Semaglutide Impurities

Semaglutide Impurities | Simeglutide Impurity Control | Impurity Custom Synthesis and Structure Confirmation | Science-Peptide

Soma Lutide (Simeglutide) impurity control - for GLP-1 drug quality study, generic drug submission.Science-Peptide provides custom synthesis of Soma Lutide related impurities, including missing peptides, oxidized impurities, fatty acid exfoliation products, PEG-chain related impurities, etc., accompanied by structural confirmation data. We can support your impurity profile research. Welcome to contact us.

Semaglutide (also known as Semaglutide) has been on fire these years. Novo Nordisk relies on it to push the market value to the world's second, domestic manufacturers of peptide generics, almost no not stare at it. Oral dosage form and injectable dosage form are all big markets. After the expiration of the patent, who can first do the quality research, who will have the opportunity to grab the first generic.

 

However, the quality study of somatostatin is, frankly speaking, more difficult than that of many peptides. It is a 31-peptide with a fatty acid chain (octadecanedioic acid) and a PEG linker. This structure determines its impurity spectrum is particularly rich - missing peptides, oxidized impurities, fatty acid shedding products, PEG chain-related impurities, dimers each have to have a control, each have to be clear. Especially the PEG chain, which is not found in ordinary peptides, is unique to Somalutide.

 

We have accumulated a lot of experience in the synthesis of complex peptide impurities. We have specialized in the study of somatostatin, and we know what are the difficulties in its impurity profile and what are the essential control items. We can customize the synthesis of various Semaglutide Impurities controls according to your needs, with structural confirmation data, and help you establish the method, so that you will be less likely to be issued a supplement when filing.

The molecular structure of somatostatin determines that its impurity profile is much more complex than that of ordinary peptides. When we do impurity studies, we mainly focus on these categories:

Missing peptide
The 31 amino acids, any one of which is missed during the synthesis process, is an impurity. The retention times of the missing peptides on HPLC were widely distributed, with different polarity of the missing peptides in different positions. Some are missing at the N-terminus, some at the middle, and some near the fatty acid attachment site. We have received an order from a customer who asked for a dozen or so missing peptides in different positions to locate all possible missing impurities in their process.

Oxidizing impurities
Somalutide has methionine (Met) in its sequence, which is susceptible to oxidation to sulfoxide and then to sulfone. Oxidized impurities often appear in stability studies and grow after a period of time. We have done a comparison, under accelerated conditions for a month, the oxidation peak can grow to more than 0.3%, without control.

Fatty acid shedding products
The fatty acid side chain (octadecanedioic acid) of somatostatin is attached to lysine through a linker, and this modification may be partially shed during synthesis or storage. More problematically, the shedding can occur at different locations - between the fatty acid and the linker, and between the linker and the peptide - resulting in different impurities. We have synthesized several fatty acid-related impurities for our customers, ranging from complete shedding to just a small section.

PEG chain-related impurities
This is the most specific type of impurity in somatostatin. It has a PEG (polyethylene glycol) linker, and the PEG chain may break, shorten, or polymerize during synthesis, resulting in a series of related impurities. These impurities are not found in ordinary peptides, but are unique to somatostatin, and are difficult to study in quality studies. We have made various variants of PEG chain deletion, PEG chain shortening, and PEG chain oxidation.

Dimers/polymers
Two or more somatostatin molecules cluster together to form a dimer or higher. The molecular weight of the dimer is twice that of the main peak, and it is often a broad peak on HPLC, so it has to be specially separated and purified before it can be used as a control. We have done the preparation of dimers, and it took several rounds of purification to achieve a purity of more than 95%.

Deamidated impurities
Asparagine (Asn) and glutamine (Gln) are easily deamidated under acidic or heating conditions, resulting in isomers. There are several Asn and Gln in the sequence of somatostatin, and the deamidation impurity often appears in the forced degradation test, so the control product has to be used to locate the impurity.

Diastereoisomers
During the long chain synthesis, individual amino acids may undergo racemization, resulting in diastereoisomers. The content of this kind of impurity is usually not high, but experts will ask when declaring, and it is better to have a control product for confirmation.

Many of these impurities cannot be purchased and need to be custom synthesized. We have already done a lot of projects on the customization of somatostatin impurities, covering all the above categories.

The deletion of the peptide series
We synthesize whatever is missing. For example, the lysine at position 20 is missing, or the amino acid near the fatty acid attachment site is missing. We will synthesize according to your process impurity profile, and the purity is usually >95%, with MS and NMR confirmation. We have synthesized a set of peptides with 5 amino acid spacing from N-terminal to C-terminal.

Oxidizing impurities
Met in Somatostatin is oxidized to sulfoxide or sulfone, and we can control the oxidation conditions and synthesize the oxidized control product. We can control the oxidation conditions and synthesize the oxidized control product. The purity of the product is >95%, and we can provide the LC-MS spectrum to confirm the degree of oxidation. Sulfoxide and sulfone are separated by HPLC, and we can do both.

Fatty acid shedding products
This is the main focus of Somalutide impurities. The fatty acid chain may be completely or partially dislodged. We can synthesize a series of variants for different positions of shedding. In one of the most complicated projects we have ever done, the customer asked us to synthesize an impurity with 6 carbons missing from the fatty acid chain, and it took us two months to get it right.

PEG chain-related impurities
This is one of the most difficult impurities of somatostatin, and it is also our strength. PEG chain may be missing, shortened, broken, oxidized, and various variants may be produced. We have done the impurity with the PEG chain completely missing (i.e. de-PEGylated somatostatin), the variant with the PEG chain length halved, and the product with the PEG chain oxidized. The customer was given these controls, and the spectrum of the PEG-related impurity was fully established.

Dimer
Dimers formed by cross-linking or non-covalent interactions can be prepared by different methods and isolated and purified to provide high purity controls. Dimers are laborious to purify, but we have the experience to know how to separate the monomers.

Deamidated impurities
For the Asn and Gln sites in the sequence, we can prepare deamidated impurity controls by forced degradation or targeted synthesis. The difference in molecular weight after deamidation is only 1, which is not easy to be distinguished by MS, so we usually use NMR or special chromatographic conditions to confirm.

Dther customized impurities
If you find a new unknown impurity in your research, we can help you analyze the structure and synthesize it. Send us the sample, we will do the LC-MS analysis, speculate the structure, then directional synthesis, and then compare the retention time and mass spectrum to confirm the agreement. We have done this process many times and the success rate is quite high.

Analytical method development and validation
When setting up an HPLC or LC-MS method, an impurity control is required for localization, determination of separation, verification of linear range and recovery. Without the control, the method validation is missing a piece. Many customers ask us to do a few key impurities first to set up the method, and then slowly make up the rest.

Heterogeneous mass spectrometry
When a generic drug is declared, a comprehensive qualitative and quantitative analysis of process impurities and degradation products is required. The location, content and structure of each impurity need to be confirmed by a control product. We have seen the declaration of the information was sent to make up, nine times out of ten is the impurities of this piece did not understand.

Stability studies
In long-term stability and accelerated tests, it is necessary to determine which degradation products are dominant and what the trend in content is. With an impurity control, it is possible to accurately quantify and monitor. A customer was doing the stability of somatostatin preparation, and found that a degradation peak grew rapidly under accelerated conditions, so we analyzed it by MS and synthesized it to confirm the structure, and then the customer felt relieved to report it.

Batch release testing
After commercialization, each batch of API or formulation needs to be tested for the substance in question. Impurity controls are essential tools for release testing.

Information on generic drug declarations
Impurity studies are a key section of the filing information. Providing complete impurity profiling and control data significantly reduces the risk of a review release.

Case 1: A pharmaceutical company, Somalutide generic drug program
They are developing a generic version of somatostatin and need a complete set of impurity controls for method validation. We customized 15 impurities for them: 6 missing peptides, 2 oxidized impurities, 1 dimer, 2 fatty acid exfoliation products, 3 PEG chain related impurities, and 1 deamidation impurity. The purity of each was above 95%, with MS and NMR data. The project manager said, "The impurities of Somalutide are more complicated than other peptides, especially the PEG one, which we have been looking for a number of companies, but they all said they couldn't do it. But you were able to do it all, and the data were complete, which was a great help." Subsequently, the validation of their method was successfully completed, and they are now preparing for filing.

Case 2: A CRO, special study on impurities in the PEG chain
They undertook a quality research project on somatostatin, which required a comprehensive analysis of the impurities associated with the PEG chain. We systematically synthesized the PEG-related impurities: complete absence of PEG chain, halving of PEG chain length, oxidation of PEG chain ends, and breaking of PEG chain into two parts. synthesized a total of 8 PEG-related impurities. The client used these controls to establish a complete set of PEG impurity detection method, which became the highlight of their filing information.

Case 3: Stability studies, a biotechnology company
They were doing a stability study of somatostatin formulation and found that the content of a degradation product increased rapidly under accelerated conditions, but they did not know what it was. We analyzed the sample by LC-MS, assumed that it was a fatty acid shedding impurity at a certain location, and then synthesized it in a targeted manner and confirmed it by comparison. They established an assay using this control, and accurately monitored the trend of this degradation product. Later, when submitting the report, this part of the data was emphasized by the experts, and because of the solid data, no compensation was issued.

Somatostatin is a super popular product, but impurity study is a delicate job, especially PEG chain related impurities and fatty acid exfoliation products, which many manufacturers can't handle. If you are doing quality research or generic development of somatostatin, and need impurity control, welcome to talk to us. We have done a lot of work, we know what are the difficulties, and we know how to make it out.