Overcoming RNA Bottlenecks

March 13, 2025

The road to bringing RNA-based therapeutics to market comes with distinct advantages over traditional biologics, particularly in manufacturing simplicity, scalability, and consistency. Regulatory agencies recognize these benefits, yet the novelty of RNA-based products introduces unique regulatory and CMC challenges that must be carefully navigated. While RNA production benefits from lower process complexity and variability, its pioneering nature means regulatory agencies demand rigorous evidence to ensure product safety, efficacy, and consistency.

As your end-to-end CDMO partner specializing in RNA, we understand how crucial it is to establish a robust regulatory and CMC strategy early in development.

In today’s blog, we explore the key regulatory and CMC challenges in RNA manufacturing and outline concrete solutions to navigate them successfully.

Key Regulatory and CMC Challenges in RNA Manufacturing

1. Evolving Regulatory Landscape for RNA Therapeutics

Regulatory pathways for RNA therapies are still evolving, with agencies like the FDA and EMA continuously refining guidelines. Differences in regional requirements can create complexity for companies seeking global market approval.

Solution:

• Optimize mRNA sequence design— including codon usage, UTR configuration, and nucleotide modifications— to enhance stability and translation efficiency while ensuring regulatory compliance. Demonstrate the safety and functionality of novel modifications, such as pseudouridine, to minimize unwanted immune responses.
• Engage with regulatory authorities early through pre-IND/IMPD meetings to align expectations.
• Stay updated on evolving guidelines and leverage regulatory intelligence to anticipate changes.
• Implement a flexible regulatory strategy that accounts for regional differences and accelerates approval timelines.

2. Defining and Controlling Critical Quality Attributes (CQAs)

RNA-based therapeutics require precise definition and control of CQAs such as purity, integrity, potency, and immunogenicity to meet regulatory standards.

Solution:

• Develop a robust analytical framework with validated assays for RNA integrity, residual impurities, and functional activity.
• Utilize orthogonal analytical techniques, such as LC-MS and capillary electrophoresis, to ensure comprehensive characterization.
• Employ risk-based approaches, such as quality-by-design (QbD), to optimize and standardize manufacturing processes while maintaining control over CQAs.

3. Ensuring Scalable and GMP-Compliant Manufacturing

Transitioning from early-stage research to commercial-scale GMP production presents a major hurdle, as RNA processes must remain reproducible and compliant.

Solution:

• Make process decisions early in development and aim to maintain a consistent manufacturing approach from discovery through to GMP production to enhance efficiency and ensure regulatory alignment.
• Adopt a scale-out approach, such as Quantoom Bioscience’s Ntensify platform – available at Exothera –, which enables modular, GMP-compliant RNA production without compromising consistency.
• Implement robust process validation strategies, including design of experiments (DoE), to ensure reproducibility across batches.
• Integrate real-time process monitoring and in-line analytics to establish in-depth process knowledge and understanding.

4. Addressing Stability and Storage Requirements

RNA’s inherent instability makes long-term storage and distribution challenging, requiring careful formulation and preservation strategies.

Solution:

• Develop optimized buffer formulations, lipid composition and lyophilization techniques to enhance RNA shelf life.
• Utilize ultra-low temperature storage solutions to mitigate degradation risks.
• Conduct extensive stability studies under ICH guidelines to establish clear product shelf-life parameters.
• Select the appropriate lipid nanoparticle (LNP) formulation to optimize mRNA delivery, enhance stability, and control biodistribution, while ensuring compliance with safety, biocompatibility, and regulatory quality requirements.

5. Streamlining Documentation for Regulatory Submissions

Regulatory filings for RNA products require comprehensive documentation, including CMC sections, batch records, and stability data.

Solution:

• Establish structured CMC documentation templates aligned with regulatory expectations and collect development data in a structured traceable way to ensure adhesion to CMC strategy.
• Maintain electronic batch records (EBR) and automated data tracking to streamline submission preparation.
• Conduct internal regulatory audits to ensure readiness for inspections and regulatory reviews.

Building a Strong Regulatory and CMC Foundation for RNA Success

Successfully navigating the regulatory path and addressing CMC challenges requires strategic planning and expert guidance. By proactively engaging with regulators, optimizing manufacturing processes, and ensuring stringent quality control, you can accelerate RNA development and approval.

At Exothera, we provide comprehensive regulatory and CMC support, including preparation for Scientific-Technical Advice meetings, helping our partners navigate these challenges with confidence. Our expertise in RNA manufacturing and testing, combined with innovative technologies like the Ntensify® platform, ensures a smooth transition from discovery to commercialization.

Let’s work together to bring your RNA therapies to market. Contact us today to discuss your regulatory and CMC needs.

Authors: Dmitrii Sorokin, Head of CMC, Exothera and Hanna Lesch, Chief Technology Officer, Exothera

About Exothera

Exothera is a specialized CDMO partner delivering preclinical and clinical process development, manufacturing optimization and CMC support for virus and RNA based therapeutics and vaccines.

 With headquarters in Belgium, at the heart of Europe, we assist clients worldwide from start to scale, up to commercial manufacturing, including analytical testing and regulatory consultation. Thanks to our optimal technologies and experienced team, we help bring innovative therapies from bench to patient with quality, at speed and cost-effectively.