Semaglutide is a GLP-1 agonist (glucagon-like peptide 1), marketed by Novo Nordisk as Wegovy for weight loss and Ozempic for type 2 diabetes.

To say these medications are popular is an understatement. Novo Nordisk cannot keep up with demand. The same goes for Eli Lilly that markets tirsepatide (Zepbound for weight loss and Monjaro for type 2 diabetes.

The FDA publishes a drug shortage list. That list currently has 131 entries. It includes atropine sulfate injection, cefotaxime injection, and lidocaine injection. Drugs go in and out of this list. For example, the shortage of mannitol was resolved. Same with mepivacaine injection.

If a medication is on this list, federal law allows compounding pharmacies to make “essentially a copy.”

Semaglutide and tirzepatide are currently on that list. This allows compounding pharmacies to get in the game. But not without limitations.

The FDA sent warning letters to some entities selling compounds with similar sounding names – but a different compound. Such as semaglutide sodium salt. The sodium salt is probably effective, but that’s not how it was tested to gain FDA-approval. And there are some entities, particularly online, selling complete fakes.

But there are legal versions of GLP-1 agonists medications that can be and are purchased from reputable compounding pharmacies; pharmacies that follow state and federal laws, and only dispense via a health care provider prescription.

Some background. Compounding pharmacies come in two varieties. 503 A and 503 B.

503 A pharmacies are state licensed pharmacies and physicians.

503 B pharmacies are federally regulated outsourcing facilities regulated by the FDA.

The 503 B regulations emerged after 2012 meningitis / epidural abscess outbreak connected to compounded epidural steroid injections. 503 B pharmacies address medications for IV or intrathecal use.

Semaglutide is injected subcutaneously, so it does not require 503 B scrutiny.

The compounding pharmacies must obtain the active ingredients from FDA-registered facilities, which adhere to Current Good Manufacturing Practices (cGMP). This secures quality, efficacy, and safety.

So, the compounded versions are not “FDA approved.” But they are “FDA-allowed” as long as the medications are on the shortage list. And as long as the compounding pharmacy follows a number of rules.

Note, GLP-1 agonists can be addressed by either 503A or 503B compounding pharmacies. Notably, a 503 B pharmacy has an additional layer of regulation (by the FDA) and may provide an additional level of quality assurance.

What else can prescribing physicians do (or patients request)? They can request a Certificate of Analysis from the compounding pharmacy. This ensures the compound is what it purports to be. 

Also, some nomenclature. Some entities are marketing generic semaglutide. Generic semaglutide does not yet exist on the market. (A generic drug is one whose original patents have expired, allowing third parties to manufacture and sell it – the semaglutide patents and the others are still very much in force).

How is this stuff actually made?

Actual semaglutide for human use, as furnished by Novo Nordisk, is produced by first engineering yeast cells to make the underlying peptide. That product is quite similar to naturally occurring GLP-1, but with some key modifications. The first six amino acids at the N-terminus of GLP-1 are gone, and the alanine at position 8 is changed to the unnatural dimethyl version (Aib, 2-aminoisobutyric acid) – that’s to prevent enzymatic breakdown by the DPP-IV enzyme in vivo. A lysine at position 28 is switched out for an arginine, which leaves another lysine at position 26 free to be modified with a long fatty-acid/ethylene glyol-like chain, which improves the drug’s half-life in the blood even more (by binding to serum albumin). That side-chain modification is done chemically after purifying the underlying peptide from the fermentation step, and you can be sure that that process, along with the yeast expression DNA sequence, the fermentation conditions, and the purification steps have been pretty well tuned up by the Novo Nordisk folks. 

It’s certainly not an impossible process to duplicate, but it’s not a casual synthesis either, and you wouldn’t try it without the financial motivations that we see at the moment. And there are other ways to make the drug, likely somewhat more expensive or harder to scale, at least for now, as a look at the patent literature will show you. You don’t have to do the fermentation, for example, since peptides of this size can be made by straight synthesis, but if I were frantically trying to supply my most profitable product at the largest scale available I would certainly want cultured cells doing as much of the work as possible. I don’t know who’s making the sodium salt form or what process they’re using, although it’s surely very close to the regular semaglutide routes. 

The compounding pharmacy workaround to address a medication shortage is helpful, as long as it’s done properly. Derek Lowe, writing on science.org, summarized the conundrum eloquently.

So it’s a confusing landscape out there. My guess is that a significant amount of the stuff coming from the compounding pharmacies is not quite Ozempic, since there’s not enough of that to go around at the moment, and in some cases it may be even worse than that. There is truly no way for the patients involved to know what they’re getting in such cases, which is where the libertarian “let ’em try it” position starts to break down. The barriers to verification by the end users are just too high, which is why we have the bureaucratic, expensive, often infuriating supply chain regulations that we have. Because the alternative is you pay someone to send you a syringe full of stuff – cloudy, maybe a slightly different color than the last one, and with a different return address on the package this time – and you roll up your shirt and inject it under your skin anyway. And you see what happens.

What do you think?

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Dr. Jeffrey Segal, Chief Executive Officer and Founder of Medical Justice, is a board-certified neurosurgeon. Dr. Segal is a Fellow of the American College of Surgeons; the American College of Legal Medicine; and the American Association of Neurological Surgeons. He is also a member of the North American Spine Society. In the process of conceiving, funding, developing, and growing Medical Justice, Dr. Segal has established himself as one of the country’s leading authorities on medical malpractice issues, counterclaims, and internet-based assaults on reputation.

Dr. Segal was a practicing neurosurgeon for approximately ten years, during which time he also played an active role as a participant on various state-sanctioned medical review panels designed to decrease the incidence of meritless medical malpractice cases.

Dr. Segal holds a M.D. from Baylor College of Medicine, where he also completed a neurosurgical residency. Dr. Segal served as a Spinal Surgery Fellow at The University of South Florida Medical School. He is a member of Phi Beta Kappa as well as the AOA Medical Honor Society. Dr. Segal received his B.A. from the University of Texas and graduated with a J.D. from Concord Law School with highest honors.

In 2000, he co-founded and served as CEO of DarPharma, Inc, a biotechnology company in Chapel Hill, NC, focused on the discovery and development of first-of-class pharmaceuticals for neuropsychiatric disorders.

Dr. Segal is also a partner at Byrd Adatto, a national business and health care law firm. Byrd Adatto was selected as a Best Law Firm in the 2023 edition of the “Best Law Firms” list by U.S. News – Best Lawyers. With over 50 combined years of experience in serving doctors, dentists, and other providers, Byrd Adatto has a national pedigree to address most legal issues that arise in the business and practice of medicine.