Regulated as medicinal products

Semaglutide

Last reviewed

Reviewed by HelixEvoLabs Research Team

Technical, analytical and regulatory reference for semaglutide as a manufactured peptide material across its injectable and oral routes.

Identity and nomenclature

INN
semaglutide
Synonyms
Ozempic, Rybelsus, Wegovy
Development codes
Not verified

Mechanism

Semaglutide is an acylated analogue of human glucagon-like peptide-1 that acts as an agonist at the GLP-1 receptor. The European assessment report records 94 per cent structural homology to native GLP-1.

The molecule is an Aib8, Arg34 analogue of GLP-1(7-37), acylated at the epsilon-amino group of Lys26. The acyl side chain comprises two 8-amino-3,6-dioxaoctanoic acid spacers, one gamma-glutamic acid spacer and a fatty diacid, 1,18-octadecanedioic acid.

The assessment record demonstrates a direct correlation between bioactivity and main-peak content determined by reversed-phase chromatography, in both active substance and finished product and including forced-degraded samples. On that basis the bioassay is limited to one batch in ten in routine testing, and the finished product carries no bioactivity release test at all, with bioactivity controlled indirectly through content.

Analytical and manufacturing profile

Analytical data sheet

Semaglutide

Identity

Molecular formula
Not verified
Molecular weight
4113.58 g/mol (theoretical average); 4111.115 (theoretical monoisotopic)
CAS number
Not verified
UNII
53AXN4NNHX
Chemical name
Not verified
Appearance
Not verified

Primary structure

HAEGTFTSDVSSYLEGQAAKEFIAWLVRGRG

31 residues

Modifications

  • The sequence above is derived from the assessment report’s description of the molecule as an Aib8, Arg34 analogue of GLP-1(7-37), rather than quoted from a nomenclature authority. It should be confirmed against the WHO INN list before publication.
  • Position 2 in the 1-31 numbering, corresponding to position 8 in GLP-1 numbering, is 2-aminoisobutyric acid. The one-letter sequence encodes it as A.
  • Position 28 in the 1-31 numbering, corresponding to Arg34 in GLP-1 numbering, is arginine in place of the lysine of native GLP-1.
  • The Lys26 epsilon-amino group is acylated with two 8-amino-3,6-dioxaoctanoic acid spacers, one gamma-glutamic acid spacer and 1,18-octadecanedioic acid. The acylation descriptor recorded in the assessment report is (S)-22,40-dicarboxy-10,19,24-trioxo-3,6,12,15-tetraoxa-9,18,23-triazatetracontan-1-oyl.
  • Manufactured by recombinant expression in Saccharomyces cerevisiae followed by chemical modification. The expressed precursor is [Arg34]GLP-1-(9-37); no animal-derived substances are used. This is a different route from the solid-phase synthesis used for tirzepatide, and the impurity control strategy differs accordingly.

Solubility

Aqueous solution
Described in the assessment report as good solubility. No quantitative figure is published, and no figure is published for any organic solvent

Storage

FormTemperatureDuration
Active substanceFrozen, -20 °C ± 5 °C60 months
Solution for injection, Ozempic presentation2-8 °C, away from the cooling element, protected from light36 months
Solution for injection, Wegovy presentation2-8 °C24 months
Oral tablet, Rybelsus presentationOriginal blister package, protected from moisture and light30 months

Stability

  • The isoelectric point is reported as pH 5.4, and a preformulation study reports markedly greater degradation between pH 4.5 and 5.5, concluding that finished formulations should be maintained above pH 7.0.
  • A buffer screening exercise recorded in the assessment report found that alternative buffer systems and tonicity agents did not improve product stability.
  • A degradation study reports that four of thirteen tracked impurities appeared only when water was used as the solvent and were absent across all buffered pH conditions, which is a practical argument against unbuffered aqueous handling.
  • Solid-state work reports that the native alpha-helical structure is maintained to 60 degrees Celsius with significant conformational loss above that, that the material remained amorphous under all conditions tested, and that modulated differential scanning calorimetry established a glass transition temperature of 169 degrees Celsius.
  • In aqueous solution the peptide aggregates slowly into spherical micelles above a critical aggregation concentration reported as 0.06 per cent by weight, with a small population of needle-shaped fibrils and dimer and trimer species at lower concentrations. The alpha-helical conformation is retained through micelle assembly.
  • Two acceptable sources disagree on forced-degradation behaviour under differing conditions. A 2023 review reports no degradants under acidic, neutral, photolytic or thermal stress, with two under alkaline and one under oxidative conditions. A 2026 study reports 12.0 to 14.8 per cent degradation across acidic, basic, oxidative, thermal and photolytic stress. The conditions differ; both are recorded rather than reconciled.
  • Photostability under the ICH Q1B protocol is documented only for the oral tablet, where unpacked samples changed in visual appearance while product in its primary packaging did not. No equivalent ICH photostability result is published for the injectable presentations, whose labelling states only that they be protected from light.

Analytical methods

MethodPurposeSpecification
RP-HPLC / RP-UHPLCAssay, purity and related substances, and uniformity of dosage units. The assessment record concludes that main-peak content by this method is a reliable measure of bioactivity in both active substance and finished productNot verified
SE-HPLCControl of aggregation and high molecular weight proteinsNot verified
High-resolution LC-MSIdentification of the components present in isolated major impurity peaks from the active substanceNot verified
Cell-based bioassayPotency, by indirect measurement of adenylate cyclase activation of the cloned human GLP-1 receptor. Limited to one batch in ten in routine active-substance testing; not a finished-product release testNot verified
Peptide mappingIdentity test on the finished product, alongside chromatographic retentionNot verified
Karl Fischer titrationWater content of the oral tablet finished productNot verified
Nitrogen determinationValue assignment of the primary reference material, related to the theoretical nitrogen content and corrected for the sum of impurities by chromatographyNot verified
UPLC-HRMS peptide mappingPrimary-structure confirmation and localisation of the fatty acid modification site, using Glu-C and chymotrypsin digests to achieve full sequence coverageNot verified

Impurities and degradation products

  • Three D-amino acid isomeric impurities have been characterised and named in the peer-reviewed literature: D-Ser8, D-His1 and D-Asp9, in the 1-31 renumbering of GLP-1(7-37).
  • The assessment report records that product-related impurities are structurally related to semaglutide and are generated as by-products in fermentation by the host organism, in recovery and purification of the precursor, in the chemical modification steps, and in final purification. Individual impurities are not named in the public assessment record.
  • A characterisation study found that no new impurities are generated during manufacture of the finished product.
  • Host cell proteins are controlled as a critical in-process test, which is specific to the recombinant manufacturing route.

Handling

  • The active substance is stored frozen and the finished products refrigerated and protected from light. No occupational exposure limit or personal protective equipment guidance is published in any acceptable source, so containment is determined by the receiving facility under its own assessment.
  • The precursor peptide is produced in a yeast strain, which is not a host for mammalian viruses, and no raw materials or excipients of human or animal origin are used. The assessment record concludes there is no risk of contamination with mammalian viruses and no TSE concern.

Clinical development

STEP 1

NCT03548935
Phase
3
Enrolment
1961
Duration
68 weeks
Status
reported
Population
Adults with overweight or obesity without diabetes, with a body mass index of at least 30, or at least 27 with a weight-related comorbidity
Primary endpoint
Change in body weight as a percentage from baseline to week 68, and proportion of participants achieving a body weight reduction of 5 per cent or more

Reported outcomes

Outcomes as reported by STEP 1, attributed to trial arm and timepoint
MetricArmValueComparatorTimepoint
Change in body weight, per cent (treatment-policy estimand)Semaglutide 2.4 mg once weekly, subcutaneous-15.6% (SD 10.1); treatment difference -12.44 percentage points, 95% CI -13.37 to -11.51Placebo -2.8% (SD 6.5)Week 68
Change in body weight, per cent (on-treatment estimand)Semaglutide 2.4 mg once weekly, subcutaneous-16.9% (SD 9.4); treatment difference -14.42 percentage points, 95% CI -15.29 to -13.55Placebo -3.1% (SD 6.4)Week 68
Proportion achieving body weight reduction of 5 per cent or moreSemaglutide 2.4 mg once weekly, subcutaneousOdds ratio 11.22, 95% CI 8.88 to 14.19Placebo referenceWeek 68

Figures as reported by this trial. They are not statements about what the compound does for a person.

Sponsor Novo Nordisk A/S · New England Journal of Medicine, 2021 · doi:10.1056/NEJMoa2032183 · PMID 33567185 · verified 2026-07-30

SUSTAIN-6

NCT01720446
Phase
3
Enrolment
3297
Duration
104 weeks
Status
reported
Population
Adults aged 50 or over with type 2 diabetes at high cardiovascular risk; 83 per cent had established cardiovascular disease, chronic kidney disease, or both
Primary endpoint
Time from randomisation to first occurrence of a major adverse cardiovascular event, defined as cardiovascular death, non-fatal myocardial infarction or non-fatal stroke

Reported outcomes

Outcomes as reported by SUSTAIN-6, attributed to trial arm and timepoint
MetricArmValueComparatorTimepoint
First major adverse cardiovascular eventSemaglutide 0.5 mg and 1.0 mg once weekly, pooled6.6% (108 patients); hazard ratio 0.74, 95% CI 0.58 to 0.95Placebo 8.9% (146 patients)End of follow-up, week 109
Non-fatal strokeSemaglutide 0.5 mg and 1.0 mg once weekly, pooled1.6%; hazard ratio 0.61, 95% CI 0.38 to 0.99Placebo 2.7%End of follow-up, week 109
Retinopathy complicationsSemaglutide 0.5 mg and 1.0 mg once weekly, pooledHazard ratio 1.76, 95% CI 1.11 to 2.78 — higher with semaglutide than placeboPlacebo referenceEnd of follow-up, week 109
Change from baseline in glycated haemoglobinSemaglutide 1.0 mg once weekly, subcutaneous-1.41 percentage points (SE 0.05); treatment difference -1.05, 95% CI -1.19 to -0.91Matched placebo -0.36 percentage points (SE 0.05)Week 104

Figures as reported by this trial. They are not statements about what the compound does for a person.

Sponsor Novo Nordisk A/S · New England Journal of Medicine, 2016 · doi:10.1056/NEJMoa1607141 · PMID 27633186 · verified 2026-07-30

Regulatory status by jurisdiction

  • European Union

    European Medicines Agency
    Approved medicine

    Authorised under three separate marketing authorisations covering two routes of administration. Indications differ by brand: the two diabetes authorisations are distinct from the weight-management authorisation, and the oral route is authorised for diabetes only.

    Wegovy EPAR product information, Annex IVerified 2026-07-30

  • United Kingdom

    MHRA
    Approved medicine

    Authorised under four brands covering both routes, including an oral tablet for weight management authorised on 11 June 2026 which has no EU equivalent. The indication wording differs from the corresponding EU text for every brand.

    MHRA products database, semaglutide summaries of product characteristicsVerified 2026-07-30

  • United States

    FDA
    Approved medicine

    Approved across several separate applications, and the US indication set is materially wider than the EU or UK one. It carries two indications neither of the others records: reduction of major adverse cardiovascular events, and treatment of noncirrhotic metabolic dysfunction-associated steatohepatitis with moderate to advanced fibrosis, the latter under accelerated approval. Ozempic was authorised in December 2017, ahead of both the EU and the UK.

    Wegovy (semaglutide) injection and tablets, US prescribing informationVerified 2026-08-05

Supply classification and permitted use

Semaglutide is an approved medicinal product in multiple jurisdictions. HelixEVO does not supply medicinal products for human administration. Material is supplied to businesses for research and manufacturing purposes only.

  • Authorised indications differ by brand, by route and by jurisdiction. A statement of approval in one territory does not describe the position in another.
  • The FDA has issued warning letters concerning unapproved products containing semaglutide that were labelled for research purposes or not for human consumption.
  • Supply of material does not constitute authorisation to place a finished medicinal product on any market.

How supply classifications work · Documented safety signals

References

  1. [1]RegulatorWEGOVY (semaglutide) injection, for subcutaneous use, and WEGOVY (semaglutide) tablets, for oral use — US prescribing information — Novo Nordisk, via DailyMed (US National Library of Medicine), 2026 · accessed
  2. [2]RegulatorDrugs@FDA application records for semaglutide: NDA 209637, NDA 213182, NDA 215256, NDA 218316 and ANDA 220314 — US Food and Drug Administration, 2026 · accessed
  3. [3]RegulatorSEMAGLUTIDE — Global Substance Registration System record, UNII 53AXN4NNHX — Global Substance Registration System (NIH/NCATS), 2026 · accessed
  4. [4]RegulatorAssessment report — Ozempic (semaglutide), EMA/CHMP/715701/2017 — European Medicines Agency, 2017 · accessed
  5. [5]RegulatorOzempic EPAR product information, Annex I summary of product characteristics — European Medicines Agency, 2026 · accessed
  6. [6]RegulatorAssessment report — Rybelsus (semaglutide), EMA/95374/2020 — European Medicines Agency, 2020 · accessed
  7. [7]RegulatorRybelsus EPAR product information, Annex I summary of product characteristics — European Medicines Agency, 2026 · accessed
  8. [8]RegulatorAssessment report — Wegovy (semaglutide), EMA/112307/2022 — European Medicines Agency, 2022 · accessed
  9. [9]RegulatorWegovy EPAR product information, Annex I summary of product characteristics — European Medicines Agency, 2026 · accessed
  10. [10]RegulatorFirst oral GLP-1 treatment for weight management — European Medicines Agency, 2026 · accessed
  11. [11]RegulatorMHRA products database, semaglutide summaries of product characteristics — Medicines and Healthcare products Regulatory Agency, 2026 · accessed
  12. [12]Peer-reviewedZhang B, Xu W, Yin C, Tang Y. Characterization of low-level D-amino acid isomeric impurities of semaglutide using liquid chromatography-high resolution tandem mass spectrometry — Elsevier, Journal of Pharmaceutical and Biomedical Analysis, 2023 · doi:10.1016/j.jpba.2022.115164 · PMID 36462248 · accessed
  13. [13]Peer-reviewedKim SH, Kim SS, Kim HJ, Park EJ, Na DH. Peptide mapping analysis of synthetic semaglutide and liraglutide for generic development of drugs originating from recombinant DNA technology — Elsevier, Journal of Pharmaceutical and Biomedical Analysis, 2025 · doi:10.1016/j.jpba.2025.116682 · PMID 39847923 · accessed
  14. [14]Peer-reviewedMalgave A, Akbar S, Tiwari A, Hande S, Joseph A, Malayandi R. Influence of buffering capacity, pH, and temperature on the stability of semaglutide: a preformulation study — Wiley, Journal of Peptide Science, 2025 · doi:10.1002/psc.70039 · PMID 40635175 · accessed
  15. [15]Peer-reviewedMalgave A, Akbar S, Joseph A, Aishwarya D, Peraman R, Malayandi R. Effect of pH, buffers, molarity, and temperature on solution state degradation of semaglutide using LC-HRMS — Elsevier, European Journal of Pharmaceutics and Biopharmaceutics, 2025 · doi:10.1016/j.ejpb.2025.114780 · PMID 40490042 · accessed
  16. [16]Peer-reviewedAkbar S, Malgave A, Joseph A, Kumar A, Malayandi R. Thermally stressed solid-state stability of semaglutide: understanding the influence of temperature on protein content, secondary structure, phase transition, and chemical degradation — Springer, Pharmaceutical Research, 2026 · doi:10.1007/s11095-026-04094-4 · PMID 42086873 · accessed
  17. [17]Peer-reviewedHamley IW, de Mello LR, Castelletto V, et al.. Semaglutide aggregates into oligomeric micelles and short fibrils in aqueous solution — American Chemical Society, Biomacromolecules, 2025 · doi:10.1021/acs.biomac.5c00342 · accessed
  18. [18]Peer-reviewedKhalil HA, Hassanein NA, El-Yazbi AF, Mahgoub H. A multimodal HPLC stability indicating approach for the estimation of semaglutide and tirzepatide in bulk, pharmaceutical dosage forms, and rat plasma — Springer, BMC Chemistry, 2026 · doi:10.1186/s13065-025-01716-7 · accessed
  19. [19]Peer-reviewedGumieniczek A, Berecka-Rycerz A. Metabolism and chemical degradation of new antidiabetic drugs: a review of analytical approaches for analysis of glutides and gliflozins — MDPI, Biomedicines, 2023 · doi:10.3390/biomedicines11082127 · accessed