Novo May Have Just Built the Case to End Compound Semaglutide

I’m starting to believe that semaglutide will be added to the FDA’s Demonstrable Difficulties for Compounding list.

That may sound like a dramatic prediction, but it is the conclusion I reached after reviewing a document we recently uncovered (January 12th, 2026) regulatory filing submitted by Novo Nordisk to the U.S. Food and Drug Administration. The document reads like a technical supplement to the company’s earlier petition, but buried inside it is a collection of laboratory findings that could reshape the entire debate over compounded semaglutide.

If regulators accept Novo’s argument, the era of widespread compounded semaglutide could come to an abrupt end.

The filing does not simply criticize compounding practices. It attempts to demonstrate that semaglutide itself may be inherently difficult to compound safely.

Before we go any further, it is worth saying something that many readers may disagree with. The evidence Novo presented will almost certainly be interpreted very differently depending on where someone stands in the compounding debate. Supporters of compounding will see selective data gathered by a company protecting its market. Critics of compounding will see laboratory results that confirm their long held safety concerns. The truth may ultimately lie somewhere in between, but the regulatory implications are very real.

The FDA maintains what is known as the Demonstrable Difficulties for Compounding list, commonly referred to as the DDC list. Drugs placed on that list are considered so complex to formulate that pharmacies cannot reliably reproduce safe and effective versions through traditional compounding. Once a drug is added to the list, compounding pharmacies operating under both 503A and 503B authorities effectively lose the legal pathway to produce that medication at scale.

Novo Nordisk’s submission is an attempt to convince regulators that semaglutide belongs on that list. Eli Lilly and Company is pursuing a similar strategy with tirzepatide, its blockbuster dual GIP and GLP-1 therapy marketed as Mounjaro and Zepbound, by urging regulators to recognize the drug’s complexity and the risks associated with large scale compounding. Both pharmaceutical giants appear to be making parallel regulatory arguments aimed at limiting compounded versions of their medications by demonstrating to the FDA that these peptide drugs present inherent challenges that pharmacies cannot reliably overcome through traditional compounding processes.

Testing the Supply Chain

The company’s filing outlines a series of laboratory analyses performed on both semaglutide active pharmaceutical ingredients and finished compounded products obtained from across the supply chain. Novo argues that these analyses reveal a pattern of impurities, structural peptide variations, and potency inconsistencies that suggest the molecule is unusually difficult to reproduce reliably outside the company’s tightly controlled manufacturing process.

One detail in the filing stands out because of where the tested ingredients originated.

Several of the semaglutide API samples Novo analyzed came from manufacturers appearing on the FDA’s Import Alert 66-80 “Green List.” The Green List was created by the FDA as a way to allow certain foreign API suppliers to continue shipping ingredients into the United States without automatic detention at the border. Placement on that list indicates that the agency has evidence suggesting those manufacturers appear to follow current good manufacturing practices.

In other words, Novo Nordisk is not claiming these impurities came from obscure research chemical suppliers on the internet. The company says it detected them in semaglutide ingredients sourced from manufacturers the FDA itself had already allowed into the U.S. supply chain.

Despite that status, Novo Nordisk reports finding notable impurity levels in semaglutide APIs originating from those suppliers. In one case, the company detected roughly 0.46% unknown peptide related impurities in material sourced from a Green List manufacturer. Another sample reportedly contained about 0.38% unknown peptide impurities along with structural peptide alterations involving amino acid additions. A third supplier’s material showed approximately 1.33% unknown peptide related impurities along with truncated peptide fragments and elevated high molecular weight protein aggregates.

For a biologically active peptide drug like semaglutide, those types of variations can matter because the molecule interacts directly with hormone receptors in the body. Even relatively small structural differences can affect how the drug binds to receptors, how long it remains active in the bloodstream, or how the immune system responds to it. Novo’s argument is that these differences introduce uncertainty that could translate into reduced effectiveness, unexpected side effects, or immune responses that would not occur with the approved drug.

What Novo Found in Compounded Products

The findings become more striking when the company turns to testing finished compounded products.

In one compounded sample, Novo reports detecting semaglutide at roughly 302% of the labeled strength, meaning a patient expecting a standard dose could receive more than three times that amount. At the opposite extreme, a compounded sublingual tablet reportedly contained only 0.4% of the labeled semaglutide, essentially delivering almost none of the intended medication. Another compounded injectable product reportedly contained 86.2% peptide related impurities, including roughly 29% tirzepatide and tirzepatide related impurities, despite being labeled as semaglutide.

Novo also reported detecting oxidized peptide fragments, semaglutide aggregates, truncated peptide chains, and formaldehyde related adducts in certain samples. In some cases those altered molecules accounted for the majority of what was present in the formulation, suggesting that much of the material in the vial may not have been intact semaglutide at all.

For patients, variability of that magnitude could translate into dramatically different experiences with what appears to be the same medication. One patient might unknowingly receive a dose far stronger than intended, increasing the risk of severe gastrointestinal side effects or other complications. Another patient might receive so little active drug that the treatment appears ineffective, even though they believe they are taking the same medication as someone else.

Those are the types of findings Novo Nordisk is using to argue that semaglutide may simply be too complex to compound reliably at scale.

The Green List detail strengthens that argument because it shifts the conversation away from the idea that quality problems exist only among fringe suppliers. If impurities and structural variations appear even in APIs produced by manufacturers the FDA has allowed to ship ingredients into the United States under its import framework, Novo can argue that the difficulty lies not only with individual suppliers but with the inherent complexity of the molecule itself.

That distinction is central to the company’s case for adding semaglutide to the DDC list.

Different Manufacturing Paths

The filing also revisits a technical difference between branded semaglutide and the APIs commonly used in compounded formulations. Novo Nordisk manufactures semaglutide using recombinant DNA technology in yeast cells, a fermentation based process that involves genetically engineered microorganisms producing the peptide. Compounded versions of semaglutide generally begin with chemically synthesized peptide APIs produced by third party manufacturers.

Novo argues that those different manufacturing pathways can produce different impurity profiles and structural variants, which could affect the drug’s stability and behavior in solution. The company uses that distinction to reinforce its broader claim that replicating semaglutide outside its proprietary production system introduces risks that are difficult to control.

For paid subscribers:

The manufacturing scrutiny surrounding Novo’s Catalent facility adds a deeper and more complex layer to this story.

Also, see how the compounding industry is responding to this information.