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How did Medicines For All Institute design a low-cost synthesis route without adding complexity?

 

Industry:

Pharmaceutical process development and API manufacturing (pharma / CDMO)

Challenge:

Enzyme reuse can be the main economic lever, but conventional impeller mixing may mechanically damage supported (immobilized) enzymes. In M4ALL’s public description, protecting the enzyme may require extremely slow stirring, which increases operational fragility and can limit practical reuse.

Key results:

  • Potential raw material cost reduction $260/kg → $160/kg
  • Operational constraint addressed: reduce dependence on extremely slow stirring to protect supported solids
  • Multi-batch use reported without adding new enzyme

 

About the project

When the pandemic accelerated demand for COVID antivirals, the team at Medicines for All Institute (M4ALL) set out to make molnupiravir (MK-4482, EIDD-2801) affordable at scale. The goal was simple, reduce the cost of producing a high-quality API so access would not be limited by manufacturing economics.

M4ALL’s approach was to build a low-cost, two-step route from cytidine, using process intensification principles to keep unit operations down, favor common solvents, and avoid unnecessary isolations.

Early on, the route looked promising, but a major cost driver emerged, the polymer-supported lipase enzyme Novozyme 435 represented roughly half of the estimated raw material cost, which was about $260 per kg.

What made enzyme immobilization difficult in practice?

The next step was to make enzyme recycling practical without destroying the supported catalyst. Conventional stirring created mechanical stress, and the process demanded extremely gentle agitation to avoid decomposition.

How did reactor design enable protected mixing and catalyst reuse?

This work showed a clear lesson from that period, when the cost and sustainability of a biocatalytic route are constrained by catalyst handling, reactor design can be the difference between an attractive lab result and a scalable process.

In practice, teams running immobilized-enzyme processes often run into constraints like

  • Attrition and particle damage from impellers, baffles, and high shear, which can reduce activity and create fines that complicate filtration.
  • Mass-transfer limits when teams slow down agitation to protect the solid, which can reduce reaction rate and increase cycle time.
  • Poor mixing in viscous or multiphase systems (slurries, immiscible liquids, gas-liquid reactions), where gentle stirring leads to gradients and inconsistent performance.
  • Scale-up fragility when lab conditions rely on very specific impeller speeds, liquid levels and careful solids handling that is hard to reproduce at plant scale.
  • Operational losses around solids handling: settling, channeling, clogging, and difficult solid recovery between batches, especially when reuse targets increase the number of handling steps.

The RBR reduces these constraints by separating mixing intensity from mechanical stress on the immobilized solid, improving robustness without sacrificing performance.

Further Reading:

What difficulty is your team facing when scaling immobilized enzyme processes?

If your team is developing or scaling an immobilized enzyme or supported catalyst process and catalyst breakdown, reuse, or raw material cost is limiting progress, explore how protected catalyst mixing in an RBR can help you reduce mechanical damage and enable practical recycling.