Four Major Steps Involved in mRNA Manufacturing

November 16, 2022 / by Nate Spangler, Ph.D.

From potential to solution

For more than two decades, in vitro transcribed (IVT) messenger RNA (mRNA) has been considered for its potential to address unmet medical needs and to transform the development and manufacture of medicines. This potential was suddenly realized by the unprecedented response to Covid 19, ushering in a new era in the application of mRNA technologies to solve challenging health problems.

Therapies and vaccines based on IVT mRNA represent exciting frontiers in medicine and manufacturing, which I touch on here and in several following posts.

Messenger and self-amplifying RNA

For the development and manufacture of therapies and vaccines, two types of IVT mRNA are widely used: conventional mRNA and self-amplifying mRNA (SAM or saRNA). Manufacturing processes for both are similar but the approaches taken must be tailored to the idiosyncrasies and applications of each. saRNA constructs are much larger and more susceptible to degradation in production, while conventional mRNA can have more stringent purity requirements due to higher dosages.

Steps of a New Manufacturing Program
The transition of IVT mRNA production from preclinical to clinical use generally involves four major steps:

1. Process exploration and design or tech transfer
2. Scale-up process development
3. At-scale engineering run in cGMP
4. cGMP manufacturing

Step 1 can begin with the sponsor’s bench-scale method or none at all, and the output will be a robust and scalable process design to deliver consistent product quality attributes in preclinical, clinical, and commercial stages of manufacturing. Activities performed concurrently with Steps 1 and 2 include development and qualification of product/sponsor-specific release tests, and the production of master cell bank and linear DNA template starting materials for mRNA synthesis by IVT. These parallel efforts converge at the engineering run (Step 3) followed by cGMP manufacture of the first batch of mRNA for human use in Step 4.

How long does all this take?
The four-step path spans about 8-9 months, and timelines have been reduced by half for urgent programs. This exemplifies a key advantage of IVT mRNA: its production is simpler, more scalable, and more easily expedited than for other types of drugs and vaccines.

For new mRNA programs entering the clinic, aggressively short timelines driven by sponsor urgency are common. This is a challenge because the duration of early steps can vary depending on the sponsor’s readiness plus other risks factors such as supply shortages. Regarding the supply of linear DNA template and process enzymes for IVT mRNA production, our ability to make these critical materials under the same roof and quality system is a significant, risk-mitigating benefit.

In my next post, considerations for and approaches to manufacturing conventional mRNA and saRNA for preclinical through clinical stages of development will be described.

• Want to learn more? Contact Nate Spangler with your questions
• Watch Nate's presentation, Self-amplifying and messenger RNA for Vaccines and Therapies
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• Visit the mRNA section of our website