RNA therapeutics are advancing quickly, but many development programs hit the same bottleneck: finding a partner who can scale custom building blocks without compromising quality or timelines. Synthesizing phosphoramidites and modified nucleosides at the milligram scale is straightforward. Delivering grams (or kilograms) while maintaining purity and consistency is a different challenge entirely.
This "scale-up gap" becomes critical as programs transition from early research into preclinical work and clinical trials. Unless your CDMO partner understands how to maintain quality across this scale range, timelines begin to slip.
In this article, we'll explore what actually changes during scale-up and why choosing a partner equipped to manage these complexities has become essential for RNA therapeutic success.
Why is scaling custom RNA building blocks different from scaling catalog compounds?
Scaling custom RNA building blocks differs from catalog compounds because custom molecules require first-time optimization at each scale, while catalog compounds benefit from proven manufacturing processes refined over years.
Custom phosphoramidites and modified nucleosides, by contrast, require route development every time you increase scale. Without established procedures, every scale-up is essentially a first-time synthesis.
At larger volumes, general chemistry challenges intensify:
RNA building blocks then layer on molecule-specific complexities:
They increase, both in concentration and complexity. Impurities that appeared trivial at a small scale often become critical problems at larger volumes. Even small impurities in a phosphoramidite can multiply through sequential coupling steps, compounding to significant levels in the final oligonucleotide.
The shift happens because reaction conditions fundamentally change at scale. Longer reaction times give side reactions more opportunity to occur. Equipment surfaces and heat-transfer differences introduce new impurity pathways. The result: a 10-gram batch's impurity profile often differs substantially from a 100-gram batch unless scale-dependent variables are carefully controlled from the start.
Purification strategies must also evolve. Chromatography works beautifully at lab scale but becomes impractical and expensive during manufacturing. Successful scale-up depends on developing alternative purification strategies: crystallization, extraction, and other methods that work economically at large volumes.
Without this expertise, purity often drops as scale increases, forcing companies into difficult choices: accept lower-quality material, invest months in purification development, or start over with a new partner.
Three in-house analytical tools are essential: HPLC to detect and quantify impurities, LCMS to identify unknown impurities for immediate route adjustment, and NMR to confirm structure and purity at each development stage.
Real-time access to these capabilities enables rapid troubleshooting during scale-up. Outsourced analytics can add multi-week delays for each testing cycle, a lag that's unworkable when teams need same-day information to resolve scale-up issues. The difference between in-house and outsourced analytics often determines whether programs stay on schedule or slip by months.
Equally important: using the same analytical methods from milligrams through kilograms ensures consistency and eliminates variability that method transfers can introduce.
Process development enables successful scale-up by transforming lab routes into economically viable manufacturing processes. Routes that work in a discovery lab often fail when translated directly to manufacturing, making systematic optimization essential at each scale increase.
Route-scouting identifies more practical alternatives for scale, even if they differ from the elegant, research-focused pathways used early on. Process development replaces chromatography with crystallization or extraction, optimizes reaction conditions for larger reactors, and thoroughly characterizes each step to ensure reproducibility.
These optimization decisions compound as scale increases. Solvent selection becomes more complex at manufacturing volumes, and purification strategy can determine commercial feasibility. Partners who understand the molecule early can anticipate these scale-up challenges and guide decisions that prevent costly restarts later.
Integration matters more than equipment lists. Focus on:
GL CHEMTEC is passionate about your success and solving your most complex chemistry challenges. We offer fast, flexible, cutting-edge solutions to take your RNA building blocks from discovery through clinical development. Our commitment to a collaborative partnership means we scale and adapt precisely to meet your evolving needs.
GL CHEMTEC provides: