GLP-1 (glucagon-like peptide-1 receptor agonists) drugs have been the focus of most of the public discussion. However, our concerns about mass compounding are categorical rather than specific to GLP-1s. They are also reinforced by a recent FDA statement (here) that reflects the agency’s mounting concerns on this topic.
Here is why:
Not All Types of Compounding Are the Same
Compounded drugs are made by altering, mixing, or combining ingredients in a prescription medicine so a person can take the drug when they require a different dosage or form. This is legal, necessary, and honorable when the compounding is intended for an individual patient, addresses shortages, or fulfills certain hospital and specialty care needs.
Outside of these situations, “mass compounding of commercially available drugs” is not permitted by law (i.e., producing copies of FDA-approved products when not covered by an FDA shortage designation). This is because FDA considers compounded medicines as “unapproved drugs” that are exempt from strict drug safety rules due to their limited intended use.
Yet–in the case of GLP-1 weight loss drugs–mass-compounding continues, despite FDA declaring an end to the shortage of the branded drugs a year ago.
The result is a situation never anticipated by regulators: a loosely regulated market in which untested, unapproved drugs compete with FDA-approved drugs (both branded and generic) that have undergone clinical testing, obtained FDA approval, and bear labels that include safety risks (here).
This two-tier system inadequately protects consumers. In addition, it fosters fraudulent marketing, represents a threat to FDA’s authority, and could have far-reaching consequences for R&D, regulation, and marketing (here). This has led three prominent FDA law firms to recently issue client advisories urging clients to re-evaluate any mass-compounding activities and refrain from making false claims in advertising (here, here, and here).
Safety of FDA-Approved Versus Mass Compounded Drugs
For FDA-approved products, manufacturing is regulated by a comprehensive statutory infrastructure, with significant safety guardrails. These include using ingredients from FDA-approved and inspected facilities, following good manufacturing practices, and requiring adverse events to be reported. Moreover, the regulatory framework relies on corporate compliance and is enforced by expert FDA inspectors. If there is an issue, a company receives a much-feared Form 483 (Inspectional Observations) (here) or a warning letter.
In contrast, “manufacturing” of compounded products is overseen by state boards of pharmacy and relies on pharmacist compliance rather than corporate compliance.
Although some adjustments have been made, the regulatory system is largely based on the premise that compounding involves a single licensed pharmacist modifying a drug for a specific individual. This is in sharp contrast to regulatory oversight of manufacturing.
By design, comprehensive safety guardrails are not a major focus in compounding because the assumption is that compounding is limited in scope.
Unapproved Drug-Drug Combination Products Do Not Create “Individualization”
A number of compounders have started dispensing GLP-1s in combination with other drugs, such as cyanocobalamin (Vitamin B-12) and pyridoxine (Vitamin B-6). The rationale is that the combination of drugs provides a medical or material advantage not present with the commercially available GLP-1 drug alone. As a result, it is claimed, without clinical evidence, that this practice constitutes beneficial individualized treatment.
Leaving aside that this new trend is a thinly veiled approach to justify mass compounding of commercially available products, the practice raises serious concerns for consumer, patient safety, and safe medicine use advocates.
Notably, FDA’s rules for approval of drug-drug combination products are exacting. A company seeking approval for such a product would be required to demonstrate that the combination is safe, effective, and more beneficial than the two substances given separately. Yet mass compounders are assuming, without testing or FDA review, that the combination is okay to manufacture.
Advocates of “personalization” ask: “What is the problem?” After all, compounding pharmacists who provide individual treatments create such compounds all the time, drawing on their knowledge of drug products and their overall compounding experience.
However, there is an important difference. Under the law, a patient requiring a compounded GLP-1 with a separate ingredient like Vitamin B12 added for a medical purpose, would be treated and monitored closely by a physician and a pharmacist jointly under FDA’s individual needs exception.
Yet this is not what mass compounders are doing. Instead, telehealth platforms and med-spas promote the wellness and longevity benefits of adding vitamins and specific ingredients to GLP-1s without telling consumers that these combinations have not been studied, that there are potential safety risks from off-label use, and that monitoring is needed. This is receiving renewed focus in FDA’s latest statement on restrictions to mass compounding of GLP-1 products (here).
Interpreting Two Recent Compounding Studies from Name-Brand Manufacturers
There are two recent manufacturer-generated studies on the safety and efficacy of compounded GLP-1 products. Note: We do not argue that either study is definitive, only that they are hypothesis-generating and deserve further investigation.
The first study is from Novo Nordisk (here, h/t to David Knapp for reporting on it). It finds that the semaglutide active pharmaceutical ingredients (APIs) from importers on FDA’s green list often have high impurity levels and that dosage strengths ranged from roughly 302% to 0.4% of the labeled strengths.
We should all want to know: what is the normal deviation and variability in the finished Novo semaglutide manufactured products compared to the same specs for mass-compounded semaglutide products? Is the difference sufficiently great to support an FDA finding that semaglutide is demonstrably difficult to compound?
We don’t know the answer, just that it should result in a more formal investigation by FDA or a neutral third party
The second study, from Lilly (here and here), finds that the combination of tirzepatide (branded or mass-compounded) and B12 produces a byproduct or impurity not present in either drug alone. While this is a small study, it highlights the risk of combining two products without medical justification or clinical trials. In this case, the combination includes a mass-compounded ingredient and creates a drug-drug combination that does not remotely meet FDA review standards.
In Summary
When compounding is used to treat individual needs or to alleviate documented shortages, it is an important professional activity.
Mass compounding of a commercially available product is another story altogether. It is not legal. Furthermore, compared with the manufacturing of FDA-approved branded and generic drugs, mass-compounded products are untested, uninspected, underregulated, and unproven, posing a threat to patient safety.
FDA exists for a reason. When the agency doesn’t fully enforce the Food, Drug, and Cosmetic Act, we are all vulnerable to unsupported product claims and clever marketing that plays on our dreams of quick, effective, and cheap solutions.
Individualized and shortage compounding are necessary exceptions to the FDA’s standards. Mass compounding of commercially available drugs is not.
