Executive Summary

For RNA therapeutic programs targeting UK and EU submissions, developing a phase-appropriate potency assay strategy is a primary determinant of regulatory success. A single, static assay is insufficient. The approach must evolve, reflecting the mechanism of action (MOA) from early non-GxP research through to validated GxP-compliant assays supporting an Investigational Medicinal Product Dossier (IMPD). This requires a deep understanding of how to measure intended biological activity – whether protein expression for an mRNA therapeutic, target knockdown for an siRNA, or functional correction for a tRNA therapy – while building a data package that satisfies MHRA and harmonized ICH requirements. Franklin Biolabs utilizes its >100,000 sq ft GxP-compliant facilities to support the typical 18-24 month path to IND submission.

Aligning Potency with Mechanism of Action for RNA Payloads

The potency of an RNA therapeutic is a direct measure of its intended biological function. For an mRNA payload delivered via a lipid nanoparticle (LNP), this is typically the quantity and activity of the translated protein. For an siRNA, it is the specific knockdown of a target transcript. A scientifically sound potency assay strategy must be directly reflective of the therapeutic’s specific MOA.

Regulatory bodies, including the MHRA, expect more than simple quantification of the RNA molecule. The analytical method must confirm the functional activity of the therapeutic. This distinction is important, as a robust potency assay provides the functional data to complement safety and toxicology assessments, ensuring the product’s biological activity is well-characterized.

Evolving Assay Requirements from Preclinical to IMPD Submission

A potency assay strategy must be dynamic, adapting to the increasing regulatory scrutiny at each stage of development.

• Early Discovery/Preclinical: In vitro cell-based assays are typically employed to screen candidates and confirm MOA. These assays prioritize throughput and relative comparisons over absolute quantification and are performed in a non-GxP environment.

• IND-Enabling Toxicology: As a program enters formal IND-enabling studies, the potency assay must be refined. Method qualification begins, establishing performance characteristics like precision, accuracy, and linearity. The assay is used to confirm the activity of toxicology batches, ensuring the material tested is representative of future clinical lots.

• IMPD/Clinical Phase: For clinical manufacturing, the assay must be fully validated under GxP conditions. It becomes a release test for every batch, with pre-defined acceptance criteria. The development of high-sensitivity, validated assays for biological markers in patient-derived matrices serves as a strong template for creating these robust methods (PMID: 39282076).

Our analytical laboratories are equipped to support this entire lifecycle, from custom assay development to full GxP validation for multi-jurisdictional submissions.

Building a Data Package for Global Regulatory Alignment

While this focus is on MHRA requirements for an IMPD, a successful strategy anticipates global needs. By adhering to ICH guidelines, the potency assay data package can be leveraged for submissions to other agencies, such as the FDA. This involves meticulous documentation, rigorous validation, and a clear scientific rationale connecting the chosen analytical method to the RNA therapeutic’s clinical application.

This forward-looking approach minimizes redundant testing and accelerates global clinical development timelines. It ensures the analytical methods established for the first clinical trials are scalable and robust enough to support the program through commercialization.

The analytics and CMC strategy is a foundational component of the overall program, directly integrated with the work detailed in our Vector | CMC | Analytics Services.