Three Signs Your Synthetic Route Will Collapse at Scale

Red flags in drug development we watch for, Part 2.

A synthetic route can look perfectly serviceable at gram scale: yields hold, impurities appear manageable, the operations seem familiar enough – all’s looking good. But scale has a way of exposing weaknesses that remain invisible in early development. As reaction volumes rise, heat transfer changes, impurity pathways compete differently and operational tolerances tighten in ways that small-flask chemistry can’t reveal. Many routes that behave well in the fume hood fail abruptly once they reach kilo scale. 

At Symeres, our process chemists and impurity-synthesis teams have spent decades watching otherwise promising routes unravel during scale-up. Those experiences taught us to read early data differently. Before a route reaches pilot scale, we look for three recurring red flags – signals that the apparent stability is deceptive and that the process may collapse under real manufacturing conditions.

When a route tolerates almost nothing

The first warning sign is a process that works only within narrow operating windows: strict temperature brackets, rigid pH ranges, exact water activity or precise sequence timing ​(1)​. These restrictions often appear manageable at gram scale but become brittle when multiplied across larger reactors ​(2)​. 

Mechanistically, tight windows usually indicate the reaction is balanced on an unfavourable thermodynamic or kinetic edge. Slight thermal lag at scale can push the system into a side reaction; minor pH variation can accelerate decomposition; trace water can trigger impurity pathways that never appeared in the hood. 

We challenge these sensitivities early. Our teams run parallel scouting experiments, thermal profiling and early impurity modelling to see how the reaction behaves when pushed, not protected. The goal less about proving a delicate route can be followed precisely and more to understand whether it will tolerate the variability inherent in manufacturing. 

When we flag a narrow window, we do it openly and early. Clients consistently cite this transparency as a Symeres strength: problems are surfaced while they are still inexpensive to solve, not after a campaign fails. This openness is a deliberate stance – a route that needs handholding at 50 g will not survive 5 kg.

When impurities grow faster than product

A second red flag is impurity formation that accelerates with scale. Trace species that appear at the 1–2% level in early runs can dominate the mass balance when volumes expand and the reaction environment becomes less forgiving. 

This shift is mechanistically predictable. At scale, even slight changes in mixing efficiency, temperature gradients, or reagent concentration profiles can widen the window for alternative pathways. Some side reactions may have higher activation energy and therefore compete more aggressively once the reaction warms unevenly. Others may be catalysed by trace metals or by-products introduced inadvertently during workup. 

We identify these risks early because impurity synthesis and mechanistic elucidation are built into our development model. Chemists, solid-state teams and analytical scientists interpret impurity profiles together rather than passing them sequentially between departments. This integration allows us to distinguish between ‘impurity noise’ and ‘impurity trajectory’ – and it’s the trajectory that predicts trouble. 

Our customer research reinforces the importance of this approach. Several clients described previous CRO experiences in which concerning impurity trends went unmentioned until batches failed. Symeres’ practice is the opposite: we raise the concern as soon as the pattern emerges, because ignoring it only increases cost and risk later.

When a process depends on‘artisan chemistry’

A third signal is a route whose success depends on operations difficult to reproduce at scale: delicate crystallisations, emulsions that refuse to break, multi-solvent washes that require intuition or highly exothermic reagent additions that only work when executed by an expert hand. 

Chemists might master these manoeuvres on the bench, but they don’t always translate cleanly into controlled manufacturing. Operators can’t rely on judgment calls like “add until it looks right” or “stir until the mixture clears”. If a transformation requires craftsmanship rather than robustness, it’s almost certainly going fail in a plant environment. 

Symeres’ response to artisan operations is simple: redesign, don’t improvise. Our teams stabilise these steps by focusing on process safety first: mapping exotherms, identifying unstable or highly reactive species (e.g., organolithiums), and designing controlled addition and mixing strategies so heat generation never outpaces heat removal at scale. 

This approach reflects our broader model, where medicinal chemistry, process chemistry and CMC disciplines are fully connected. We don’t treat a crystallisation problem as an isolated event but rather evaluated it in the context of material properties, downstream purification and analytically defined control strategies.

Catching scale collapse before it happens

A synthetic route is only as good as its ability to survive scale-up. Narrow windows, accelerating impurities and artisan operations are often predictors of collapse. 

Symeres’ standard is clear: we don’t advance a route unless we believe it’s going to withstand real manufacturing conditions. That means challenging assumptions early, sharing concerns openly and redesigning proactively when the data demands it. This combination of openness, nimbleness and deep expertise is what allows our teams to prevent months of re-engineering later and keep programs moving toward IND with confidence. 

Robust chemistry is measured by whether the chemistry behaves when the stakes – and the volumes – get larger.

References

​​1. D. Levin, Managing Hazardous Reactions and Compounds in Process Chemistry. ACS Symp. Ser., 3–71 (2014). 

​2. E. H. Stitt, M. J. H. Simmons, Process Understanding. 155–198 (2011).