Taking mRNA’s Measurements

November 13, 2024 by Nate Spangler, Ph.D.

Analytical Challenges in mRNA Therapeutics

As I discussed in prior posts (listed below), messenger RNA (mRNA) technology is creating new possibilities for disease prevention and treatment. Promising applications include prophylactic and therapeutic vaccines, cell therapy, protein replacement, gene editing, and more. Consequently, new mRNA-based medicines are rapidly entering clinical stages of development, necessitating a unified approach to defining quality attributes and analytical testing procedures.

In response to this need, health agencies, quality experts, and regulatory bodies are working to establish quality standards. The World Health Organization (WHO) published an "evaluation of mRNA vaccine quality, safety, and efficacy” in 2021; this was soon followed by draft guidelines from the United States Pharmacopeia (USP).

Now in its second edition, the USP guidelines include methodologies for both mRNA drug substance (DS) and drug product (DP), as well as analytical approaches to lipid nanoparticles (LNPs). More recently, the European Medicines Agency (EMA) began developing a comprehensive guideline on the quality aspects of mRNA vaccines.

This will encompass materials, control strategy, product specifications, potency testing, LNP composition, and stability studies. EMA guidance will also address challenges for testing more complex mRNA vaccines like bivalent, multivalent, and self-amplifying, as well as those using non-LNP delivery systems.

To ensure the safety and efficacy of mRNA-based medicines, health authorities mandate comprehensive testing. Data demonstrating identity, quality, purity, potency, and stability are necessary for all phases of development, and requirements increase according to the phase.

Traditional methods can be suitable for quality testing, but the unique properties of mRNA and LNPs are analytically challenging. mRNA is complex and susceptible to degradation. Identification and quantification of product and product-related impurities can be difficult, especially when encapsulated within LNPs, and when there are multiple mRNA components.

LNPs vary in size, charge, and other properties. There is also variation in the possible reactions between lipid impurities and mRNA. Limitations of established test methods can include lack of specificity, inadequate sensitivity, slow processing, and high cost.

These analytical challenges are being addressed with solutions, such as microfluidics for the detection of microbial contaminants, and long-read sequencing to ensure mRNA identity and integrity. Innovations that simplify testing workflows, decrease time, and improve sensitivity will be crucial to unlocking the full potential of next-generation mRNA-based medicines.

• Have questions on this topic? Contact Us
• Visit the mRNA section of our website
• Read Streamlining mRNA Production
• Read When Less Is More
• Read A Focused Approach
• Have an idea for a topic? Let us know!

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