The process amplification of API refers to the enlargement of the production of API from laboratory scale to industrial scale, which is the only way from research and development to production of pharmaceutical preparations. Process scale-up is an indispensable development process for APIs to adopt large-scale production and realize industrialization. Its purpose is to verify, review, and improve the reaction conditions determined by the laboratory process, and to study the structure, material, and material of the selected industrial production equipment. Installation and workshop layout, etc., can provide data, materials and consumption for formal production, and are effective measures to reduce industrialization risks. Today, let’s take a brief look at the process of API process amplification and the problems that may arise in the process of API process amplification.
The process of bulk drug process amplification
Step1:
In pharmaceutical product development, the API development stage is an early stage in the life cycle of the drug product. The ultimate goal of this stage is to design a process suitable for commercial production that can consistently produce a product that meets its key quality attributes.An intermediate is a material produced in the process of an API that must undergo further molecular changes or refinements before it can become an API. Drug production depends on the customized synthesis of pharmaceutical intermediates. After an hour of research on the synthesis of the API, the control parameters for the chemical reactions are obtained to achieve the purpose of manufacturing in compliance with the quality standard API. In the scaling-up stage of API process, material balance and time balance should be done step by step according to the production process of small test, and documents should be sorted out.The purpose of material balance is to select the appropriate size of equipment, the purpose of time balance is to obtain the production time of a single batch, and ultimately derive the total batch or the planned time to complete a task.
Step2:
To choose the most suitable equipment, you can ignore the existing equipment and just draw a simple flow chart. Every equipment should be reflected on the map, every logistics should be reflected on the map, and related controls will not be considered for the time being.
Step3:
Consider the stirring blade of the reactor, consider the public engineering system, such as the heat exchange medium of the reactor, the cooling of the condenser, the public engineering required by the medium, the vacuum source, and the compressed air; consider the key control instruments or central control measures, such as Online PH, online sampling, temperature and pressure control, etc. To perfect the drawings on the basis of Step 2, documents must be obtained for each process, not ideas in the brain.
Step4:
Make recommendations for equipment rectification in comparison with existing equipment.
Step5:
Get process flow chart, equipment plan and equipment list. Draw a complete process flow chart with control points on the basis of the first four steps. Draw the equipment plan and compile a complete equipment list.
Amplification of the API process, that is, the production of APIs from laboratory scale to industrial scale, is an indispensable development process for APIs to adopt large-scale production and realize industrialization. Medicilon is committed to providing customers with fast and efficient services. Its unique “customized” pharmaceutical process research and development model also fully embodies this concept, enabling customers to obtain APIs as soon as possible for clinical research. Medicilon’s process research and development department has rich experience in process optimization and the development of new, safe and environmentally friendly process routes, and is committed to helping customers develop stable and low-cost processes suitable for mass production.
Problems that may occur in the process of API process amplification
(1) Change of reaction selectivity
The most common problem in process scale-up is the change of reaction selectivity, which will affect the yield and purity of the product. This is mainly due to the inconsistency of the mixing effect and production in the small-scale trial. If the influence of the speed has been evaluated in the small test, when a problem occurs, the cause will be quickly found. The reactors in the pilot plant are equipped with frequency conversion speed control, and appropriate adjustments can be made to determine the appropriate speed.
(2) New crystal forms appear in process amplification
During the scale-up, the separation of the product will also cause problems, the washing effect of the filter cake in the production does not reach the level of the small test, and the impurities cannot be completely washed away. The three-in-one filter, washing and drying equipment with stirring can replace the centrifuge under certain process conditions. The three-in-one equipment can be directly added to the solvent for washing and beating after filtering. The washing effect is better than that of the centrifuge.
(3) The impact of production operation time
It is necessary to carry out experiments on the impact of extended time on products for small trials. In actual production, due to the extension of the distillation time, the product decomposes and side reactions occur many times.
The preparation of API is very important in pharmaceutical preparation research and development. It can provide qualified API for pharmacological and toxicological research, preparation and clinical research in the process of drug development, and provide detailed information for drug quality research. Therefore, it is important to provide the preparation technology of API in line with industrial production.
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Several Major Issues that Need to be Paid Attention to API Process Scale-up
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