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APIs are the active ingredients used in the manufacture of pharmaceutical formulations; they are typically bulk drugs obtained through chemical synthesis, semi-synthesis, microbial fermentation, or the isolation of natural products, and are produced via one or more chemical reactions and related processes. The research on the pharmaceutical synthesis process of active pharmaceutical ingredients is an important part of drug research and production; it forms the basis of drug development and constitutes a crucial stage in the establishment of drug quality. Next, we will briefly introduce the key elements involved in the research on the synthesis process of these active pharmaceutical ingredients. Drug synthesis is at the heart of pharmacology; it is crucial for modifying drugs and testing designed medications, and holds an extremely important position in the pharmaceutical industry. Medici is a comprehensive biopharmaceutical R&D services company; its unique \"customized\" process development approach enables clients to obtain APIs at an early stage so as to proceed with clinical research. Typically, an excellent drug synthesis process has the following characteristics: (1) Feasibility – whether the proposed synthetic route can be used to produce the target compound. (2) Controllability – Good reproducibility is required to ensure consistency in product quality across different batches, and to meet the requirements of quality standards. (3) Rationality – Feasibility of industrialization, requirements of the process route regarding raw materials, equipment, reaction conditions, etc ； Prefer solvents and reagents with low toxicity ； Environmental protection and labor protection ； Cost accounting. 1. First, the selection and design of the synthesis route must be based on certain principles and be reasonable. (1) The research on the pharmaceutical synthesis process of active pharmaceutical ingredients is an important part of drug research and production; it lies at the foundation of drug development and constitutes a crucial stage in the formation of drug quality. The general procedures for designing and selecting synthetic routes include: a. Conducting literature research on the target compound to be synthesized, and designing or selecting a suitable synthetic route ； b. Conduct a preliminary analysis of the selected route to gain an overall understanding of the research status of this compound both domestically and internationally, as well as its intellectual property situation ； c. A preliminary assessment of the process used is conducted, providing a reliable basis for the evaluation of the drug through the above research. (2) For new chemical entities, ① based on their structural characteristics, comprehensive consideration is given to: a. the ease of obtaining the starting materials ； b. Length of the synthesis steps ； c. The level of yield ； d. Post-treatment of the reaction, and whether the reaction conditions meet industrial production and environmental protection requirements ； Determine a reasonable synthetic route. ②Based on a comprehensive analysis of literature reports on similar structured compounds from both domestic and international sources, an appropriate synthesis method was determined. (3) For drugs with known structures, comprehensive information on the research related to their synthesis is obtained through literature review, with particular attention paid to: a. Feasibility (whether the raw materials are readily available and whether the reaction conditions can be applied on an industrial scale) ； b. Controllability (whether the reaction conditions are mild and easy to control) ； c. Stability (whether the quality of intermediates can be controlled, and whether the quality and yield of the final product are stable) ； d. Advancement (the advancement of the adopted approach compared to approaches in the literature) ； e. Rationality (costs and the prices and toxicity of raw materials, reagents, solvents, etc.). 2. Secondly, the starting materials, reagents, and organic solvents must meet standards, with an emphasis on standardization. Regarding the control of starting materials, GMP requirements aim to ensure product quality from the source. (1) The following requirements apply to synthetic products: a. List of materials: Specify the names of the materials used in the manufacturing process of the active pharmaceutical ingredient (such as raw materials, starting materials, solvents, reagents, catalysts), indicate the steps in which each is used, and identify the key materials ； b. Testing methods for materials: Explain the quality control information related to these materials ； c. Key material supplier COA: Quality standards and inspection reports ； Those using animals, plants, or their tissues and organs as raw materials—should provide information such as the genus, species, origin, harvesting season, and storage conditions of the raw materials, along with the quality requirements; for biologically synthesized antibiotics, details on the strain’s genus and species as well as the composition of the culture medium must be provided. (2) Principles for selecting starting materials: a. The quality should be stable and controllable; there must be information regarding the source, standards, as well as inspection reports from suppliers. If necessary, internal control standards should be established in accordance with the requirements of the synthesis process. b. For special dedicated intermediates, it is especially important to provide the relevant process routes and internal quality control standards. c. There should be a certain understanding of the impurities that may be introduced during the preparation of the starting materials; in particular, research should be conducted on the impurities and isomers introduced by the starting materials, and quality control methods should be provided ； For starting materials with chiral centers, limits should be established for the enantiomeric or diastereomeric isomers as impurities. Regarding the length of the synthetic route for the active pharmaceutical ingredient, the FDA believes that in the preparation process, the starting materials selected should be such that there are multiple reaction steps between them and the final intermediate of the active pharmaceutical ingredient ； Furthermore, there should be isolated and purified intermediates in the sequential reactions. This can effectively reduce the negative impact that changes in the preparation process of the starting materials may have on the quality of the active pharmaceutical ingredients. It should be noted that a reaction may involve multiple purification steps, but it should be considered as a single-step reaction. If the final intermediate is separated and purified during the process, then the reaction for synthesizing the final intermediate can be considered a one-step reaction, whereas the mutual conversion between the free acid (or free base) and the salt should not be regarded as a one-step reaction. Furthermore, a key raw material must be identified among the starting materials, and this material should also be produced in a facility that meets GMP requirements. (3) Principles for selecting solvents and reagents: Reagents with lower toxicity should be chosen ； When selecting organic solvents, it is generally advisable to avoid using Category 1 solvents and to restrict the use of Category 2 solvents ； It is necessary to describe the toxicity of the reagents and solvents used, so as to enable control during the production process. 3. Finally, the synthesis intermediate process needs to be controlled, with an emphasis on controllability. The control of the intermediate process is divided into quality control of the prepared intermediates, and the selection, optimization, and control of process conditions and parameters. (1) Quality control of the intermediates prepared The provided information should demonstrate how key intermediates and general intermediates were identified through research, and how process control is achieved by applying various controls over these intermediates, thereby ensuring better quality of the final product. This includes information on the purification methods for intermediates, internal quality standards, test results, and analysis of impurity profiles. The FDA classifies major intermediates as follows: a. Hub intermediates: intermediates that can be synthesized through different methods; b. Key intermediates: intermediates that are typically formed for the first time as an important part of the molecule. For example: intermediates in which chiral atoms are introduced for the first time in molecules with stereoisomerism. c. Final intermediate: The step prior to the final reaction in the synthesis of the active pharmaceutical ingredient. (2) Selection, optimization, and control of process conditions and parameters ① The description of the process operation steps should be detailed ； ②Process conditions, such as the reaction apparatus, temperature, pressure, time, solvent, pH value, light exposure, etc., must be strictly controlled ； The determination of the reaction endpoint (indicating the degree of conversion of the starting material into the desired product, the formation of impurities, etc.) should be clear. The study of the drug substance preparation process is the starting point of drug development, and it also runs through the entire process of drug development. In the research on the manufacturing process of active pharmaceutical ingredients, particular emphasis is placed on controlling the entire process, accumulating data, analyzing impurities, and ensuring proper control over starting materials and reagents. The goal is to establish a feasible, controllable, and stable manufacturing process, while also providing a basis for quality studies. At the same time, the evaluation of the API manufacturing process is not isolated; it should be conducted in conjunction with evaluations of quality control, safety, and efficacy. From the perspective of drug evaluation, it is hoped that the actual manufacturing process can be assessed in order to achieve a rational and comprehensive evaluation of the drug.