From pilot-scale process to integration with factory production

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The intermediate experimental phase is dedicated to further studying the patterns of changes in the conditions of various chemical reactions in reactors of a certain scale, as well as addressing issues that cannot be resolved or identified in the laboratory. Although the nature of chemical reactions remains unchanged regardless of the scale of experimentation, the optimal process conditions for each step of the chemical reactions may vary depending on external factors such as the scale of the experiment and the equipment used. Therefore, pilot-scale scaling is very important. Conditions required for pilot-scale testing in the laboratory: 1. Stable yield in pilot tests and reliable product quality. 2. The experimental 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 the materials of certain equipment and pipelines, and the necessary general equipment is available. 4. A material balance was performed. Preliminary methods have been developed for dealing with the issues of waste water, waste gas, and solid waste. 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: 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 a form of amplification that makes use of computer technology, and it represents the direction for future development. In addition, 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 rapid construction. Tasks for pilot-scale scaling up: There are mainly the following ten points; in practice, it is possible to determine the priorities based on different circumstances and carry out the work in a planned and organized manner. 1. Final determination of the process route and unit reaction operation methods. Especially when the originally selected route and unit reaction method reveal major problems that are difficult to resolve during the pilot-scale scaling up phase, other routes should be selected instead, and pilot-scale scaling up should be carried out using the new route. 2. Selection of equipment material and model. Special attention should be paid to the selection of equipment materials when dealing with corrosive materials. 3. Investigation of agitator types and agitation speeds. Many reactions are heterogeneous, and they involve significant heat effects. In small-scale tests, due to the small volume of material, the stirring effect is good and problems related to heat and mass transfer are not prominent. However, during pilot-scale scale-up, it is necessary to consider how the type and speed of stirring affect the reaction, based on the properties of the material and the characteristics of the reaction, so as to select a suitable agitator and determine the appropriate stirring 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 main 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 making the reaction and post-treatment operating methods meet the requirements of industrial production. Pay special attention to shortening processes, simplifying operations, and improving labor productivity. Thereby finally determining the production process flow and operating methods. 6. Perform material balance calculations. Once the reaction conditions and operating procedures for each step are determined, material balance calculations should be carried out for those reactions that yield low yields, produce many by-products, and generate 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, recycling by-products and their comprehensive utilization, as well as the control of 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 insufficient, 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 on a short-term basis, a process specification can be formulated for production. 10. From laboratory research to pilot production. The ultimate goal of the research is to produce drugs of qualified quality for medical use. Before the research results can be put into large-scale production, it is necessary to develop a mature, stable technical process suitable for industrial production. The development process is carried out in stages, including: the experimental research stage, the stage of producing small quantities of the product, the pilot production stage, and only then can it proceed to industrial production. The various stages are connected and reinforce each other; the tasks differ from one another, as do the focus areas of research, while the scale of production gradually increases from small to large. Pilot-scale production should be completed before applying for the registration of a new drug. The following uses synthetic drugs as an example to illustrate the main tasks at each stage. 1. Laboratory research phase: This is the exploratory stage of new drug research, aimed at identifying lead compounds and modifying their structures in order to find promising candidates for new drugs. Its main task is to reasonably design the compounds and complete their synthesis as soon as possible ； Use various methods to confirm the chemical structure of the compound ； Determine the main physical parameters of the compound ； Understand the general properties of the compound, without conducting excessive research on its synthesis methods. To prepare small amounts of samples for pharmacological screening, every separation and purification method is employed, such as repeated fractionation, multiple recrystallizations, and various chromatography techniques. Obviously, such a synthesis method is far from industrial production. 2. Small-scale pilot production phase: Once a promising new drug candidate is identified, small-scale pilot production (hereinafter referred to as “pilot testing”) should be carried out immediately to produce a sufficient quantity of the drug for pre-clinical evaluation. Its main task is to carry out a comprehensive and systematic reform of the existing synthesis 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 synthetic route, increasing yield, simplifying operations, reducing costs, and ensuring safe production. The study identified an optimal synthetic route: 1) A compound can often be synthesized through different routes and methods, and the route and method initially used in the laboratory are not necessarily the best ones. At that time, little consideration was given to reaction conditions, equipment, and the source of raw materials, nor were high demands placed on yield; however, these factors are very important for industrial production. Synthetic steps and methods that are not suitable for industrial application should be modified through pilot-scale studies. A relatively mature synthetic process route should feature short synthesis steps, high overall yield, simple equipment requirements and process flow, as well as an abundant and inexpensive supply of raw materials. 2) When replacing chemical reagents with industrial-grade materials for small-scale synthesis in the laboratory, the reagents and solvents of standard grades are not only expensive but also not available in large quantities. For mass 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 whether it has an impact on the yield and quality of the product. Through pilot-scale 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: Synthesis reactions generally require large amounts of solvents. 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 showing that the use of recycled materials and solvents does not affect the quality of the product. The recycling of raw materials and solvents not only reduces costs but also contributes to the treatment of waste streams and environmental hygiene. 4) Safe production and environmental hygiene are crucial for industrial manufacturing; 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 are flammable or explosive; 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 waste materials; if not properly handled, this can have a serious impact on 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. 3. Pilot production stage: Pilot production is an essential link in the transition from laboratory to industrial production, serving as a bridge between the two. Pilot production is an expansion of pilot testing and a microcosm of industrial production; it should be carried out in a factory or a dedicated pilot plant. The main tasks of pilot production are: 1) to evaluate the synthetic process route provided by the lab tests, to determine whether there are any special requirements in terms of process conditions, equipment, raw materials, etc., and whether it is suitable for industrial production. 2) Verify whether the synthetic process route provided in the pilot study is mature and reasonable, and whether the key economic and technical indicators meet the requirements for production. 3) During the scaled-up pilot study, the process route should be further evaluated and refined, ensuring that basically stable data are obtained for each reaction step and unit operation. 4) Formulate or revise the quality standards for intermediates and finished products, as well as the analysis and identification methods, based on the results of pilot-scale studies. 5) The number of batches for preparing the intermediates and the final product should generally be no less than 5 batches, in order to accumulate data and improve the materials for pilot production. 6) Based on raw materials, energy consumption, labor hours, etc., conduct a preliminary calculation of economic and technical indicators to determine the production cost. 7) Conduct step-by-step planning for the materials at each stage, and propose measures for recycling and reuse as well as for the treatment of waste materials. 8) Propose the process flow for the entire synthesis route, the technical specifications for each unit operation, as well as the safety operation requirements and regulations. 4. The experimental research on the active monomers of natural drugs involves pilot-scale studies and pilot production that are largely similar to those for synthetic drugs, with extraction, separation, and purification processes being used in place of various chemical synthesis reactions. 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 Practice for Drugs (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. Selection of equipment and design of process management: 1. Based on the results of pilot tests, equipment is selected in multi-functional and pilot production facilities. First, it is necessary to consider whether the equipment capacity is appropriate, whether the material of the equipment and the piping is suitable for the process medium and resistant to corrosion, and whether the heating, cooling, and mixing speeds meet the required standards. 2. Methods of material transfer (feeding, discharging, transfer between various stages), and how to prevent issues such as material leakage, solidification, and blockages. 3. Methods for measuring and adding materials, such as how to effectively control dropwise addition? 4. Is any gas produced in the reaction? Will there be a rush on materials? If necessary, a gas-liquid separator should be added, and a return pipe installed. 5. Are the separation conditions such as centrifugation and pressure filtration met? Based on the above conditions and other process requirements, the equipment and pipelines are adaptively modified. Preparations before material feeding: 1. For equipment, especially newly installed or retrofitted equipment as well as equipment that has been idle for a long time, pressure testing and leak testing must be conducted. These tests should be carried out in conjunction with cleaning operations as part of a joint commissioning process, to ensure that no hot work is required after material feeding. Only when there are no leaks can insulation be applied to the equipment and pipelines. 2. Carry out proper cleaning of the equipment and clearing of the work area to ensure that no debris enters the reaction system, prevent cross-contamination, and maintain an orderly working environment. 3. Determine the feeding coefficient according to process requirements and test needs; calculate the amount of materials to be fed so as to ensure that raw materials are issued in a coordinated manner, meet quality standards, have clear markings, and are stored in designated locations based on classification. 4. Plan and prepare containers and storage areas for the intermediates. 5. Inspection of production conditions: Check whether steam, oil bath, cooling water, and brine flow smoothly (you can feel the temperature difference before and after opening the valve with your hand). Also, verify whether the valve operation meets the requirements. 6. Is the material homogeneous? Is the stirring sufficient to ensure uniform mixing? Do solids accumulate in the recesses of the bottom valve, especially solid catalysts or poorly soluble raw materials? What measures can be taken to prevent such accumulation? 7. Are all the instruments functioning properly? It is necessary to determine whether a thermometer can be inserted into the material throughout the entire process (when there are changes in the level of the material and when too little material is added). 8. Develop proper operating procedures and safety protocols. 9. Train employees in process-related skills (especially by clearly explaining the control parameters and key points, the hazards of violating operating procedures and the layout of pipelines, as well as the control of valve opening and closing); meanwhile, implement emergency measures for situations where control parameters are exceeded or emergencies occur. Conduct safety training and occupational health and safety training. 10. Identify the responsible persons for the project, organize the shift schedule properly, assign key personnel to assist, and clarify the methods for communication between workers, key personnel, and senior management during nighttime. 11. Prepare emergency response plans and carry out the necessary preparatory work. Pilot scale-up and production process specifications: The purpose of pilot scale-up is to verify, review, and refine the reaction conditions determined in laboratory experiments, as well as to study the structure, materials, installation, and workshop layout of the industrial production equipment selected. It aims to provide data for full-scale production, along with information on product quality and consumption levels. (1) Research contents for pilot-scale scaling up 1. Overview of the process—In the production process, all factors that are directly related to the sequence and conditions of chemical synthesis reactions or biosynthetic pathways (such as ingredient ratios, temperature, reaction time, mixing methods, post-treatment methods, and purification conditions) are collectively referred to as process conditions. The other processes become auxiliary processes. 2. The importance and characteristics of pilot-scale scaling: Once the laboratory-scale process for chemical pharmaceutical manufacturing has been developed, that is, once the drug production process has been finalized through evaluation, it is generally necessary to carry out pilot-scale scaling, which involves increasing the scale by 50 to 100 times compared to the small-scale tests. This step allows for further investigation into how the reaction conditions change in facilities of a certain size, as well as for addressing any issues that could not be resolved or were not identified during the laboratory phase. A certain quantity of samples is also required in new drug development to supply clinical trials and for drug testing as well as sample retention for monitoring. Depending on the dosage of the drug and the duration of the treatment course, usually 2 to 10 kg is required, which is difficult to achieve under normal laboratory conditions. Once the process route is determined, each chemical synthesis or biosynthesis step does not undergo significant changes due to differences in pilot-scale, pilot plant-scale, or large-scale production conditions. However, the optimal process conditions for each step may need to be adjusted depending on external factors such as the scale of the experiments and the equipment used. The methods for pilot-scale scaling include empirical scaling, similarity scaling, and mathematical simulation scaling. 1) Experience amplification method—mainly relies on experience to explore the characteristics of the reactor by gradually scaling up (experimental unit, intermediate unit, medium-scale unit, large-scale unit). In the process development of synthetic drugs, pilot-scale scaling is primarily carried out using the empirical scaling method, which is also the main approach in chemical engineering research. 2) Similarity scaling method—mainly applies similarity theory for scaling. It is used in physical processes and has certain limitations. 3) (Non-linear) mathematical simulation amplification method—a amplification method that utilizes computer technology, and it represents the main direction for future development. (Digital Factory) 3. Pilot-scale scaling studies 1) Review of the production process route. Generally, the methods for individual reactions and the production process route should be basically determined at the laboratory stage. During the pilot-scale-up phase, the specific process operations and conditions are determined to suit industrial production. However, when a selected process route and process steps give rise to significant problems that are difficult to overcome during pilot-scale scaling up, it is necessary to review the laboratory process route and modify its process steps. 2) Selection of equipment material and type: When starting up pilot-scale scale-up, the material and type of various devices required should be considered to determine their suitability; particular attention should be paid to the selection of materials for devices that come into contact with corrosive substances. 3) Investigation of mixer type and stirring speed: Most reaction processes in drug synthesis are heterogeneous reactions, which involve significant heat effects. In the laboratory, due to the small volume of the materials and good mixing efficiency, problems related to heat and mass transfer are not apparent. However, when scaling up to pilot scale, these issues of heat and mass transfer become prominent due to the effects of mixing efficiency. Therefore, during pilot-scale scaling up, it is necessary to consider the type of stirrer based on the properties of the materials and the characteristics of the reaction, and to examine the impact of stirring speed on the reaction behavior. Especially in solid-liquid heterogeneous reactions, it is essential to select a stirrer type that meets the requirements of the reaction as well as an appropriate stirring speed. 4) Further study of reaction conditions: The optimal reaction conditions obtained at the laboratory stage may not meet the requirements for scale-up to pilot scale. In-depth experimental studies should be conducted on the main influencing factors, such as the feeding rate in exothermic reactions, the heat transfer area and coefficient of the reaction vessel, as well as the refrigerant, in order to understand their variation patterns in pilot-scale units and thus determine more suitable reaction conditions. 5) Determination of the process flow and operating methods: During the pilot-scale-up phase, as the amount of material to be processed increases, it becomes necessary to consider how the reaction and post-treatment procedures can meet the requirements of industrial production; particular attention should be paid to shortening the processes and simplifying the operations. 6) Quality control of raw materials, auxiliary materials, and intermediates ① Measurement of the physical properties and chemical parameters of raw materials, auxiliary materials, and intermediates. ②Formulation of quality standards for raw materials, auxiliary materials, and intermediates. (II) Material balance: Material balance is one of the most fundamental and important aspects in chemical engineering calculations. It is also the basis for energy balance. Through material balance, the production process can be analyzed in depth; by obtaining a quantitative understanding of the entire production process, it is possible to determine the standard consumption of raw materials and to identify the efficiency of material utilization ； Find out whether the product yield has reached its optimal value, and what potential remains for the equipment’s production capacity ； Whether the production capacities of various devices are matched, etc. (1) The theoretical basis of material balance: Material balance is the study of the changes in the amount and composition of materials entering and leaving a system. The so-called system refers to the scope of material balance; it can be one piece of equipment or multiple pieces of equipment, it can be a unit operation or the entire chemical process. The theoretical basis for material balance is the law of conservation of mass: the amount of material entering the reactor – the amount of material leaving the reactor – the amount of material that undergoes conversion within the reactor = the amount of material accumulated in the reactor. In a chemical reaction system, the conversion of substances follows the laws of chemical reactions, and the quantitative relationships related to such conversion can be determined using chemical reaction equations. (2) Determine the basis for material balance calculations and the annual operating time of the equipment. 1) The common bases used for material balance calculations include: ① A batch operation basis, which is applicable to material balance calculations for batch-operated equipment, as well as standard or fixed-type equipment; batch operations are commonly used in the production of chemical pharmaceutical products. ②Based on unit time, it is applicable to material balance for continuously operating equipment. 3) Based on per kilogram of product, to determine the consumption quotas for raw materials and auxiliary materials. 2) Annual equipment operation time: The number of days per year during which the equipment in the workshop is operational for normal production is generally taken as 330 days, with the remaining 36 days allocated for maintenance work in the workshop. (3) Collecting data related to calculations and material balance: 1) Collecting data related to calculations: the mixing ratios of reactants, the concentration, purity, or composition of raw materials, auxiliary materials, semi-finished products, finished products, and by-products, as well as the overall yield of the workshop, stage-wise yields, and conversion rates. 2) Conversion rate: For a particular component, it refers to the ratio of the amount of that component consumed as a reactant to the total amount of reactant used in the reaction. It is generally expressed as a percentage. 3) Selectivity: The fraction of the main product among various primary and secondary products. Example: In the production of methoxypenicillin, the process involves the methylation of gallic acid to produce trimethoxybenzoic acid. It was found that 25.0 kg of gallic acid (1) was used as the starting material, 2.0 kg of unreacted gallic acid remained, and 24.0 kg of trimethoxybenzoic acid (2) was produced. Determine the selectivity and yield. (4) Overall yield of the workshop: The overall yield of the workshop is the product of the yields of each processing step. (5) Step 1 of material calculation: Collect the basic data necessary for calculation. 2) List the chemical reaction equations, including the main reactions and side reactions ； Draw a flowchart based on the given conditions. 3) Select the basis for material calculation. 4) Perform material balance calculations 5) Prepare the material balance table: ① Material balance table for inputs and outputs ； ②Waste discharge statistics table ； ③Calculate the consumption quota for raw materials and auxiliary materials (kg). (III) Production process specifications: A drug can employ several different production processes, but one of them must be the most reasonable, most economical, and best suited to ensuring the consistent weight of the product under specific conditions. When the various aspects of such a production process are documented, it is known as a production procedure. The production process specification is an important document that guides production and serves as the basic basis for organizing and managing production ； It is even more a core secret of factory enterprises. Advanced production process specifications are the collective creation of engineering and technical personnel, workers on the job, and enterprise managers; they fall under the category of intellectual property. It is necessary to actively apply for patents in order to protect the legitimate interests of inventors and enterprises. (1) The main functions of production process specifications: ① Production process specifications are guiding documents for organizing industrial production. Only by arranging production according to these specifications can coordination among various production stages be maintained, thereby enabling tasks to be completed as planned. ②The production process specifications also serve as the basis for production preparation work. ③The production process specifications are also the basic technical requirements for building new or expanding production workshops or factories. (2) Original materials and basic contents for formulating production process specifications. To formulate production process specifications, the following original materials and basic contents are required: 1) Product introduction: Describe the product specifications, pharmacological effects, etc., including the name (trade name, chemical name, English name) ； Chemical structural formula, molecular formula, molecular weight ； Properties (physicochemical properties) ； Quality standards and testing methods (identification methods, accurate quantitative analysis methods, impurity testing methods, and methods for determining the maximum allowable levels of impurities, etc.) ； Pharmacological effects, toxic and side effects (adverse reactions), uses (indications, usage) ； Packaging and storage. 2) Chemical reaction process: Based on chemical synthesis or biosynthesis, describe the main reactions, side reactions, and auxiliary reactions (such as catalyst preparation, by-product treatment, recycling, etc.) step by step, along with their reaction principles. It should also include methods for controlling the reaction endpoint and rapid testing methods. 3) Production process flow: Focusing on the chemical reactions that occur during the production process, it uses graphical representations to illustrate physical and chemical processes such as cooling, heating, filtration, distillation, extraction and separation, neutralization, and purification. 4) Equipment list: Position name, equipment name, specifications, quantity (capacity, performance), material, motor capacity, etc. 5) Equipment processes and maintenance: An equipment flow diagram represents the interconnections between various devices in the production process through schematic illustrations of those devices. 6) Operating hours and production cycle: Describe the names of processes and operating times at each workstation. 7) Quality standards for raw materials, auxiliary materials, and intermediates: Listed by job title, raw material name, molecular formula, molecular weight, and specification items. 8) Production process: ingredient ratio ； Process operation ； Main process conditions and their descriptions ； Intermediates in the production process, their physicochemical properties, and control of the reaction endpoint ； Post-treatment methods and yields, etc. 9) Production technical and economic indicators: Production capacity (annual, monthly) ； Intermediate and final product yields, stepwise yields and overall product yield, yield calculation methods ； Labor productivity and costs ； Consumption quotas for raw materials, auxiliary materials, and intermediates. 10) Technical safety, fire protection, and explosion prevention; 11) Usage of main equipment and safety precautions; 12) Inspection methods for finished products, intermediates, and raw materials; 13) Comprehensive utilization of resources and treatment of waste gases, wastewater, and solid waste; 14) Appendices (including constants and calculation formulas, etc.). Precautions during the production process: 1. Operate strictly in accordance with the operating procedures and safety regulations; no changes should be made arbitrarily. If new issues are found that require changes, there must be a solid basis provided by pilot tests. 2. Strictly control reaction conditions such as temperature and pH value; if these parameters exceed the specified limits, prompt action should be taken (this should be considered during pilot testing, and destructive tests should be conducted to find appropriate solutions). 3. Pay attention to the differences in heat transfer sensitivity of thermometers during pilot production compared to pilot testing – there is a delay in temperature changes, so this factor should be taken into account in advance when carrying out relevant operations. 4. How to check for and deal with leaks in the vacuum system, especially under high-temperature conditions, when emergency measures should be taken promptly. 5. In the event of sudden power outages, steam interruptions, water cutoffs, or interruptions in chilled brine supply, necessary emergency measures must be taken immediately (such as activating backup power sources and implementing N2 protection, if required).
6. Be mindful of the amplification effect during production; generally, scaling up should be done gradually. Progress alone must not be the sole consideration; otherwise, “haste makes waste.” Proceed step by step. 7. Due to unforeseeable factors and amplification effects, the amount of material fed in each batch must be controlled, and a hierarchical approval system should be implemented. 8. Carefully and thoroughly observe the phenomena that occur during the reaction process, keep accurate records in a timely manner, and analyze these phenomena promptly. It is also necessary to carry out pilot tests or follow-up verifications. All relevant personnel must have a high sense of responsibility, closely monitor the entire production process, and take timely action to resolve any issues that arise. 9. There must be clear indicators and methods to determine the end point of each step; strict control is applied at each stage, and this can be combined with the phenomena that occur during the reaction for assessment. 10. Choose the appropriate post-treatment method. Unit operations such as extraction, crystallization, and recrystallization are carried out; when selecting extractants and solvents, the principle of \"like dissolves like\" is properly applied to consider the solubility of impurities and the product. When selecting a solvent, it is necessary to consider not only the suitability for the process but also economic and practical factors such as price, toxicity, and whether it can be recycled or is easy to recycle. These aspects should be taken into consideration when carrying out post-treatment in pilot tests. Safety issues: 1. Thorough pilot testing is the guarantee of successful pilot-scale production and full-scale manufacturing. Invest more effort in pilot testing, and consider in detail various implementation methods and feasibility aspects for pilot-scale and production phases; the more careful and thorough the planning, the smoother the pilot-scale production and manufacturing process will be, with fewer production accidents and safety incidents. 2. The safety of technical modifications is crucial for safety efforts. Since multiple projects are carried out in the same workshop, one project may be undergoing technical modifications while other projects are in production; or within the same system, one product might have been manufactured previously and now another product is being produced instead; or technical modifications may be carried out midway due to issues that were not anticipated in advance. In any case, whenever work involving open flames can be carried out outside the workshop, it must be done there; efforts should be made to avoid performing such work inside the workshop. If it is absolutely necessary to carry out the work inside, thorough cleaning and isolation measures must be taken (including of equipment, containers, and pipelines), ensuring that no dead corners remain, and strict rules regarding the use of open flames must be followed. 3. Employee training, as well as strict adherence to rules and procedures, are key aspects of safety work. 4. The division of responsibilities must be clear; before starting production, the “Trial Production Project Overview Table” should be filled out to identify the responsible persons. Communication among them should be timely, strict rules and a high level of responsibility are necessary. Key personnel should be on site, and appropriate measures should be taken promptly in case of any issues. 5. Potential safety issues, environmental protection problems, and labor protection issues should be anticipated in advance, and corresponding measures should be taken.