Webinar: Developing Processes for Successful Clinical-Grade mRNA Manufacturing

December 11, 2024 by Aldevron

Process Development for Clinical Success

The complexities of process development for successful clinical-grade mRNA manufacturing provide a challenge for developers, and how to meet that challenge was the focus of our webinar, Developing Processes for Successful Clinical-Grade mRNA Manufacturing.

Featuring Venkata Indurthi, Chief Scientific Officer at Aldevron, and Nathan Lee, Senior Director of CMC at Poseida Therapeutics, the webinar covered how producing high-quality mRNA suitable for clinical applications requires intricate process development.

It all begins with understanding the manufacturing aspects of mRNA and self-amplifying RNA (saRNA) rather than their design. Indurthi emphasized the importance of the process development for production of clinical grade mRNA, with an overview of the crucial components of mRNA:

• 5' Cap
• 5' Untranslated Region (UTR)
• Coding Region
• 3' UTR
• Poly (A) tail

Indurthi also referenced self-amplifying RNA, which includes an additional replicase region. saRNA can amplify itself once inside a cell, leading to higher protein output with lower doses, but the larger size of saRNA poses unique challenges in optimizing purity and recovery during manufacturing.

Manufacturing Challenges and Solutions
mRNA manufacturing is inherently complex due to the molecule's sensitivity. Indurthi pointed out that key decisions in the capping and tailing processes can impact the quality and yield of mRNA. He elaborated that capping can be performed either enzymatically or co-transcriptionally using cap analogs, while tailing can be encoded or added post-transcriptionally. Also emphasized were the considerations for mRNA process development:

• Purity
• Impurities
• Critical Process Parameters
• Modified Nucleotides
• Capping Technology

Process Development Strategies
Two case studies were referenced during the webinar. The first dealt with self-amplifying RNA with enzymatic capping, which faced challenges with a low full-length purity product and poor recovery rates. Through diligent process development, yields increased by 95% and final FLP was improved by 50%. Key improvements included optimizing purification conditions and transitioning to a one-part IVT and capping reaction.

For the second case study, Lee discussed projects that aimed to improve low IVT yield and FLP percentages. By optimizing IVT conditions and refining enzymatic tailing methods, significant improvements in both yield and purity were achieved.

During the Q&A session, the audience engaged with the presenters on various aspects of mRNA production, seeking detailed insights into the case studies and Aldevron's capabilities in supporting mRNA process development. The presenters elaborated on the optimization of mRNA production, highlighting advanced chromatography techniques and process enhancements.

Key topics discussed included oligo dT affinity chromatography, fed-batch IVT processes, and the quality attributes of mRNA. For a comprehensive insight into the discussion and more details, watch the full video.

Watch the on-demand webinar, Developing Processes for Successful Clinical-Grade mRNA Manufacturing

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tl;DR: The webinar highlighted the importance of tailored process development for mRNA manufacturing. The sequence and size of the construct, reaction parameters, and downstream conditions all play critical roles in achieving high-quality mRNA.

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