Why mRNA quality control is still stuck in the central lab

An mRNA production run moves through a series of steps. The mRNA is made, purified, formulated and filled. At several points along the way, someone needs to know whether the material is what it should be. Is the mRNA intact? How much is there? Is it free of impurities?

The methods that answer these questions are well established, and regulatory guidance names them. Almost all of them live in a specialised analytical laboratory.

The workhorse methods

The European Medicines Agency’s 2025 draft guideline and the World Health Organization’s 2022 regulatory considerations both describe the kinds of methods used to test mRNA.^{1 2}

Integrity by size separation. To measure the share of full-length molecules, the mRNA is separated by size. In capillary gel electrophoresis, the sample is driven through a thin, gel-filled capillary by an electric field, so shorter fragments and full-length molecules arrive at the detector at different times. Agarose gel electrophoresis works on the same principle in a slab of gel. The EMA draft names both, along with ion-pair reversed-phase HPLC, for determining the proportion of intact mRNA in the finished product.¹

Chromatography. High-performance liquid chromatography (HPLC) separates molecules as they pass through a packed column. Several kinds appear in the EMA draft: ion-pair reversed-phase HPLC for degraded mRNA and other product-related impurities, anion-exchange and size-exclusion HPLC among the options for RNA content, and HPLC with charged aerosol detection for the lipids in the formulation.¹ WHO gives size-exclusion, anion-exchange, affinity and reversed-phase methods as examples.²

And more. RNA content is measured by UV absorbance or fluorescent dye assays, particle size by dynamic light scattering, and functionality by cell-based assays that confirm the mRNA is taken up by cells and translated into the right protein.¹

Why these tests sit in a central lab

None of these methods is exotic, and each is the right tool for its job. But they share features that keep them in a dedicated quality control lab.

• Instruments. Capillary electrophoresis and HPLC systems are specialised equipment that has to be installed, maintained and qualified.
• People. Running these methods, and interpreting what comes out, takes trained analysts.
• Validation and standards. Methods used for release have to go through formal method validation. The EMA draft expects reference standards where needed, for example to confirm the correct length of the transcript when testing integrity.¹
• More than one method. WHO recommends orthogonal methods, meaning different techniques applied to the same attribute, because different methods can give different results.²

This is not a criticism. It is what makes release data trustworthy. But it means that a question asked on the production floor becomes a sample in a queue.

The methods are excellent. The bottleneck is where they live, and how long a routine question waits for them.

Characterisation, release and everything in between

WHO draws a useful distinction. Characterisation studies are in-depth investigations that are not performed on every lot. In-process and lot-release tests, by contrast, are performed on every lot.²

Release testing will always need the full analytical toolkit. The in-process questions are different. A process engineer deciding whether purified mRNA is fit to move on to formulation needs a timely, reliable answer to a narrower question.

WHO also asks manufacturers to develop tests and acceptance criteria for critical steps of the manufacturing process, so that those checks provide feedback on process control.² The value of that feedback depends on how quickly it arrives.

When every check runs through the central lab, one of two things happens. Either the batch waits for the answer, or the process moves ahead and risks adding the cost of formulation and fill to material that later fails. Neither is good for a manufacturer, and both get harder as the number of products and sites grows.

Where this is heading

WHO’s guidance already treats mRNA integrity as a critical quality attribute for release,² and the EMA’s draft guideline carries it through to stability and shelf life.¹ That direction will not change, and it should not. What can change is how quickly routine in-process questions get answered, and by whom. We think that gap is worth closing, and that it can be closed without taking anything away from the central lab’s role at release.

Footnotes

1. European Medicines Agency, Committee for Medicinal Products for Human Use. Guideline on the quality aspects of mRNA vaccines (draft). EMA/CHMP/BWP/82416/2025, 27 March 2025. ema.europa.eu ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶

2. World Health Organization. Evaluation of the quality, safety and efficacy of messenger RNA vaccines for the prevention of infectious diseases: regulatory considerations. Annex 3, WHO Technical Report Series No. 1039, 2022. who.int ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶

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