APIs are the prerequisite for the production of pharmaceutical preparations. In all links of the pharmaceutical industry chain, they play the role of processing and manufacturing basic pharmaceutical industry APIs, and most of them are outsourced production. API drug outsourcing process services refer to pharmaceutical companies entrusting other pharmaceutical R&D institutions to conduct API outsourcing process R&D and production. The production process of APIs includes chemical synthesis, fermentation, and animal and plant extraction.
At present, outsourcing has become an important purchase and sales model in the global pharmaceutical intermediates and API market. Most of the APIs and intermediates required by foreign preparation manufacturers are outsourced or developed and produced through drug outsourcing processes. Compared with the drug outsourcing process of most pharmaceutical products, the production process of APIs is much more complicated, with long processes, numerous pipelines, complicated operations, and many unstable APIs, which have high requirements for environmental parameters such as temperature, humidity, and light. , The related APIs are also flammable and explosive.
Different from the preparation product process, the production process of APIs is mostly a combination of chemical processes and chemical and physical processes, such as product dissolution, decolorization, extraction, washing and adsorption, etc. Therefore, the production of APIs pays attention to various process parameters And the control of environmental parameters, such as temperature, light, pressure, etc.
According to the source of acquisition, APIs are generally divided into chemical synthesis APIs, animal and plant extract APIs, and APIs obtained from production, fermentation and cell culture; APIs are also classified into non-sterile APIs according to the product’s microbiological level and target dosage form And sterile APIs. The typical API production process is as follows:
Chemical synthesis of APIs refers to the production methods of APIs in which various chemical APIs in industrial production undergo chemical reactions under certain conditions to obtain products with certain medicinal effects, and then undergo crystallization and drying processes to achieve various indicators of drugs. Medicilon provides a complete set of chemical drug development services, realizing end-to-end integrated services, providing one-stop services from pre-prescription research, drug analysis, drug stability research, formulation research and development, to a full set of CMC services.
Chemical synthesis of drugs is the main method for the production of APIs. Usually, the starting material and other compounds are chemically reacted in several steps to obtain the specific chemical structure of the target product, such as condensation, substitution, acylation, redox, etc.; and then another step Or a few steps of refining, such as decolorization, recrystallization, etc., to obtain the final API product. Among them, the production of intermediates and crude products is generally carried out in a general area without cleanliness, while the finishing process of the final product is carried out in a clean area. The quality of the design of the chemical synthesis API workshop (hereinafter referred to as the synthesis workshop) is crucial to the production of API manufacturers. The layout of the workshop is an important part of the process design. Only a reasonable process layout can realize the advanced process and equipment, and create a good environment for workshop production, operation, equipment installation and maintenance, and for safety, health, and environmental protection.
Fermentation is also one of the important methods of the production process of APIs, especially antibiotic APIs, such as penicillins, cephalosporins, etc., are usually obtained through a semi-synthetic method combining fermentation and chemical synthesis. Firstly, the main structure of the target compound is obtained through biological fermentation, such as the specific 3-lactam structure of penicillin, and then the structure is modified to obtain the final target compound; finally, the final bulk drug product is obtained through refining and recrystallization. The fermentation process generally needs to go through the process of culture medium preparation, canning treatment, inoculation, fermentation, wall breaking, filtration, precipitation, centrifugation, drying and other processes.
Similar to sterile preparations, sterile APIs are also divided into terminally sterilized sterile APIs and non-terminally sterilized sterile APIs. However, since most APIs are sensitive to high temperature and heat, high humidity and pressure, radiation, etc., There are few sterile APIs for terminal sterilization. At present, non-terminally sterilized sterile APIs usually combine the final step of product refining or salt formation with sterilization processes, and use pre-filtration plus two-stage 0.22 um sterilization filtration to achieve sterility of the final product. The material liquid after sterilization and filtration is usually crystallized, freeze-dried or spray-dried to obtain the final sterile bulk drug product.
In the traditional production of sterile APIs, the dissolution and decolorization of crude products are carried out in a C-level clean area, and sterilization filtration, product formation, centrifugation/filtration, drying, and packaging are carried out in a local A-level environment under a B-level background. of. At present, aseptic APIs are increasingly used in closed production, especially the use of three-in-one, isolation, crushing, and packaging equipment integrated isolation, crushing and packaging system, which greatly reduces product contamination by microorganisms or pyrogens Possibility. Therefore, the production of closed sterile APIs can also be carried out under a C-level background, and laminar flow protection or isolation environments are only set up in places where there is a risk of local exposure.
Compared with non-sterile APIs, the production of sterile APIs not only needs to pay attention to the requirements of chemical quality indicators such as product impurities and physical and chemical properties, but also needs to pay attention to product sterility assurance from the beginning of process design. Therefore, the production of sterile APIs has higher requirements on the environment and equipment
Nature is a treasure house of natural compounds. Through their own metabolism, animals or plants produce many compounds that cannot be synthesized but are of great significance for the treatment of diseases. Therefore, animal and plant extraction is an important method for obtaining target compounds and one of the main methods for producing APIs. one. For example, artemisinin used to treat malaria and heparin extracted from animal organs used to treat cardiovascular diseases. In recent years, advanced intermediates for the production of APIs have been extracted from animal and plant tissues, and then through certain chemical synthesis and structural optimization, the target compound is finally obtained, which can not only greatly improve its curative effect, but also further reduce its toxic and side effects. For example, the anti-cancer drug camptothecin has been further modified to obtain drugs such as irinotecan hydrochloride and topotecan with better selectivity and less toxic side effects.
The drug outsourcing process services provided by many pharmaceutical R&D companies provide a guarantee for the process that runs within the predetermined process parameters to continuously and effectively produce drugs that meet the predetermined specifications and quality. In the process of R&D and production of APIs, the production quality management of major drugs is also required. Pharmaceutical production quality management practices are based on production, and quality can only be achieved if there is production. The quality of medicines is produced, not inspected, and the production management of medicines is carried out in accordance with GMP.
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