Industrial production of polypeptide API by solid phase synthesis
Polypeptide drugs generally refer to compounds formed by 2-100 amino acids linked by peptide bonds. They are characterized by high biological activity, strong specificity and small side effects. There are three main methods for the preparation of peptide drugs: chemical synthesis, gene recombination and natural extraction.
The solid-phase chemical synthesis of peptides has the advantages of high yield, high purity, stable quality and environmental friendliness. It is widely used in the production of peptide raw materials with 3-50 sequences.
In the late 1980s, the United States and Europe took the lead in industrialized production of polypeptide raw materials with solid-phase synthesis technology as the core. Famous peptide pharmaceutical manufacturers, such as Bachem, polypeptide and American peptide, were successively established.
At the same time, such Fengyun drugs as leuprorelin, salmon calcitonin and octreotide were born. However, at that time, peptide raw materials were rare. Once upon a time, a gram of imported salmon calcitonin API was comparable to a real estate.
In recent years, with the development of peptide solid-phase synthesis technology, equipment and process, the cost of peptide drug research and development and production has decreased significantly. After the expiration of peptide drug patents, China and India have become the main production areas of polypeptide API (generic drug).
The industrial production of polypeptide raw materials in China started in the new century. After more than ten years of development, it has transformed from the former gram based product to the kilogram production of single batch products. At the same time, it has given birth to the listing of finished domestic generic drugs, gradually getting rid of the embarrassing situation that polypeptide drugs can only rely on import.
In recent years, as peptide drugs are gradually incorporated into the medical insurance payment system, the once unattainable peptide drugs gradually benefit the majority of patients.
However, there are not many enterprises in China that have mastered the core technology of large-scale production of solid-phase peptide synthesis, and few enterprises have the market access qualification in line with European and American regulations.
The international competitiveness of polypeptide API is directly determined by the quality standard, mature and appropriate process flow and large-scale assembly line production. If we find the balance point of quality, regulation and cost, we are expected to hatch the competitive products with international competitiveness.
Main factors of industrial production of polypeptide API
1、 Quality standard
Pharmacopoeia standards are often the lowest threshold for market access, and each enterprise generally establishes its own quality standards for products produced, and customers will also have corresponding requirements for purchasing products.
At present, most of the raw materials and excipients used in the production of polypeptide APIs are produced in China, and the whole East Asia region is also the main supply area of raw materials and excipients for polypeptide API production in the world. In the selection of raw materials and accessories, we should consider the quality, price, process matching degree and other aspects. The extreme value of a single parameter is often confirmed to be not the optimal choice.
In the aspect of polypeptide API product quality, we usually pay attention to the purity, content, solvent residue and other detection items and pursue high standards. If necessary, double HPLC environmental detection or ion detection will be introduced. For the same product, the European and American Pharmacopoeia has higher requirements than the Chinese pharmacopoeia in terms of residual solvents, burning residues and impurities.
Moreover, European and American regulatory market customers will pay more attention to some quality standards beyond COA, such as biological activity, spatial structure, in-depth study of impurities, etc., which is based on the preparation effect to evaluate the quality of API.
Some customers will set high standards on specific quality details, for example, the API used for nasal spray needs to limit the acetic acid content, and the products used for sustained-release and controlled-release preparations need to further limit the residual solvents, etc. China’s enterprises in these areas need to step up the pace of catch-up, and strive for excellence to produce high-quality products in line with the needs of the international market.
2、 Production layout and process exploration
At present, the traditional compartment layout method is still used in the production of polypeptide API in China, that is, according to the production process steps, the synthesis, purification and freeze-drying workshops are set up in different spaces, and different clean area grades are specified to meet GMP requirements. Among them, the production equipment of each product is independent and dedicated.
Meanwhile, the clean process and verification are strictly implemented in the areas with cross contamination risk between products, while the transfer of intermediates is still in the mode of manual transfer. The overall production of high demand for manpower, work efficiency is general.
Throughout Europe and the United States, due to the large production of single product, the integrated layout is generally adopted, that is, synthesis, purification, freeze-drying are located in the same clean area, and the transportation and recovery system of raw and auxiliary materials and intermediates in closed pipelines is adopted.
Through the arrangement of annual production plan, only a single product can be produced in the same area at the same time, so as to effectively avoid the risk of cross contamination. The overall production of human requirements, high efficiency.
The general process of solid-phase synthesis of peptide API is synthesis, peptide cutting, purification, concentration, freeze-drying and packaging. The main factors affecting the process yield are: quality of raw materials and excipients, process formula, reaction time, reaction conditions, purification route, concentration method, freeze-drying curve, etc.
At the same time, some easily overlooked details will also determine the yield and quality, such as the material of the reaction axe, the humidity of the environment, the iron carbon ratio of stainless steel materials, the storage conditions of intermediates, etc.
From R & D to pilot scale-up to industrial production is the most important link in the whole peptide API manufacturing. On the one hand, we can find clues from the published patents or documents, on the other hand, more importantly, practice. Capacity amplification is a complex multivariable model affected by many factors. We should not only focus on the yield of a certain section, but also consider the whole.
For example, a product has two sets of synthetic processes, a and B. the purity of crude peptide obtained by process a can reach more than 90%, but there are unknown impurities that are difficult to separate. The purity of crude peptide obtained by process B is only 80%. However, the purification and separation are relatively easy and the impurity structure and properties are clear. Therefore, process B is selected based on the consideration of final product quality.
In the process of process exploration, the personnel of each section should regularly summarize and discuss, establish a reasonable communication and coordination mechanism, evaluate various factors such as quality, laws and regulations, yield, cost, new drug registration, environmental protection, safety management and other factors, and finally determine the mature mass production process. Process amplification involves almost all departments of the company, not only the R & D department. After the large-scale production, we should also regularly review the production process, and update the process if necessary.
3、 Both hardware and software are indispensable
Efficient drug production is inseparable from the excellent system construction. In addition to the use of excellent hardware equipment and the implementation of optimized production technology, talent and management have become an important factor in determining the competitiveness of enterprises.
High standard GMP management and even cGMP management can effectively ensure the good operation of production. It is said that talents in the 21st century are the most expensive. A good technician can not be found. An excellent team is a treasure of time.
In the face of complex difficulties, the excellent team can rely on careful thinking and rich experience to find a breakthrough, so that mature products can be listed as soon as possible, so as to occupy the market opportunity.
epilogue
The competition depends on the details. Excellent software and hardware environment, appropriate production scale and coordinated operation mode can jointly create high cost performance of products. Industrial production is an art of practice.
Selecting the right canvas, determining the style of painting, and reasonable color matching will surely create a perfect work. It is hoped that China’s polypeptide pharmaceutical industry will take the lead in the world as soon as possible.
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