Contents of pilot-scale scale-up studies

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Overview: The concept of the process. In the production process, all factors that are directly related to the sequence of chemical synthesis reactions or biosynthetic pathways, as well as the conditions involved (including ingredient ratios, temperature, reaction time, mixing methods, post-treatment procedures, and purification conditions), are collectively referred to as process conditions. The other processes become auxiliary processes. 1. The concept of pilot testing: Once the laboratory-scale processes for drug development are completed, that is, once the drug manufacturing process has been finalized through validation, it is generally necessary to carry out pilot testing on a scale that is 50 to 100 times larger than the laboratory scale. This allows for further investigation into how the conditions of various reaction steps change in facilities of a certain size, as well as to address any issues that could not be resolved or were not identified during the laboratory phase. Simply put, pilot testing is a small-scale production simulation experiment, and it is an essential step between laboratory testing and industrial production. Pilot testing is conducted to explore industrializable solutions based on lab-scale experiments; it further investigates the patterns of changes in the conditions for various chemical reactions in plants 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 due to differences in experimental scale, the optimal conditions for each step of the chemical reaction may vary depending on external factors such as the scale of the experiment and the equipment used. Generally speaking, the pilot-scale scale-up is an important transitional stage from a high level of development to industrial production, and its standard represents the level of industrial production. Research institutions generally focus on pilot-scale studies, while companies focus on industrial production. However, due to constraints in human resources, materials, and funding, intermediate experiments are often overlooked by research institutions and companies. We should understand that the preparation of active pharmaceutical ingredients should follow the principles of their research and development, that is, it should be carried out scientifically in accordance with the sequence of pilot testing – pilot production – industrial-scale manufacturing. The general steps for the development of active pharmaceutical ingredients and intermediates are: literature review – pilot-scale exploration – pilot plant studies – industrial production. Second, the purpose of pilot testing. First, let’s talk about the purpose of pilot testing. Pilot testing is an essential transitional step from laboratory experiments to industrial production ； The transition from pilot testing to actual production on the modeled 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 studies, 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. In short, pilot-scale scaling up must demonstrate that the process conditions and operating procedures for each chemical unit reaction enable the production of products with the desired quality specifications on a pilot plant, using specified raw materials, while ensuring good reproducibility and reliability. Economic and technical indicators such as the raw material consumption per unit of the product are acceptable to the market ； The formulation of treatment plans and measures for the three types of waste can be accepted by environmental protection authorities ； Measures such as safety, fire prevention, and explosion protection can be accepted by fire control and public security authorities ； The labor safety protection measures provided are acceptable to the health occupational disease prevention and control authorities. III. Contents of pilot-scale scale-up 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 testing, 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, it is necessary to consider the material and type of various devices required, and to assess whether they are suitable; particular attention should be paid to the selection of materials for devices that come into contact with corrosive substances. 3. Examination of mixer type and mixing speed: Most reactions in drug synthesis are heterogeneous reactions, which involve significant heat effects. In the laboratory, due to the small volume of the materials, mixing is effective, and problems related to heat and mass transfer are not very apparent. However, when scaling up to pilot scale, issues of heat and mass transfer become prominent due to differences in mixing efficiency. Therefore, during pilot-scale scaling up, it is necessary to consider the type of mixer based on the properties of the materials and the characteristics of the reaction, and to examine the impact of mixing speed on the reaction dynamics. Especially in solid-liquid heterogeneous reactions, it is essential to select a mixer type that meets the requirements of the reaction as well as an appropriate mixing 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 the thermal reaction, the heat transfer area and coefficient of the reaction tank, 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 operation methods: During the pilot-scale-up phase, as the amount of material to be processed increases, it is 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 and intermediates: Measurement of the physical properties and chemical parameters of raw materials and intermediates. Formulation of quality standards for raw materials and intermediates. IV. Conditions for pilot testing: At what stage of the experiments should pilot testing be carried out? Simply put, pilot testing is a matter of combining pilot-scale processes and equipment. Therefore, to carry out pilot testing, the following conditions must be met at least: 1. The synthesis route for pilot scale testing has been determined, the pilot process is mature, and the yield of the product is stable with reliable quality. The requirements for a mature pilot-scale process are: the synthetic route must be determined ； The operation steps are clear ； Reaction conditions determined ； The purification method is reliable, etc. 2. The process evaluation for the pilot test has been completed. Stable and comprehensive experimental data from multiple batches of the pilot-scale process have been obtained ； 3 to 5 batches of pilot-scale stability tests were conducted, demonstrating that the pilot process is stable and feasible. 3. The methods and requirements for the refining, crystallization, separation, and drying of the finished product have been determined. 4. Quality standards and testing analysis methods have been established and finalized. Testing and analysis methods for the final product, intermediates, and raw materials. 5. Corrosion resistance tests have been conducted on certain equipment and pipeline materials. 6. Material balance was performed. 7. Preliminary methods have been developed for dealing with the issue of three wastes. 8. The specifications and unit consumption amounts for the raw materials have been specified. 9. Requirements for safe production have been put forward. V. Methods of pilot-scale scaling Up. The following are important methods for pilot-scale scaling up: Experience-based scaling *** Illegal information; those who discover it are asked to report it to the administrator ****: This approach relies on research and development experience, involving gradual scaling up (from lab-scale devices to intermediate devices, then to medium-scale and large-scale devices) in order to determine the characteristics of the reactor and the optimal reaction conditions. It is also the main method used in current drug synthesis. Similar scaling *** illegal information; those who discover it are asked to report it to the administrator ***: It mainly involves using the principle of similarity for scaling. This method has certain limitations and is only applicable to the amplification of physical processes. and is not suitable for the scaling up of chemical processes. Mathematical simulation for spreading *＊illegal information; those who discover this should report it to the administrator *＊＊: It is the use of computer technology to spread *＊illegal information, and those who find it should inform the administrator *＊＊. It is a commonly used simulation method in industrial research, and is widely applied in the arms industry. Now the pharmaceutical industry has been introduced; it is the direction for future development. Furthermore, the development of micro intermediaries is also progressing rapidly, with micro intermediaries being used to replace larger ones in order to provide accurate design data for industrial applications. Its advantages are low cost and fast construction. Now, foreign manufacturers of pharmaceutical equipment have taken note of this demand and have designed and produced such devices. 6. Tasks in the pilot-scale production phase: Pilot-scale production is an essential link in the transition from laboratory testing 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 tasks of pilot production mainly include the following ten points; in practice, it is possible to determine the priorities based on different circumstances and carry out the work in an organized and planned manner. 1. Final determination of the process route and unit reaction operation methods. During the scaled-up pilot study, the process route should be further evaluated and refined, and basically stable data should be obtained for each reaction step and unit operation. Evaluate the synthetic route provided in the pilot test to determine whether there are any special requirements regarding process conditions, equipment, raw materials, etc., and whether it is suitable for industrial production. 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 material for equipment that comes into contact with corrosive substances. 3. Investigation of mixer type and mixing speed. Many of these reactions are heterogeneous, and they have large heat effects. During pilot tests, due to the small volume of the material, mixing is effective and heat and mass transfer issues are not significant. However, when scaling up to pilot plant scale, it is necessary to consider the properties of the material and the characteristics of the reaction, as well as the influence of mixing patterns and speeds on the reaction, in order to select an appropriate mixer and determine the suitable mixing speed. 4. Further study on reaction conditions. The optimal reaction conditions obtained at the laboratory stage may not fully meet the requirements of pilot-scale scaling. Therefore, in-depth studies should be conducted on the 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. The process flow for the entire synthesis route is presented, along with the operational procedures for each unit operation, as well as the safety operation requirements and regulations. It is necessary to consider meeting the requirements of industrial production for the reaction and post-treatment procedures. Pay special attention to shortening processes, simplifying operations, and improving labor productivity. Thereby finalizing the production process flow and operating methods. 6. Conduct material balance calculations, plan the materials for each step, and propose measures for recycling and treatment of waste gases, waste liquids, and solid waste. Once the reaction conditions and operating methods for each step are determined, material balance calculations should be carried out for those reactions that result in low yields, numerous by-products, and a large amount 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. Based on the results of pilot-scale studies, the quality standards for intermediates and finished products, as well as the analysis and identification methods, are formulated or revised. 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 raw materials, energy consumption, labor hours, etc., preliminary calculations of economic and technical indicators are carried out to determine the production cost. Based on the summary report of the pilot-scale study, infrastructure design can be carried out, and a procurement plan for the model equipment can be formulated. Design and manufacture of non-standard equipment, as well as construction of production workshop buildings and installation of equipment in accordance with the construction drawings. All production equipment and auxiliary equipment have been installed. If the trial production is successful and stable during the short-term trials, a process specification can be developed for full-scale production. The work steps required for the pilot-scale production of active pharmaceutical ingredients and intermediates include: 1. Conducting material balance calculations and designing the pilot-scale process flow based on the procedures used in lab-scale experiments. Material balance includes raw material consumption and production cost estimation. The raw material consumption table should include an estimation of the recovery of recycled solvents. The process flow should be a comprehensive representation of the operational steps and the equipment used. 2. Install the pilot plant equipment in accordance with the flowchart and the pilot process. Important aspects include: in the modification workshop, considerations must be given to safety, ventilation, heating, lighting, and power distribution; operation platforms should be arranged according to the layout of the equipment, along with its installation and debugging. 3. With complete equipment, prepare the pilot-scale operation procedures based on the small-scale test steps and processes. 4. Conduct trial runs simultaneously in conjunction with the operation training for workshop staff. The general principle for testing is to proceed step by step, examining each operation and the testing conditions, and then carry out everything simultaneously. 5. Begin the formal experiment. The main items to be examined during the formal experiment include: 1) verifying the process and achieving stable yields. 2) Verify the operations used in the pilot test. 3) Determine the product purification method. 4) Verify solutions such as solvent recovery and reuse. 5) Verify the special operational processes in industrialization. 6) Observe in detail the heat effects of each reaction step. 7) Determine safety measures. 8) Generally, at least 3 to 5 batches should be produced for the intermediates and the final product, in order to accumulate data and improve the materials for pilot production. 6. Propose an industrial production process plan and determine the main production process flow. This is the ultimate goal of pilot testing. Industrial production is carried out based on the data from pilot tests, along with the selection of feasible process routes and equipment, to conduct industrial design, installation, commissioning, and then put the production into operation. The bulk drug 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. 7. Uses of the test products: 1) Confirming product quality (impurities, solvent residues, etc.); 2) Equipping with working standards; 3) Conducting necessary degradation studies, stability studies, and method development. 4), provided to customers for preliminary formulation studies.