API &Intermediates Trial Design And Verification Workshop
With the expansion of China's API &Intermediates in the United States, Europe, Japan and other international markets, raw material drug manufacturers and R & D companies to increase research and development of new drugs, generic drugs, after a small laboratory to scale production, the need to enlarge scale pilot. Its purpose is: to verify the process conditions of small test, explore the amplification effect and adjust the process parameters for the follow-up to enlarge the production of equipment selection and operation guidelines to provide guidance; successful research and development of new products, sales in the potential country, the use of the registration declaration; Production of a certain amount of products, the rapid occupation of the market; pilot equipment investment less effectively reduce the risk of pre-project investment.
1 design requirements
Pilot plant in the pilot plant to produce the main line of dextromethorphan, taking into account the flexibility of other products. Designed to meet the requirements of the new version of the GMP issued by the State Pharmaceutical Administration, API &Intermediates are exported to markets such as Europe, the United States and Japan to meet the regulatory requirements of the U.S. FDA, European EDQM and Japan PMDA, and the cleanliness of the clean area reaches Grade D requirements.
Pilot chemical unit reaction condensation, addition, cyclization, hydrolysis, acylation, sulfonation and other general processes, but also oxidation, chlorination, fluorination, hydrogenation, nitration, diazotization and other high-risk processes; chemical unit operation such as Concentrated, crystallized, extracted, filtered, centrifuged, dried and the like. Temperature range -20 ° C ~ 300 ° C, the pressure range of -0.1 ~ 4.0 MPa.
2 design process
Pilot scale two sets of amplification gradient design
Laboratory pilot scale to 100 ~ 1000 mL glass bottles, up to 10 L scale. Pilot test for the study of laboratory technology, amplification gradient to 10 to 50 times is appropriate, for the mechanism to grasp the amplification gradient can be 50 to 100 times. The design has enlarged 10 to 30 times the production capacity of small-scale production lines and small-capacity production line based on the amplification of 10 times the gradient of the two production lines of high-capacity production lines.
Small capacity production line with 30 ~ 100L autoclave reactor as a separate unit, 5 ~ 300L auxiliary processing equipment, supporting the public works (freezing, cooling, steam, hot water), the use of removable storage tanks, centrifuges, filter press Machine and other facilities, quick opening interface, the use of hose connections. The advantages of flexible combination, applicability, the disadvantage is the cleaning workload, long operating cycle, low productivity. For the investigation of the reaction mechanism, the main amplification effect, but also for the production of sales kg level, high value of the API &Intermediates.
Large-capacity production line to the production of dextromethorphan pipeline layout, the reaction unit or between the operating unit equipment using fixed pipe connections, two units with metal hose and quick-open connection. Production line with 500 ~ 1500 L reactor, 50 ~ 3000 L auxiliary processing equipment. The advantages of the production process for the smooth, high utilization of equipment, no cross-contamination, easy operation and can achieve a certain yield. The disadvantage is that when switching other products, the need to re-combination of equipment, pipe installation costs are high. Used to verify the production process amplification, but also mass production of tens of kilograms to 100 kilograms.
Verify the file system
API &Intermediates plant workshop, production equipment and facilities, purified water systems, clean areas and air-conditioning systems for verification management, a complete document system. The file system supports GMP files and GMP files, supports GMP files with user requirements (URS), purchase contract specifications, product certificate provided by the supplier, design drawings, and completion verification reports; GMP files mainly include DQ, IQ, OQ, PQ, PV, equipment preventive maintenance plan, maintenance, review summary.