On the methods of pilot-scale scaling up

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Regarding the methods of pilot-scale scaling up, the pilot stage is an essential path for a product to develop from its initial form to its mature state; it serves as the link in the product’s life cycle. During this intermediate experimental phase, efforts are made to study the patterns of change in the conditions of various chemical reactions in facilities of a certain scale, as well as to address issues that cannot be solved or identified in the laboratory setting. Although the nature of chemical reactions does not change depending on the differences in experimental setup, the optimal conditions for each step of these reactions may vary due to external factors such as the scale of the experiment and the equipment used. Therefore, pilot-scale scaling is very important. At what stage of the experiment is pilot testing carried out? At least the following conditions must be met: 1. The yield in pilot tests is stable, and the product quality is reliable. 2. The manufacturing conditions have been determined, as well as the analysis and testing methods for the products, intermediates, and principles. 3. Corrosion resistance tests have been conducted on certain equipment and pipeline materials, and the necessary general equipment is available. 4. Material balance was performed. Preliminary methods have been developed for dealing with the issue of three wastes. 5. The specifications and unit consumption amounts for the raw materials have been specified. 6. Requirements for safe production have been put forward. Methods for pilot-scale scaling up include: empirical scaling up: which relies on experience to explore the characteristics of the reactor through progressive scaling up (pilot plant – intermediate plant – medium-sized plant – large plant). It is also the main method used in drug synthesis at present. Similar scaling: It mainly involves using the principle of similarity for scaling. This method has certain limitations and is only applicable to the amplification of physical processes. and is not suitable for the scaling up of chemical processes. Mathematical simulation amplification: It is a form of amplification that makes use of computer technology, and it represents the direction for future development. Furthermore, the development of micro intermediary devices is also progressing rapidly; that is, micro intermediary devices are being used to replace larger ones in order to provide accurate design data for industrial applications. Its advantages are low cost and fast construction. The tasks during the pilot-scale-up phase mainly include the following ten points; in practice, it is possible to determine the priorities based on different circumstances and carry out the work in an organized and planned manner. 1. Final determination of the process route and unit reaction operation methods. Especially when the originally selected route and unit reaction method reveal significant problems that are difficult to resolve during the pilot-scale scale-up phase, other routes should be selected and pilot-scale scale-up should be carried out using the new routes. 2. Selection of equipment material and model. Special attention should be paid to the selection of material for equipment that comes into contact with corrosive substances. 3. Investigation of mixer type and mixing speed. Many of these reactions are heterogeneous, and they have large heat effects. During pilot tests, due to the small volume of the material, mixing is effective and heat and mass transfer issues are not significant. However, when scaling up to pilot plant scale, it is necessary to take into account the properties of the material and the characteristics of the reaction, paying attention to the influence of mixing patterns and speed on the reaction, in order to select an appropriate mixer and determine the suitable mixing speed. 4. Further study on reaction conditions. The optimal reaction conditions obtained at the laboratory stage may not fully meet the requirements of pilot-scale scaling. Therefore, in-depth studies should be conducted on the key influencing factors, such as feeding rate, mixing efficiency, the heat transfer area and coefficient of the reactor, as well as the refrigerant, in order to understand how these factors change in pilot-scale installations. Obtain more suitable reaction conditions. 5. Determination of the process flow and operating methods. It is necessary to consider meeting the requirements of industrial production for the reaction and post-treatment procedures. Pay special attention to shortening processes, simplifying operations, and improving labor productivity. Thereby finalizing the production process flow and operating methods. 6. Perform material balance calculations. Once the reaction conditions and procedures for each step are determined, material balance calculations should be carried out for those reactions that result in low yields, numerous by-products, and significant amounts of waste. The accuracy that must be achieved in material balance is that the total weight of the reaction products and other by-products equals the sum of the amounts of each material fed in before the reaction takes place. In order to address the weak points. Provide data on tapping into energy savings, improving efficiency, recovering and comprehensively utilizing by-products, as well as controlling waste gases, waste liquids, and waste solids. Research on analytical methods should be conducted for chemical components for which no such methods exist. 7. Determination of the physical properties and chemical constants of raw materials and intermediates. To address the issues in production processes and safety measures, it is necessary to determine the properties and chemical constants of certain materials, such as specific heat, viscosity, and explosion limits. 8. Formulation of quality standards for raw material intermediates. If the quality standards in the pilot tests are not sufficient, they should be revised and improved based on the pilot-scale experiments. 9. Determination of consumption quotas, raw material costs, labor hours, and production cycles, etc. Based on the summary report of the pilot-scale study, infrastructure design can be carried out, and a procurement plan for the model equipment can be formulated. Design and manufacture of non-standard equipment, as well as construction of production workshop buildings and installation of equipment in accordance with the construction drawings. All production equipment and auxiliary equipment have been installed. If the trial production is successful and stable during the short-term trials, a process specification can be developed for full-scale production. Steps for pilot-scale scaling: I previously wrote a post on pilot-scale scaling, and it received good feedback. Now I have the idea of systematizing the content in this area. Based on my own experience, I will share some things over time for everyone to discuss. First, let’s talk about the purpose of pilot testing. Pilot testing is a transitional stage between lab-scale experiments and industrial production ； It is a production process that makes use of small-scale manufacturing equipment; the design requirements, selection, and working principles of such equipment are essentially the same as those in large-scale production ； After the pilot scale testing is completed, pilot plant trials are carried out to study feasible industrial processes and equipment selection, providing a basis for industrial design. The work steps required for the pilot-scale production of active pharmaceutical ingredients and intermediates include: 1. Conducting material balance calculations and designing the pilot-scale process flow based on the procedures used in lab-scale tests. Material balance includes raw material consumption and production cost estimation. The raw material consumption table should include an estimation of the recovery of recycled solvents. The process flow should be a comprehensive representation of the operational steps and equipment combined. 2. Install the pilot plant equipment in accordance with the flowchart and the pilot process. Important aspects include: in a modification workshop, considerations must be given to safety, ventilation, heating, lighting, power distribution, and other factors. Arrange the operation platform according to the equipment layout. Equipment installation and commissioning. 3. With complete equipment, prepare the pilot-scale operation procedures based on the pilot test steps and processes. 4. Conduct trial runs simultaneously in conjunction with the operation training for workshop staff. The general principle for testing is to proceed step by step, examining each operation and the testing situation, and then carry out everything simultaneously. 5. Begin the formal experiment. The main items to be examined during the formal experiment include: 1) verifying the process and achieving stable yields. 2) Verify the operations used in the pilot test. 3) Determine the product purification method. 4) Verify solutions such as solvent recovery. 5) Verify the special operational processes in industrialization. 6) Observe in detail the heat effects of each reaction step. 7) Determine safety measures. 6. Propose an industrial production process plan and determine the main production process flow. This is the ultimate goal of pilot testing. Industrial production is carried out based on the data from pilot tests, along with the selection of feasible process routes and equipment, to conduct industrial design, installation, commissioning, and then put the production into operation. The work steps required for the pilot-scale production of active pharmaceutical ingredients and intermediates include: 1. Conducting material balance calculations and designing the pilot-scale process flow based on the procedures used in lab-scale tests. Material balance includes raw material consumption and production cost estimation. The raw material consumption table should include an estimation of the recovery of recycled solvents. The process flow should be a comprehensive representation of the operational steps and equipment combined. 2. Install the pilot plant equipment in accordance with the flowchart and the pilot process. Important aspects include: in a modification workshop, considerations must be given to safety, ventilation, heating, lighting, power distribution, and other factors. Arrange the operation platform according to the equipment layout. Equipment installation and commissioning. 3. With complete equipment, prepare the pilot-scale operation procedures based on the pilot test steps and processes. 4. Conduct trial runs simultaneously in conjunction with the operation training for workshop staff. The general principle for testing is to proceed step by step, examining each operation and the testing situation, and then carry out everything simultaneously. 5. Begin the formal experiment. The main items to be examined during the formal experiment include: 1) verifying the process and achieving stable yields. 2) Verify the operations used in the pilot test. 3) Determine the product purification method. 4) Verify solutions such as solvent recovery. 5) Verify the special operational processes in industrialization. 6) Observe in detail the heat effects of each reaction step. 7) Determine safety measures. 8) Generally, at least 3 to 5 batches should be produced for the intermediates and the final product, in order to accumulate data and improve the materials for pilot-scale production. 6. Propose an industrial production process plan and determine the main production process flow. This is the ultimate goal of pilot testing. Industrial production is carried out based on the data from pilot tests, along with the selection of feasible process routes and equipment, to conduct industrial design, installation, commissioning, and then put the production into operation. The drug substance produced on a pilot scale is supplied for clinical trials and is intended for human use. All activities in pilot production must comply with the Good Manufacturing Practices for Pharmaceuticals (GMP), and the quality and purity of the products must meet pharmaceutical standards. The U.S. FDA requires that, when submitting a New Drug Application (NDA), information on the pilot-scale production (or future large-scale production) of the active pharmaceutical ingredient be provided.