (CMC) and regulatory strategies necessary to transition these RNA modalities from bench to bedside.

To move beyond the laboratory, these complex RNA-containing modalities require specialized manufacturing frameworks that prioritize structural integrity and purity across all unit operations. This involves navigating product development, manufacturing and controls from R&D to a phase appropriate GMP-compliant production processes while addressing unique product quality, stability, and delivery needs—such as encapsulation into lipid nanoparticles (LNPs) or other innovative systems—to ensure product potency and preserve the intended mechanism of action.

Key discussion topics include:

1. Process Performance and Yield Optimization: Addressing the unique manufacturing yields and purification requirements for structurally distinct RNA classes; examples would include optimization of cell-free DNA synthesis, downstream steps for removal of common impurities such as dsRNA, and assembly/formulation of the product/delivery vehicle (from components/intermediates).

2. Product Quality and Analytics: Method and development approaches to ensure the potency, purity, and identity of novel RNA species.

3. Integrated Formulation and Fill-Finish: Overcoming the challenges of encapsulating diverse RNA species into innovative gene delivery systems, such as lipid nanoparticles (LNPs) or polymeric solutions, while monitoring encapsulation efficiency, RNA stability and particle properties through in-process analytics.

4. CMC Risk Management and Regulatory Readiness: Utilizing formal risk assessments to define Quality Target Product Profiles (QTPPs) and Critical Quality Attributes (CQAs) necessary to establish a robust, IND-enabling CMC package.

Session Speakers:

Using a Risk-Based Approach to RNA Lipid Nanoparticle Development

Jeff Atkinson, Orna Therapeutics, Inc.

Adventures in Making Extreme mRNA Molecules

Aaron Larsen, Crystal NAX, Inc.

Genetic Medicines and Individualized Manufacturing for Everyone

John Schiel, Advanced Research Projects Agency for Health (ARPA-H)

Additional Panelist:

Brian Stultz, CBER, FDA

John Kerwin

Appearances