Pilot scale → Pilot plant scale → Full-scale production

Thread Content

1. Pilot stage – Development and optimization of methods. 2. Pilot-scale production stage – Verification and application of methods. 3. Process validation/commercial production stage – Application of methods, with a decision on whether to conduct validation based on any changes that occur. The small-scale production stage involves a comprehensive and systematic reform of the existing synthetic routes and methods in the laboratory. Based on the reforms, batch synthesis in the laboratory was carried out to accumulate data, thereby establishing a synthetic route that is generally suitable for pilot-scale production. Research in the pilot stage should focus closely on the key issues affecting industrial production. Such as shortening the synthesis route, increasing yield, simplifying operations, reducing costs, and ensuring safe production. Main tasks during the pilot production phase: 1. Process: reaction parameters and post-processing methods for the manufacturing process. 2. Materials: properties of the materials and control over them. 3. Structural confirmation. Tasks during the pilot scale stage: 1. Identify the optimal synthetic route: A mature synthetic route should feature few synthesis steps, high overall yield, simple equipment requirements and process flow, as well as readily available and inexpensive raw materials. 2. Replace chemical reagents with industrial-grade materials: For small-scale synthesis in the laboratory, reagents and solvents of standard grade are not only expensive but also not available in large quantities. For large-scale production, chemical raw materials and industrial-grade solvents should be used as much as possible. During the pilot stage, it is necessary to determine whether the use of industrial-grade raw materials and solvents interferes with the reaction and affects the yield and quality of the product. Through pilot studies, the optimal reaction conditions and processing methods suitable for production using industrial-grade raw materials were identified to achieve low cost, high quality, and high yield. 3. Recovery and reuse of raw materials and solvents: Synthetic reactions generally require large amounts of solvents, and in most cases the solvents remain unchanged before and after the reaction, allowing them to be directly recovered and reused. Sometimes the solvent may contain reaction by-products, unreacted residual materials, volatile impurities, or changes in solvent concentration. Small-scale tests should be conducted to find methods for recycling and processing these substances, with data demonstrating that the use of recycled materials and solvents does not affect the quality of the product. The recovery and reuse of raw materials and solvents can not only reduce costs, but also facilitate the treatment of waste and environmental hygiene. 4. Safe production and environmental hygiene: Safety is crucial for industrial production; synthetic reactions involving toxic substances and harmful gases should be eliminated as much as possible through pilot studies ； It is essential to avoid carrying out dangerous operations that involve flammable or explosive materials; if this cannot be done immediately, appropriate protective measures should be found. Try to avoid using highly toxic organic solvents, and look for alternatives with similar properties but lower toxicity. One of the characteristics of drug production is the large variety of raw materials used in large quantities, along with complex chemical reactions. This often results in the generation of large amounts of waste gas, waste residues, and other wastes; if not properly handled, this can severely impact environmental protection and cause pollution. Waste issues related to waste water, waste gas, and solid waste must be taken into consideration when selecting a process route, along with suggestions for their treatment. Differences between pilot scale and lab scale testing: The distinction between lab scale and pilot scale testing lies not only in the amount of material used and the size of the equipment employed, but also in the different tasks that need to be accomplished at each scale. Pilot testing is primarily focused on exploratory and developmental work. In chemical pilot testing, the reaction and separation processes for the specified tasks are investigated, along with the analysis and identification of the materials involved; once qualified samples are obtained and economic and technical indicators such as yield meet the desired requirements, the phase can be concluded and progress can be made to the pilot plant scale. The issue to be addressed during the pilot-scale process is: how to use industrial methods and equipment to carry out the entire process as in the pilot test, and to achieve roughly the same economic and technical parameters as in that pilot test, while also increasing the scale. Why is pilot testing necessary? 1. Different scales. 2. Different sources of raw materials. 3. Different mixing methods. 4. Different ways of heat transfer. 5. Different materials for the reactors. The purpose of pilot scale-up: Pilot testing is an essential transitional step from laboratory experiments to industrial production ； The transition from pilot testing to actual production on the manufacturing equipment has been largely completed, ensuring that products meeting the specified quality standards can be produced consistently in accordance with the operating procedures ； 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. Therefore, the purpose of pilot-scale scaling is to verify and refine the synthetic route determined through laboratory experiments, to determine whether it is mature and reasonable, and whether its key economic and technical parameters meet the requirements for production ； The study examines the structure, materials, installation, and workshop layout of the selected industrial production equipment, in order to provide data as well as optimal quantities of materials and consumption levels for actual production. The importance of pilot-scale scaling up: Pilot scale refers to small-scale production simulation tests. Pilot testing is conducted to explore industrializable solutions based on laboratory-scale experiments. It further investigates the patterns of changes in the conditions for various chemical reactions in facilities of a certain scale, and addresses issues that cannot be resolved or identified in the laboratory, thereby providing a basis for design in industrial production. 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. Generally speaking, pilot-scale scaling up is a rapid and crucial transitional stage from a high-level stage to industrial production, with its level representing the level of industrialization. Pilot-scale scaling is an essential step from research and development to production, as well as an effective measure to reduce the risks associated with industrialization. Tasks in the pilot-scale up phase: 1. Assess whether the process route provided by the laboratory has any special requirements in terms of process equipment, conditions, raw materials, etc., during pilot-scale up, and whether it is suitable for industrial production. 2. Verify whether the pilot-scale process is mature and reasonable, and whether the key economic indicators meet the requirements for production. 3. Further evaluate and optimize the process conditions, ensuring that basically stable data are obtained for each reaction step and unit operation ； Perform material balance. 4. Selection of equipment material and model. 5. Determine the requirements for heat and mass transfer for each reaction step. The feeding method in exothermic reactions, and the impact of feeding rate on the reaction. 6. Examination of mixer type and mixing speed. 7. Types and requirements for heating/cooling media (steam, hot water, cold brine) 8. Propose treatment plans for the “three wastes” ； 9. Determination of the physical properties and chemical constants of raw materials and intermediates. 10. Formulate or revise the quality standards and analytical methods for intermediates and finished products based on pilot study data ； 11. Determine the specifications or standards for the starting materials, reagents, or organic solvents to be used ； Generally, the specifications of the raw materials and reagents used in pilot testing should be the same as those used in industrial production. 12. Determination of consumption quotas, raw material costs, labor hours, and production cycles. 13. Propose the process flow for the entire synthetic route, as well as the operational procedures for each unit operation. The task of pilot-scale scaling: Once the laboratory-scale process is mature, a process report must be prepared. Pilot testing is not simply a scaled-up version of lab testing; the processes of mixing, heat transfer, concentration, filtration, and drying in pilot testing differ from those in lab testing. In lab tests, efforts should be made to simulate the conditions of pilot testing. Additionally, it is important to remember that destructive tests must be conducted at each step. Clarify the equipment used in pilot testing and the physicochemical properties of the materials. Safety first. There is pilot-scale testing followed by trial production before full-scale manufacturing; during this process, unexpected problems can arise that one simply cannot imagine. Therefore, it is necessary to carefully monitor every detail of the process, and in particular not to overlook any abnormal situations, as otherwise it can lead to serious problems. Revise and determine the applicable ranges of the optimal process parameters for each reaction step under pilot-scale equipment conditions; modify or adjust the relevant processes as necessary, and closely monitor changes in side reactions and related substances in each operational unit under pilot-scale conditions (such as local overheating and uneven distribution of the reaction medium). Methods for pilot-scale scaling up: 1. Empirical scaling up: This involves using experience to determine the characteristics of the reactor through gradual scaling up (pilot plant – intermediate plant – medium-sized plant – large plant). It is also the main method used in drug synthesis at present. 2. Similarity 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. 3. Mathematical simulation amplification: It is amplification achieved through computer technology, and it represents the direction for future development. Conditions required for pilot-scale testing: 1. Stable yield in lab-scale tests and reliable product quality. The process procedures and parameters for each reaction step have been determined (such as feeding method, reaction time, reaction temperature, pressure, end-point control, extraction, separation, crystallization, filtration, drying, etc.). 2. The methods and requirements for the refinement, crystallization, separation, and drying of the finished product have been determined (crystal form, residual solvents) ； The 3–5 batches of stability testing conducted on a pilot scale indicate that this pilot-scale process is feasible and stable ； 3. The necessary material corrosion tests have been completed ； 4. Quality control methods/standards for raw materials, intermediates, and products have been established. 5. Material balance was performed. Preliminary methods have been developed for dealing with the problems of waste water, waste gas, and solid waste. The specifications and consumption quantities for the raw materials have been specified. 6. Requirements for safe production have been established. Objectives to be achieved through pilot testing: 1. To develop draft production process specifications for the product through pilot testing (including operating procedures for each unit reaction and unit operation, detailed process control rules, product flow diagrams, material balance calculations, and the raw material consumption per unit of product). 2. Prove that the process conditions and operating procedures for each chemical unit reaction enable the production of products that meet the specified quality standards on the model production equipment, using the prescribed raw materials and auxiliary materials, while ensuring good reproducibility and reliability ； 3. Technical and economic indicators such as the raw material consumption per unit of product are acceptable to the market. 4. The plans and measures for treating waste gases, wastewater, and solid waste are acceptable to environmental protection authorities ； 5. Measures such as safety, fire prevention, and explosion protection can be accepted by public security and fire departments ； 6. The labor safety measures provided are acceptable to the authorities responsible for preventing occupational diseases. Tasks after the completion of pilot production: 1. Conduct timely summaries to identify the differences between the pilot and pilot-scale tests; based on the test results, provide a truthful and objective assessment of the pilot production process, along with suggestions for improvement, in order to lay the foundation for full-scale production. 2. Based on the pilot test results and various data from the R&D phase, prepare (or revise) product process specifications and process validation plans that meet the production requirements. 3. Based on the process specifications and taking into account the operational experience gained during pilot-scale scaling, develop (or revise) practical operation procedures suitable for use in production. 4. Prepare production records that meet the filling requirements in accordance with the process specifications, operating procedures, and various production documents. 5. Develop clear testing methods.