Compounded GLP-1 Potency: What Testing Actually Reveals

The Potency Problem: Documented Variation

When patients receive compounded medications, they expect the labeled dose—0.5 mg means 0.5 mg. But testing of compounded GLP-1 products has revealed significant variability in what patients actually receive.

Independent laboratory testing has documented compounded semaglutide potencies ranging from 68% to 122% of labeled strength—meaning a patient expecting 1.0 mg might receive anywhere from 0.68 mg to 1.22 mg.[1] This 54% variance window has significant clinical implications for a medication with a precisely designed titration schedule.

Novo Nordisk Testing Results

Novo Nordisk, which manufactures the only FDA-approved semaglutide products, has conducted extensive testing of compounded products as part of legal actions and regulatory filings. Their findings reveal concerning patterns:

The sublingual finding is particularly striking: a patient using an oral semaglutide troche labeled at 1 mg/mL would be receiving no active medication at all—explaining why some patients report that sublingual formulations "don't work" compared to injections.

The Impurity Question

Beyond potency variation, testing has revealed that compounded semaglutide often contains impurities not present in FDA-approved products. These differences stem from how the active ingredient is manufactured.

Synthetic vs. Recombinant Production

Novo Nordisk produces semaglutide using recombinant DNA technology—genetically engineering yeast to produce the peptide. This biological manufacturing process produces semaglutide with specific characteristics that are challenging to replicate.[5]

Compounding pharmacies source their active ingredient from chemical suppliers who use solid-phase peptide synthesis—essentially building the peptide chemically, amino acid by amino acid. This synthetic process introduces different impurity profiles.[6]

According to published research, these impurities arise from the solid-phase synthesis process used by generic API manufacturers.[6] Analysis of six different bulk "semaglutide" samples identified 32 impurities not present in Novo Nordisk's FDA-approved semaglutide.[5]

The Immunogenicity Concern

The presence of peptide impurities raises a specific safety concern: immunogenicity—the potential for the body to develop antibodies against the medication.

The FDA's Immunogenicity Assessment guidance for therapeutic protein products notes that impurities can serve as immune stimulants, potentially leading to anti-drug antibody formation that could neutralize the medication's effects or cause hypersensitivity reactions.[7]

Even FDA-approved Ozempic showed 1-2% of clinical trial patients developing anti-drug antibodies—with a rigorously controlled manufacturing process.[8] The theoretical risk is higher with synthetic peptides containing additional impurity variants.

The Salt Form Controversy

A distinct issue from potency variation involves the chemical form of semaglutide being used. FDA-approved products use semaglutide base—the unmodified peptide. Many compounders, however, use salt forms: semaglutide sodium or semaglutide acetate.

Why does this matter? The presence of a salt counter-ion (sodium or acetate) changes the physicochemical properties of the molecule—potentially affecting solubility, stability, and absorption.[9] These salt forms have not undergone the human safety and toxicology testing required for FDA approval.

Throughout 2024 and 2025, the FDA issued warning letters to compounders explicitly citing salt form usage as grounds for "unapproved new drug" and "misbranding" charges.[10]

Sublingual and Oral Formulations: The Bioavailability Gap

Beyond potency variation in injectable products, compounded oral formulations face a fundamental pharmacology challenge: semaglutide is a peptide, and peptides are notoriously difficult to deliver orally.

Why FDA-Approved Oral Semaglutide Requires SNAC

Rybelsus, the FDA-approved oral semaglutide tablet, relies on a patented absorption enhancer called SNAC (sodium salcaprozate). This molecule protects semaglutide from gastric acid degradation and facilitates absorption through the stomach lining. Even with SNAC technology, oral bioavailability is only approximately 0.4-1% of the ingested dose.[11]

Compounded Sublingual Products

Most compounded sublingual troches and drops do not contain SNAC—they rely on the theory of sublingual absorption (bypassing the stomach entirely). However, high-molecular-weight peptides like semaglutide absorb poorly through the oral mucosa.[11]

Combined with the potency variation documented above (including the complete absence of active ingredient in some tested products), patients using compounded sublingual semaglutide face compounded uncertainty: unknown potency × unknown bioavailability = unknown actual dose.

Adverse Events: The Safety Signal

The potency and purity variations documented in testing are not merely theoretical concerns. Adverse events linked to compounded GLP-1 products have been reported.

These adverse events encompass multiple mechanisms:

• Dosing errors: Patients confusing "units" on insulin syringes with "milligrams" of semaglutide, leading to 5-fold overdoses[9]
• Potency variance: Products with higher-than-labeled potency causing severe gastrointestinal symptoms
• Concentration switching: Patients receiving different concentrations when switching pharmacies (e.g., 2.5 mg/mL vs 5.0 mg/mL), inadvertently doubling their dose
• Contamination: Sterility failures in compounding—including the Empower Pharmacy FDA warning letter (April 2025) citing sterile-drug deficiencies[13]

State pharmacy boards have responded with warnings. Seven states (Alabama, Kentucky, Louisiana, Mississippi, North Carolina, New Jersey, West Virginia) have warned that compounded semaglutide "may not contain the same active ingredient" as FDA-approved products.[4]

Current Regulatory Status

Following the FDA's February 21, 2025 declaration that the semaglutide shortage was resolved, the legal landscape for compounding shifted dramatically.

Post-deadline, pharmacies may only compound semaglutide for documented clinical need—such as a verified allergy to an excipient in the FDA-approved product or a medically necessary non-standard dose. Simple copies for cost savings are no longer legal.

Novo Nordisk has also nominated semaglutide to the FDA's "Demonstrable Difficulties for Compounding" (DDC) lists, which would permanently restrict compounding regardless of future shortage status.[5] The FDA has not yet ruled on this petition.

Quality Markers to Evaluate

For patients who have a documented clinical need for compounded semaglutide (excipient allergy, medically necessary micro-dosing), quality indicators can help distinguish reliable pharmacies:

• PCAB Accreditation: Pharmacy Compounding Accreditation Board certification indicates enhanced quality standards
• Certificate of Analysis (CoA): Batch-specific testing documentation showing potency and purity—though CoAs can be forged and interpreting them requires technical expertise[14]
• Independent Third-Party Testing: Some providers (like Hims & Hers) publish redacted CoAs from independent labs[14]
• API Source Verification: Confirmation that the active ingredient comes from an FDA "Green List" supplier—facilities that have been inspected and approved for GLP-1 API manufacturing[15]
• 503B Facility Status: Outsourcing facilities (when operating legally) face more rigorous federal oversight than traditional 503A pharmacies

However, with the shortage now resolved, the legal avenues for obtaining compounded semaglutide have narrowed considerably. Patients should discuss FDA-approved options—including manufacturer savings programs and the new oral Wegovy tablet (approved December 2025)—with their healthcare providers.