Methods for pilot-scale up

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Methods for pilot-scale up include: Empirical scaling: This primarily relies on experience to determine the characteristics of a reactor through stepwise scaling up (from lab-scale equipment to intermediate-scale equipment, then to medium-scale and finally large-scale equipment). It is also the main method currently used in drug synthesis. Similarity scaling: This mainly involves scaling based on the principle of similarity. This method has certain limitations and is applicable only to the scaling up of physical processes. And it is not applicable to the scale-up of chemical processes. Mathematical simulation amplification: This is amplification that utilizes computer technology; it represents the direction for future development. In addition, the development of miniature intermediate devices is also progressing rapidly; that is, miniature intermediate devices are being used to replace larger ones, providing accurate design data for industrial equipment. Its advantages are low cost and rapid construction. Tasks during the pilot-scale up phase: There are mainly ten key tasks. In practice, depending on specific circumstances, their priorities can be determined, and they can be carried out in a planned and organized manner. 1. Final determination of the process route and operating methods for unit reactions. In particular, when significant and intractable problems arise during the pilot-scale amplification phase regarding the originally selected route and unit reaction method, another route should be selected, and the pilot-scale amplification should then be carried out along this new route. 2. Selection of equipment materials and models. 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 research on reaction conditions. The optimal reaction conditions determined at the laboratory scale may not necessarily meet the requirements for pilot-scale implementation. Therefore, it is necessary to conduct in-depth research on the main influencing factors, such as feed rate, stirring efficiency, the heat transfer area and heat transfer coefficient of the reactor, as well as the refrigerant, so as to understand their variation patterns in intermediate-scale equipment. More suitable reaction conditions are obtained. 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. Thus, the production process flow and operating methods are ultimately determined. 6. Perform a material balance. Once the reaction conditions and operating 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 sum of the weights of the reaction products and other products must equal the sum of the amounts of all reactants prior to the reaction; this is the degree of accuracy that must be achieved in material balance calculations. So as to address the weak links. 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 engineering constants of raw materials and intermediates. To address issues in the production process and safety measures, it is necessary to determine the properties and chemical engineering constants of certain materials, such as specific heat, viscosity, and explosive limits. 8. Formulation of quality standards for raw material intermediates. Quality standards that are inadequate in pilot tests should be revised and improved based on 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 research, infrastructure design can be carried out, and a procurement plan for model equipment can be formulated. Carry out the design and manufacture of non-standard equipment, and construct the production workshop building and install equipment in accordance with the construction drawings. All production equipment and auxiliary equipment have been installed. Once the trial production is successful and remains stable over a short period, the process specifications can be formulated and production can commence. Steps involved in pilot-scale up: Previously, I wrote a post about pilot-scale up, which received positive feedback. Now, I have the idea of systematizing this aspect. Drawing from my own experience, I will gradually post some things for everyone to discuss. First, let’s talk about the purpose of pilot testing. Pilot testing is a transitional stage between laboratory experiments and industrial production ； It is a process of production using small-scale production equipment; the design requirements, selection, and operating principles of such equipment are basically the same as those for large-scale production ； After the laboratory trials are completed, pilot tests are conducted to study the industrially feasible process and equipment selection, providing a basis for industrial design. The steps involved in the pilot-scale up of active pharmaceutical ingredients and intermediates include: 1. Performing material balance calculations and determining the pilot-scale process flow based on the laboratory-scale operating procedures. Material balance includes raw material consumption and estimation of production costs. The raw material consumption table should include an estimate of the recovery of recovered 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 retrofitting workshop, considerations must be given to safety, ventilation, heating, lighting, power distribution, etc. Arrange the operation platform according to the equipment layout. Equipment installation and commissioning. 3. With all equipment in place, formulate the pilot-scale operating procedures based on the steps and processes of the laboratory tests. 4. Simultaneously, conduct test runs in conjunction with the operational training for workshop personnel. The general principle for testing is to proceed step by step, examining each operation and the testing conditions at each stage, before moving on to simultaneous execution. The formal experiments begin, and the main parameters to be examined during these experiments include: 1. Verifying the process and ensuring stable yields. 2. Verify the operations used in the pilot test. 3. Determine the product refinement method. 4. Verify schemes such as solvent recovery and reuse. 5. Verify the special operating processes for industrialization. 6. Carefully observe the thermal effects of each reaction step. 7. Determine safety measures. The minimum requirements for conducting pilot tests include: 1. Stable yield in lab-scale tests and reliable product quality. 2. The manufacturing conditions have been determined, as well as the analysis and testing methods for the products, intermediates, and principles involved. 3. Corrosion resistance tests on certain equipment and pipeline materials have been conducted, and the necessary general equipment is available. 4. 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 work safety have been put forward. Methods for pilot-scale up include: 1. Empirical scaling: This mainly relies on experience to explore the characteristics of reactors through stepwise scaling up (laboratory-scale equipment → intermediate-scale equipment → medium-scale equipment → large-scale equipment). It is also the main method currently used in drug synthesis. 2. Similarity scaling: It mainly involves using the principle of similarity for scaling. This method has certain limitations and is applicable only to the scaling up of physical processes. And it is not applicable to the scale-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 miniature intermediate devices is also progressing rapidly; that is, miniature intermediate devices are being used to replace larger ones, providing accurate design data for industrial equipment. Its advantages are low cost and rapid construction. Tasks during the pilot-scale up phase: There are mainly ten key tasks. In practice, depending on specific circumstances, their priorities can be determined, and they can be carried out in a planned and organized manner. 1. Final determination of the process route and operating methods for unit reactions. In particular, when significant and intractable problems arise during the pilot-scale amplification phase regarding the originally selected route and unit reaction method, another route should be selected, and the pilot-scale amplification should then be carried out along this new route. 2. Selection of equipment materials and models. 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 research on reaction conditions. The optimal reaction conditions determined at the laboratory scale may not necessarily meet the requirements for pilot-scale implementation. Therefore, it is necessary to conduct in-depth research on the main influencing factors, such as feed rate, stirring efficiency, the heat transfer area and heat transfer coefficient of the reactor, as well as the refrigerant, so as to understand their variation patterns in intermediate-scale equipment. More suitable reaction conditions are obtained. 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. Thus, the production process flow and operating methods are ultimately determined. 6. Perform a material balance. Once the reaction conditions and operating 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 sum of the weights of the reaction products and other products must equal the sum of the amounts of all reactants prior to the reaction; this is the degree of accuracy that must be achieved in material balance calculations. So as to address the weak links. 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 engineering constants of raw materials and intermediates. To address issues in the production process and safety measures, it is necessary to determine the properties and chemical engineering constants of certain materials, such as specific heat, viscosity, and explosive limits. 8. Formulation of quality standards for raw material intermediates. Quality standards that are inadequate in pilot tests should be revised and improved based on 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 research, infrastructure design can be carried out, and a procurement plan for model equipment can be formulated. Carry out the design and manufacture of non-standard equipment, and construct the production workshop building and install equipment in accordance with the construction drawings. All production equipment and auxiliary equipment have been installed. Once the trial production is successful and remains stable over a short period, the process specifications can be formulated and production can commence. 10. From laboratory research to pilot production. The ultimate goal of new drug research: The final aim is to produce drugs of acceptable quality for medical use. Before new drugs can be produced on a large scale, 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 must 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 discover potential new drugs. Its main task is to reasonably design the compounds and complete their synthesis as soon as possible ； Utilize various methods to confirm the chemical structure of compounds ； Determine the main physical parameters of the compound ； Understand the general properties of compounds, without delving too much into their synthesis methods. To prepare small amounts of samples for pharmacological screening, every separation and purification technique is employed, such as repeated fractionation, multiple recrystallizations, and various chromatography methods. Clearly, 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 preclinical evaluation. Its main task is to carry out a comprehensive and systematic reform of the laboratory’s existing synthetic routes and methods. Based on the reforms, batch synthesis in the laboratory is carried out to accumulate data, thereby proposing a synthetic process route that is generally suitable for pilot-scale production. The research focus during the pilot phase should revolve closely around key issues affecting industrial production. Such as shortening the synthetic route, improving the yield, simplifying the operations, reducing costs, and ensuring safe production, etc. 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 scale-up of laboratory trials and a miniature version of industrial production; it should be carried out in a factory or a dedicated pilot plant. 4. The experimental research, pilot-scale studies, and pilot production of active monomers from natural medicines are basically similar to those for synthetic drugs; the only difference is that processes such as extraction, separation, and purification are used in place of each step of chemical synthesis. 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 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. The research identified an optimal synthetic process route: 1. A compound can often be synthesized via different routes and methods. The route and method initially adopted in the laboratory are not necessarily the best ones; at that time, there was little consideration given to reaction conditions, equipment and instruments, sources of raw materials, etc., nor were excessively high yield requirements set. However, these factors are crucial for industrial production. Therefore, through pilot-scale studies, those synthetic steps and methods that do not meet industrial production requirements should be modified. A relatively mature synthetic process route should feature: few synthesis steps, a high overall yield, simple equipment technical requirements and process flows, as well as abundant and inexpensive raw material sources. 2. Industrial-grade raw materials are used in place of chemical reagents. For small-scale synthesis in laboratories, reagents and solvents of standard grades 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 industrial-grade raw materials and solvents interfere with the reaction, and whether they affect 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; in most cases, there is no significant change in the solvents before and after the reaction, so they can 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 treating these substances, with data showing 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. Work safety and environmental hygiene are crucial for industrial production; through pilot-scale studies, synthetic reactions involving toxic substances and harmful gases should be eliminated as much as possible ； 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 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. The main tasks of pilot production are: 1. To evaluate the synthetic process route provided in the lab tests, to determine whether there are any special requirements regarding process conditions, equipment, raw materials, etc., and whether it is suitable for industrial production. 2. Verify whether the synthesis process route provided in the pilot test is mature and reasonable, and whether the main economic and technical indicators meet production requirements. 3. During the scaled-up pilot study, the process route should be further evaluated and improved, and basically stable data should be 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 3 to 5 batches, in order to accumulate data and improve the materials related to 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. Make step-by-step plans for the materials at each stage, and propose measures for recycling and reuse as well as treatment of waste residues, waste water, and waste gas. 8. Propose the process specifications, safety operation requirements, and regulations for each unit operation in the process flow of the entire synthesis route. Selection of equipment and modification of process piping: 1. Based on the results of small-scale tests, in the multi-functional pilot plant, equipment should be selected by first considering whether its capacity is appropriate, the compatibility between the equipment materials and piping materials with the process media, whether it is corrosion-resistant, and whether the heating, cooling, and stirring speeds meet the requirements. 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 metering and adding materials; for example, how can dropping addition be effectively controlled? 4. Is any gas produced in the reaction? Will there be material overflow? If necessary, a gas-liquid separator should be added, along with a return pipe. 5. Are the separation conditions such as centrifugation and pressure filtration met? Based on the above circumstances and other process requirements, make adaptive modifications to the equipment and piping. Preparations before feeding materials: 1. For equipment, especially newly installed or recently modified 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 to ensure that no hot work is required after material feeding. Once it is confirmed that there are no leaks, insulation of the equipment and pipelines can be performed. 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 orderly operations. 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 by category. 4. Plan and prepare containers and storage areas for the intermediates. 5. Inspection of production conditions: Check whether steam, oil baths, 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 instruments functioning normally? Estimate whether the thermometer can be inserted into the material throughout the entire process (when there is a slight change in the material level and when less material is fed). 8. Write up operating procedures and safety regulations. 9. Train employees on processes (in particular, clearly explain the control indicators and key points, the hazards of violating operating procedures, the routing of pipelines, the inlet and outlet controls of valves, and implement emergency measures for situations where control indicators are exceeded or emergencies occur). Conduct safety training and labor protection training. 10. Designate responsible persons for the project, organize work shifts, assign key personnel to accompany the teams, and establish methods for nighttime communication and coordination among workers, key personnel, and superior leaders. 11. Develop emergency response plans and make necessary preparations. 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 for use. It aims to provide data for full-scale production, as well as information on product quality and consumption levels. (I) Research contents regarding pilot-scale amplification: 1. Overview The process steps—In the production process, all factors directly related to the sequence and conditions of chemical synthesis reactions or biosynthetic pathways (such as ingredient ratios, temperature, reaction time, stirring methods, post-treatment procedures, and purification conditions, etc.) are collectively referred to as process conditions. Other processes become auxiliary processes. 2. Importance and format of pilot-scale scaling Up Once the laboratory-scale processes for chemical pharmaceutical manufacturing have been developed, and the drug production process has been finalized, it is generally necessary to carry out pilot-scale scaling up, which involves increasing the scale by 50–100 times compared to the small-scale tests. This step allows for further investigation of how various reaction conditions change in facilities of a larger scale, as well as addressing any issues that could not be resolved or were not identified during the laboratory phase. In the development of new drugs, a certain number of samples are also required to be provided for clinical trials, as well as for drug testing and sample retention for observation. Depending on the dosage and duration of treatment, typically 2–10 kg of the drug is required; this amount is difficult to obtain under normal laboratory conditions. Once the process route is determined, each chemical or biosynthetic reaction remains largely unchanged under different conditions—such as those in small-scale trials, pilot-scale tests, and large-scale production. However, the optimal process conditions for each step may need to be adjusted depending on external factors like the scale of the experiment and the equipment used. The methods of pilot-scale up include empirical scaling, similar scaling, and mathematical simulation scaling. 1) Empirical scaling method—Primarily relies on experience to explore the characteristics of reactors through stepwise scaling up (laboratory-scale equipment, pilot-scale equipment, medium-scale equipment, large-scale equipment). In the process research of synthetic drugs, pilot-scale up mainly employs the empirical scaling method, which is also the primary method in chemical engineering research. 2) Similarity scaling method—mainly applies similarity theory for scaling. It is used in physical processes, but 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. Research on pilot-scale scaling up 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, it is merely a matter of determining the specific process operations and conditions to suit industrial production. However, when the selected process route and process steps reveal major insurmountable problems during pilot-scale testing, it becomes necessary to re-evaluate the laboratory process route and modify its process steps. 2) Selection of equipment materials and types: When initiating pilot-scale expansion, it is necessary to consider the materials and types of various equipment required, and assess their suitability. Special attention should be paid to selecting appropriate materials for equipment that comes into contact with corrosive substances. 3) Investigation of stirrer 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 materials, the stirring efficiency is high, and problems related to heat and mass transfer are not very apparent. However, during pilot-scale scaling up, owing to the impact of stirring efficiency, these heat and mass transfer issues become prominently evident. 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 research on reaction conditions: The optimal reaction conditions obtained at the laboratory scale may not necessarily meet the requirements for pilot-scale amplification. 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 heat transfer coefficient of the reactor, as well as refrigerants, etc., in order to understand their variation patterns in pilot-scale units and thereby 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 operating methods for the reaction and post-treatment can meet the requirements of industrial production. Special attention should be paid to shortening the processing steps and simplifying the operations. 6) Quality control of raw materials, auxiliary materials, and intermediates
① Determination 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 accounting. Through material balance, the production process can be analyzed in depth; by gaining 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 ； Determine whether the product yield has reached its optimal value and how much potential there is for increasing the equipment’s production capacity ； Whether the production capacities of various devices are matched, etc. 　(1) Theoretical basis of material balance　Material balance is the study of the changes in the incoming and outgoing materials as well as their compositions within a given system; in other words, it is the balance of materials. 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) Determining 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 suitable for material balance calculations of 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 a unit of time, it is applicable to material balance calculations 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. Collect data related to calculations and material balance steps: (1) Collect data related to calculations: the mixing ratio 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 certain component, it refers to the ratio of the amount of that component consumed as a reactant to the total amount of reactant fed into the reaction. It is generally expressed as a percentage. 　(3) Selectivity: The fraction of the main product among various main and by-products. 　　Example: In the production of trimethoprim, gallic acid is methylated to produce trimethoxybenzoic acid. It was determined that 25.0 kg of gallic acid (1) was fed into the reaction; 2.0 kg of gallic acid remained unreacted, while 24.0 kg of trimethoxybenzoic acid (2) was produced. Calculate 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) Steps for material calculation 1) 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 benchmark for material calculation. 4) Perform material balance calculations, 5) Prepare the material balance table: ① Material balance table for inputs and outputs ； ②Waste discharge volume table ； ③Calculate the consumption quota for raw materials and auxiliary materials (kg). (III) Production process specifications: A drug can be manufactured using 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. Documenting all the elements of this production process results in what is known as a production process specification. The production process specification is an important document guiding production; it also serves as the basic basis for organizing and managing production ； It is even a core secret of factories and enterprises. Advanced production process specifications are the collective creation of engineering and technical personnel, operators, and enterprise managers; they fall under the category of intellectual property. It is necessary to actively organize patent applications in order to protect the legitimate interests of inventors and enterprises. (1) The main functions of production process regulations: ① Production process regulations serve as guiding documents for organizing industrial production. Only by arranging production planning and scheduling in accordance with these regulations 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. ③The production process specifications are also the basic technical requirements for building new or expanding production workshops or factories. (2) Original data and basic contents for formulating production process specifications (IV) To formulate production process specifications, the following original data and basic contents are required: 1) Product description: Outline the product specifications, pharmacological effects, etc., including the name (trade name, chemical name, English name) ； Chemical structural formula, molecular formula, molecular weight ； Properties (physical and chemical properties) ； Quality standards and testing methods (identification methods, accurate quantitative analysis methods, impurity testing methods, and maximum limit testing methods for impurities, etc.) ； Pharmacological effects, toxic and side effects (adverse reactions), uses (indications, dosage) ； Packaging and storage. 2) Chemical reaction process: According to chemical synthesis or biosynthesis, describe step by step the main reactions, side reactions, and auxiliary reactions (such as catalyst preparation, by-product treatment, recovery and reuse, etc.) along with their reaction principles. It should also include methods for controlling the reaction endpoint and rapid testing methods. 3) Production process flow: Centered on the chemical reactions in the production process, it describes physical and chemical processes such as cooling, heating, filtration, distillation, extraction and separation, neutralization, and purification in a graphical format. 4) Equipment list: job title, equipment name, specifications, quantity (volume, performance), material, motor capacity, etc. 5) Equipment processes and equipment maintenance: An equipment process diagram represents the interconnections between various pieces of equipment during the production process in the form of schematic diagrams. 6) Operator hours and production cycle: Describe the names of the processes in each position along with the operation time required. 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 operations ； 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 (per year, per month) ； Yields of intermediates and final products, stepwise yields and overall product yield; methods for calculating yields ； Labor productivity and costs ； Consumption quotas for raw materials, auxiliary materials, and intermediates. 10) Technical safety, fire prevention, and explosion prevention
11) Usage of major equipment and safety precautions
12) Inspection methods for finished products, intermediates, and raw materials
13) Comprehensive utilization of resources and treatment of waste residues
14) Appendices (relevant constants, calculation formulas, etc.)
(V) Precautions during the production process:
1. Operate strictly in accordance with operating procedures and safety regulations; no arbitrary changes are permitted. If new issues are found that require changes, there must be a solid basis provided by preliminary 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 taken into account during pilot tests, which should include destructive tests to identify appropriate solutions). 3. Pay attention to the differences in heat transfer sensitivity of thermometers during pilot production compared to those used in pilot tests, as there is a delay in temperature changes. This factor should be anticipated in advance so that appropriate actions can be taken. 4. How to inspect and handle emergencies when there is air leakage in the vacuum system, especially under high-temperature conditions; 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. Pay attention to the amplification effect during production; generally, the scale should be gradually increased. Progress alone should not be the sole consideration; otherwise, “haste makes waste.” Proceed step by step. 7. Due to unforeseen factors and amplification effects, the quantity of materials fed in a single 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, take timely records, and analyze these phenomena promptly; it is also necessary to carry out preliminary tests or follow-up verifications. All relevant personnel must have a high sense of responsibility, closely monitor the entire production process, and take timely measures to resolve any problems that arise. 9. There must be clear indicators and methods for determining the end point of each step; each step should be strictly controlled, and this can be judged by combining it with the phenomena observed during the reaction. 10. Correctly select the post-processing method. Perform unit operations such as extraction, crystallization, and recrystallization. When selecting extractants and solvents, correctly apply the “like dissolves like” principle 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 considered when performing post-processing after a pilot test. (VI) Safety issues: 1. Thorough pilot testing is the guarantee of success in pilot-scale production and full-scale manufacturing. Efforts should be devoted to pilot testing, considering in detail various implementation methods and operational aspects for these stages; the more careful and thorough such considerations are, the smoother the pilot-scale production and full-scale manufacturing will proceed, with no production or safety accidents occurring. 2. The safety of hot work during technical modifications is a key aspect of safety management. Since multiple projects are carried out in the same workshop, one project may be undergoing technical modifications while others are in production. Alternatively, in the same system, one product has been produced previously, but now the production process is being changed to produce another product. In some cases, technical modifications must be implemented midway due to unforeseen issues. 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 hidden areas remain. Strict rules regarding the use of open flames must be followed. 3. Employee training and strict adherence to rules, regulations, and operating 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 essential. Key personnel should be on site, and appropriate actions 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.