Compounded GLP-1 Potency Variation: What Lab Testing Actually Shows

This matters because GLP-1 medications require precise dosing. Patients receiving 42% of their intended dose may experience minimal therapeutic benefit, while those receiving 170% face increased risk of severe gastrointestinal side effects, pancreatitis, or other adverse events.

Injectable compounded semaglutide products showed similar inconsistencies. Testing from legal cases revealed products containing 12% to 20% less than their labeled potency, with strength variations occurring even between batches from the same clinic.2

The 32 Impurities Finding

Beyond potency variation, Liquid Chromatography Mass Spectrometry (LC-MS) testing identified 32 impurities across six bulk "semaglutide" drug substances that are not present in the semaglutide used in FDA-approved medicines.3

These impurities were found in synthetically produced bulk drug substances—the raw materials compounding pharmacies use to make finished products. The concern isn't that impurities exist (all manufactured drugs contain some), but that these specific impurities haven't been characterized for safety in humans.

Subvisible Particles and Trace Metal Contamination

Testing also revealed significantly higher concentrations of subvisible particles (between 0.1 and 10 micrometers) in compounded semaglutide compared to FDA-approved products.3 These microscopic particles, while invisible to the naked eye, can trigger immune responses when injected.

Research has shown that subvisible protein particles in this size range have the potential to cause immunogenic reactions—meaning the body may develop antibodies against the medication, potentially reducing its effectiveness over time.4

Additionally, trace metal contamination (particularly iron, copper, and magnesium) was detected in compounded bulk semaglutide samples. While the levels found have not reached concentrations likely to cause immediate harm, research indicates these metals can accelerate the formation of high molecular weight proteins—essentially causing the medication to aggregate and degrade more quickly.3

The Salt Form Question

Many compounding pharmacies have marketed products containing "semaglutide sodium" or "semaglutide acetate"—salt forms of the molecule that are chemically different from the semaglutide base used in FDA-approved medications.5

The FDA's December 2023 warning letter specifically noted that products containing semaglutide salts may not work the same way as approved semaglutide products, and the agency has not evaluated whether these salt forms are safe or effective.6

Adverse Event Comparison: Context Matters

From August 2021 to March 2024, the FDA received 210 adverse event reports for compounded semaglutide products, compared to over 20,000 reports for FDA-approved semaglutide.7

This data requires careful interpretation. The lower number of compounded reports could reflect several factors, including smaller patient populations using compounded products during much of this period, the fact that compounding pharmacies are not required to conduct adverse event surveillance, and patient and prescriber unawareness of reporting mechanisms.

The FDA explicitly warned that "adverse events from compounded versions of these drugs are underreported" and noted significant variation in data quality among reports received, with reports coming only from 503B outsourcing facilities (not traditional 503A compounding pharmacies).8

Why Semaglutide Is Difficult to Compound

Semaglutide is a 31-amino-acid peptide with a complex three-dimensional structure. Unlike small molecule drugs where the active ingredient can be relatively easily synthesized and formulated, peptides present inherent manufacturing challenges:

Synthesis complexity: Each amino acid must be added in the correct sequence with proper stereochemistry. Errors can create impurities with similar but not identical structures.

Stability issues: Peptides are inherently unstable and sensitive to temperature, pH, and handling conditions. The fatty acid chain attached to semaglutide (which extends its half-life) adds additional stability considerations.

Formulation challenges: Creating an injectable solution that maintains sterility, proper pH, and stability over time requires sophisticated quality control that may exceed typical compounding pharmacy capabilities.

Testing limitations: Proper characterization of peptide drugs requires analytical methods (like LC-MS) that many compounding pharmacies don't routinely perform on every batch.

Regulatory Status Update: February 2025

The FDA resolved the semaglutide shortage in February 2025, removing the regulatory pathway that had permitted compounding of essentially copies of Ozempic and Wegovy.9 As of May 22, 2025, compounding pharmacies may no longer produce copies of these FDA-approved products.

However, compounding under certain circumstances remains legal, including patient-specific prescriptions where the FDA-approved product is not appropriate for an individual patient. The distinction between legally permitted patient-specific compounding and now-prohibited bulk compounding of copies remains a subject of ongoing regulatory attention.

What This Means for Patients

The potency variation data presents patients with a practical challenge: without independent testing, there's no way to know whether a specific compounded product contains what it claims.

For patients who used compounded GLP-1 medications during the shortage period, the data suggests that inconsistent results—either better or worse than expected—may have been partially attributable to potency variation rather than individual response to the medication.

For patients considering compounded products going forward (where legally available), understanding the documented quality variation enables more informed discussions with healthcare providers about risk-benefit trade-offs, particularly around cost savings versus quality assurance.

The testing data doesn't prove that all compounded semaglutide is problematic—some products may be perfectly well-made. Rather, it demonstrates that the compounding process introduces variability that doesn't exist with FDA-approved manufacturing, and current quality control measures may not consistently catch these variations before products reach patients.