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Detailed Analysis of Semaglutide Impurities
Release time：
2025-07-16
The impurity control of Semaglutide needs to run through the entire process of synthesis, purification, and storage. Analysis is achieved through advanced technologies such as MALDI-TOF MS and HPLC, combined with process optimization and strict quality control standards. The strict requirements of regulatory agencies (such as FDA, EMA) further ensure that impurity levels are within a safe range.
I. Types and Sources of Impurities
1. Process-Related Impurities
Oxide and Ketone Impurities: Produced during synthesis due to oxidation reactions or side reactions, which may affect stability.
Polymers: Formed by misfolding or polymerization of polypeptide chains, such as dimers and trimers.
Leaving Group Residues: Such as Des-His-1 impurity (histidine deletion) and Des-31-Gly impurity (glycine deletion), resulting from incomplete removal of protecting groups during synthesis.
2. Degradation Impurities
Oxidative Degradation Products: Such as beta-Asp-9 impurity (aspartic acid isomerization), which easily occurs under acidic or alkaline conditions.
Hydrolysis Products: Such as deamidation impurities caused by amide bond breakage (e.g., Iso Asp impurity), affecting the binding ability to the GLP-1 receptor.
Isomerization Products: Such as 9-D-Asp impurity (D-aspartic acid), which may reduce efficacy.
3. Structural Modification Impurities
Oct-alpha-Glu-AEEA-AEEA impurity: Originates from side reactions during side chain fatty acid modification and needs to be reduced by controlling reaction conditions.
4. Starting Material Impurities
Impurities introduced in raw materials or intermediates (such as unpurified amino acids, protecting groups) need to be controlled through strict supplier entry inspection.
II. Analytical Methods
1. MALDI-TOF MS
Purpose: Rapidly confirm molecular weight, purity, and impurity composition.
Advantages: No complex sample pretreatment is required, can directly analyze crude products and final products, and identify unknown impurities.
2. Reversed-Phase High-Performance Liquid Chromatography (RP-HPLC)
Purification steps:
Using PrePulite® XP C8 filler, the purity is increased to 96.79%, with a single impurity <2%.
Purity up to 99.77%, single impurity <0.1%, total yield >65%.
Quality control: HPLC method detects purity ≥99.5%, related protein impurities (SEC-HPLC) ≤1%.
3. LC-MS/MS (Liquid Chromatography-Tandem Mass Spectrometry)
Purpose: Quantitatively detect semaglutide and its metabolites in biological matrices, and distinguish between the original form and degradation products.
Advantages: High sensitivity (detection limit as low as ng/mL), suitable for pharmacokinetic studies.
The impurity control of semaglutide needs to run through the entire process of synthesis, purification, and storage. Analysis is achieved through advanced technologies such as MALDI-TOF MS and HPLC, combined with process optimization and strict quality control standards. The strict requirements of regulatory agencies (such as FDA, EMA) further ensure that impurity levels are within a safe range.
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