Overcoming RNA Bottlenecks

March 25, 2025

RNA-based therapeutics are revolutionizing medicine, but manufacturing at scale presents formidable challenges. One of the most critical challenges is achieving consistent, high yields during large-scale production. Variability in RNA synthesis, purification, and process efficiency can lead to batch failures, increased costs, and delays in development timelines.

As your end-to-end CDMO partner specializing in RNA, we recognize that traditional scale-up approaches often introduce inefficiencies. Instead, our work with Quantoom Bioscience’s Ntensify platform leverages a “scale-out” strategy to ensure reproducible and high-yield RNA production.

In today’s blog, we explore the key hurdles in high-scale RNA manufacturing and how a scale-out approach can overcome them.

Why Consistent Yields Are Challenging in RNA Manufacturing

RNA production involves complex enzymatic reactions, delicate purification steps, and stringent quality control requirements and here, several factors may contribute to manufacturing variability.

• Enzymatic Reaction Efficiency: RNA synthesis relies on in vitro transcription (IVT), where even slight deviations in enzyme activity or raw material quality can impact output.
• Scalability Issues: Traditional batch-based IVT processes may not scale linearly, leading to inconsistent yields when moving from research-scale to GMP production.
• DSP loss: Each downstream purification step, including chromatography and filtration, risks reducing overall RNA recovery.
• Process Variability: Inconsistencies in reaction conditions and buffer compositions will significantly affect product yield

Scaling Out Instead of Scaling Up: A New Approach

 Scaling up RNA manufacturing by increasing batch size delivers diminishing returns. Instead, we adopt a scale-out modular approach, utilizing Quantoom Bioscience’s Ntensify platform.

 Advantages of Scale-Out Manufacturing

1. Consistent Yields
   Modular units run under identical, optimized conditions, ensuring reproducibility and batch-to-batch consistency.
2. Maximum Yield Control
   Multiple small runs allow precise optimization, avoiding efficiency drops typical in large reactors.
3. Faster Tech Transfer
   No need to revalidate larger scales.
4. Reduced Risk
   Decentralized production means a single batch failure won’t derail timelines. More control, fewer setbacks.

How We Ensure High Yields with Scale-Out Manufacturing

1. Process Optimization for IVT Efficiency

We fine-tune IVT conditions by:

• Using optimized enzyme formulations and nucleotide mixes tailored for high-yield reactions.
• Implementing real-time monitoring of reaction kinetics to adjust parameters dynamically.
• Leveraging automated systems to ensure precise reagent addition and reaction timing.

2. Enhancing Purification to Maximize RNA Recovery

We minimize purification losses by:

• Utilizing high-efficiency chromatography techniques to improve RNA recovery rates.
• Using a one step purification process, with Silica-based Magnetic Capture for binding, washing and elution
• Critical process parameters are tested and implemented

3. Leveraging Real-Time Data Analysis for Yield Assurance

We ensure consistent yields by:

• Systematically collecting process data at critical checkpoints throughout manufacturing.
• Using advanced data analysis to identify trends and potential deviations early.
• Applying predictive modeling to adjust process parameters proactively and maintain optimal performance.

The Future of RNA Manufacturing: Consistency at Scale

The demand for RNA-based therapies is rapidly growing, making it critical to address manufacturing challenges. Achieving consistent yields in high-scale production requires innovative thinking, moving away from traditional scale-up limitations and embracing scalable, modular solutions.

At Exothera, we combine deep RNA expertise with cutting-edge technologies like the Ntensify® platform to ensure reliable, high-yield production. By embracing a scale-out model, we help biotech, pharma, and research organizations overcome manufacturing challenges and accelerate the development of life-changing RNA therapies 

Let’s build the future of RNA manufacturing together. Contact our team to learn how we can support your high-yield production needs.

Authors: Barbara Cornelissen, Marketing Director, Exothera & Ashiqul Haque, Technical Lead Vaccine Development, Univercells Group

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.