We are all watching the rise of oral, small molecule GLP-1 receptor agonists with justified interest. The promising phase III results of Eli Lilly’s orforglipron has set the pace, and others are following close behind. However, the success of oral, non‑peptide GLP‑1s will not be determined solely by convenience or patient preference, but by whether these candidates can match peptide GLP‑1s on efficacy and safety while being manufacturable at scale. The real question is whether the clinical efficiency of GLP-1 peptides can be delivered through the simpler, cheaper, and more scalable supply chains of small molecules. If that happens, it will be because chemistry, manufacturing, and controls (CMC) made it possible.
Peptide GLP-1s have transformed metabolic care, but they have also exposed production limits that are difficult to overcome quickly, especially when demand surges. The issue is not scientific novelty; it is manufacturing physics.Large-scale solid-phase peptide synthesis (SPPS) is capital-intensive, solvent-hungry, and difficult to push toward commodity scale. Industry benchmarking places typical peptide processes at roughly 13,000 kilograms of input per kilogram of API (active pharmaceutical ingredient). This is an order of magnitude higher than small molecules, which average 168 to 308 kg of input per kilogram of API, and even above many biologics that hover around 8,300 kilograms of input per kilogram of API. SPPS also demands heavy chromatographic purification, and involves solvents such as DMF and NMP, which are under regulatory scrutiny for toxicity and sustainability. Process intensification can help, but experience so far suggests that the efficiency gains flatten sooner than in typical small‑molecule chemistry.
The manufacturing math with oral GLP-1 peptides is even tougher. Because the bioavailability of oral semaglutide is on the order of one percent, oral use demands far more API per patient than injections. For example, the oral regimen being studied for obesity is a daily dose of 50 milligrams, while injectable semaglutide is given weekly as low as 2.0 milligrams. If adoption of oral semaglutide grew widely, total API demand would skyrocket, further stressing peptide manufacturing capacity.
This is why small molecule alternatives deserve serious attention from anyone thinking about GLP‑1 access at population scale. If small molecules can match the efficacy and tolerability of GLP-1 peptides, we could manufacture with the small-molecule playbook: robust synthesis routes, cheaper inputs, well‑understood solid-form control, and site-to-site transfer techniques that have been proven over decades.
At the same time, it is important to keep our feet on the ground.Some programs have stalled on efficacy or safety, such as Terns’ disappointing phase II readout or Pfizer’s discontinuation of danuglipron due to concerns around liver toxicity. Oral GLP-1 small molecules are not guaranteed winners, because they must still clear exposure, liver safety, and gastrointestinal-tolerability hurdles.
So, what will decide whether these small molecules shift the GLP-1 landscape? Ultimately, they must clear the same high bar on efficacy and safety and stand up to rigorous CMC scrutiny. On the CMC side, three areas will matter most:
Addressing low solubility and low permeability. Most oral GLP-1 small molecules have low solubility and permeability, making absorption inefficient. Early mapping and control of the solid-state landscape, including polymorph and salt screening, particle-size management, and robust biorelevant dissolution testing, can increase bioavailability and reduce the API required per dose. Beyond easing manufacturing cost and supply pressure, this also reduces the metabolic load on the liver, a factor linked to tolerability challenges in this class.
Design routes for large volumes. Route selection should consider not only laboratory efficiency but also atom economy on scale, supply chain resilience, and early nitrosamine risk assessment. Stress testing, rapid impurity profiling with LC/MS, in-line process analytics, and plate-based mini-DoEs from the outset help ensure that the chosen route passes regulatory scrutiny and can be scaled reliably.
Determine real safety margins for stability and impurities. Incorporate forced degradation studies early and develop robust stability-indicating analytical methods. Dedicate time to mapping impurities, so that unwanted surprises don’t occur later in the process. Upfront efforts to define the safety and impurity profile of the small molecule streamlines later scale-up, technology transfer and regulatory review.
Patient preference for oral dosing is genuine and important for adherence, but convenience alone will not sustain market success unless the manufacturing economics also support broad and affordable access. These preferences matter, but administration format on its own will not decide which products succeed at scale. Peptide innovation is not standing still. Longer-acting injectables with less frequent dosing are steadily advancing, and some patients will accept a weekly pen over a daily tablet if the outcomes are better and side effects diminished. The strongest argument for small molecules is economic and operational. If a daily small molecule can deliver comparable results, we can produce far more doses per reactor-hour, at lower cost, in more locations. That improves access and reduces the supply fragility we all witnessed when GLP-1 demand exploded.
It’s likely that both modalities will have a place in the future of the industry. Peptide GLP‑1s validated the biology but encountered manufacturing limits as demand surged. Small molecules fix the issues with large-scale production but will likely require higher API dosages to match the efficacy of peptides. In the end, the difference for both approaches lies in disciplined, industrial chemistry.
As a chemist who has spent much of my career at the interface of analytical science and manufacturing, I see this next chapter of GLP-1s primarily as a manufacturing story. The true innovation will not be the molecule alone, but how we make it reliably and affordably at a scale that reaches every patient who needs it.
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