Peptide drugs are generally defined as polymers composed of amide bonds with fewer than 40 amino acid residues. Due to the high receptor activity and selectivity of peptide drugs with a low risk of side effects, there has been strong interest in peptides from the pharmaceutical industry. During this period, there were also many star drugs, which were mainly concentrated in the metabolic disease industry, such as GLP-1 analogue somalutide, gastric inhibitory peptide (GIP) glucagon-like peptide-1 (GLP-1) tesiparatide and other dual-receptor agonists. In addition, with the rise of PDC and RDC drugs. At present, the preparation methods of polypeptide drugs mainly include chemical synthesis and biological fermentation. Biofermentation is mainly used to produce long peptides. The advantages are low production costs, but the inability to introduce unnatural amino acids into the peptide sequence and the inability to perform various decorations on the peptide chain. Therefore, its application is also greatly limited. Chemical synthesis methods include solid phase synthesis and liquid phase synthesis. Solid-phase synthesis has a significant advantage over liquid-phase synthesis: an excess of material can be used for the reaction to ensure complete coupling. Excess amino acids, shrinkage agents, and by-products can be removed by simple cleaning operations, avoiding complex post-processing and purification operations and improving work efficiency, so the solid-phase synthesis method has been the most widely used. “Chemical synthesis raw materials for the synthesis of peptides include starting materials, reagents, and solvents.” Their quality, especially the quality of the initial material, can have a different impact on the quality of the API. The starting material mainly refers to the guaranteed amino acid derivatives for peptide chain modified fatty acids, polyethylene glycol, etc. As important structural fragments, they are classified as materials in the API structure, which is directly related to the quality of the API. Therefore, we should focus on the control of the starting material.
I. Rationalize the initial material selection
ICHQ11 clearly proposes that if a chemical product sold on the market is used as an initial raw material, the applicant does not normally need to discuss its reasonability. Chemical products sold on the market generally can be used not only as starting materials for drugs, but also can be sold in non-pharmaceutical markets. Customized and synthesized compounds do not belong to the chemical products sold on the market. Although there is no non-medicinal market to protect amino acids to meet the ICHQ11 definition of chemicals sold on the market, they are compact, chemically distinct and structurally clear, easy to isolate and purify, and can be identified and tested by common analytical methods. They have stable chemical properties and are easy to store, transport, and synthesize
Ii. Control of the relevant substances in the starting material
The aforementioned protective amino acids are incorporated into the API structure as an important structural part, which is directly related to the quality of the API. Therefore, we should strictly control the impurity content in the initial material, understand the transformation and removal of these impurities in the established process, and finally clarify the relationship between them and the impurities in the API.
Understanding of polypeptide drug starting materials
Third, the solvent residue in the initial material
In general, given the specificity of solid phase generation of peptides, a large amount of solvent will be used to clean the peptide resin after completing each step of amino acid coupling and detachment from protection. Crude peptides obtained by cracking the peptide resin will also be made by HPLC and freeze-dried. Thus, there is little risk that the small amount of solvent attached to the protective amino acids will be delivered to the final API. However, special attention should be paid to residues of acetate, butyl acetate, and alcohol solvents, as these solvents may cause side effects with active amino acids or peptide chains during active coupling of amino acids. For example, during amino acid coupling, the residual acetic acid will react with the exposed amino group on the peptide chain, resulting in the closed end of the peptide chain; During amino acid activity, the residual alcohol solvent may react with the active carboxyl group, leading to passivation of the active amino acid, reducing the equivalent of the amino acid, and ultimately resulting in incomplete amino acid coupling and lack of peptide impurities. The company controls butyl acetate, alcohol, methanol, and acetic acid in COA, taking an amino acid from Zheng Yuan Biochemical as an example. The standard for butyl acetate was ≤0.5% butyl acetate, which was actually detected to be 0.10%. According to the ICHQ3C, butyl acetate for three kinds of solvents, set the standard for 0.5% or less in line with the requirements of ICHQ3C, but considering the butyl acetate amino acetylation may lead to the risk, also deal with butyl acetate to standardize research, to determine a more appropriate standards.
Post time: Aug-29-2023