What Issues Should Be Paid Attention To In The Research Of API Preparation Process?

The preparation of APIs is the initial stage of drug research and development, the basis of drug research and development, mainly to provide detailed information for quality research, to provide preparation processes in line with industrial production, and to provide qualified APIs for pharmacological toxicology research, preparation research and clinical research in the process of drug development. Next, let’s look at what issues must be paid attention to in the research of API preparation process?

1 The Selection And Design Of Synthetic Lines Should Be Based On Evidence

In the registration data of the declaration, it is required to specify the background of the study, the basis of the preparation process and route. If it is a drug with a new chemical structure created, the basis and principle of creation should be explained, and if it is an imitation drug, several different literature routes should be provided, analyzed and compared, detailing the reasons for the route used, and explaining what it is How to improve and the basis for improvement. The evaluation of the synthetic circuit is aimed at ensuring the stability of product quality, and especially emphasizes the feasibility of process route selection and design (for example, whether the raw materials are readily available, the length of the synthesis steps, the level of yield, whether the reaction conditions can be industrialized), controllability (whether the reaction conditions are mild and easy to control), stability (whether the intermediate quality is controllable, whether the final product quality and yield are stable), advanced (the advanced nature of the line used compared with the literature route) and rationality (cost and raw materials, reagents, solvent price and toxicity, etc.).

2 Starting Materials, Reagents And Organic Solvents Should Be Standardized

The newly issued “Technical Guidelines for Chemical Drug Research” also indicates that raw materials include starting materials for reactions, solvents, catalysts, etc. It is also emphasized that for special special intermediate bodies, legal source certificates and relevant process routes and quality standards should be provided, and raw materials used in drug production should be purchased from units that meet the regulations.

In the process of API preparation process, the quality of starting raw materials, reaction reagents and solvents is directly related to the quality of the final product and the stability of the process route. Different specifications of starting materials, reaction reagents, solvents will directly affect the process, different quality of starting materials, reaction reagents, solvents introduced by the impurities are also different.

Therefore, the general principle of starting material selection should be:

(1) the quality is stable and controllable, there should be a source, standard and supplier inspection report, if necessary, according to the requirements of the synthesis process to establish internal control standards.

(2) Special special intermediates, but also emphasize the provision of relevant process routes and internal control quality standards.

(3) There should be a certain understanding of the impurities that may be introduced into the starting material in the preparation process, especially the impurities and isomers introduced by the starting material, and relevant research and quality control methods should be carried out; For starting materials with chiral centers, limits of enantiomers or diastereomers as impurities should be formulated.

Choice of solvents and reagents: In general, reagents with lower toxicity should be selected; The selection of organic solvents should generally avoid the use of class I solvents and control the use of class II solvents. At the same time, the toxicity of the reagents and solvents used should be explained so that they can be controlled in the production process. Detailed requirements for the selection of organic solvents can be found in the technical guidelines for the study of organic solvent residues in chemical drugs.

3 The Intermediate Process Of Synthesis Should Be Controlled

For the adopted process route, it is required to write out a detailed chemical reaction formula (including Lixiu chemical), reaction conditions and operating steps, indicate the amount of feeding (and indicate the number of moles), yield, source of raw materials and specifications, and provide process flow charts. The end-point control methods of each step of the reaction, the refining and quality control methods of the main intermediates and finished products should be detailed, and the corresponding data or maps should be provided to ensure the quality of the final product. For the relevant substances or other intermediate products that may be generated or mixed in the process, the detection method and control limits should be explained.

Because the preparation route of organic synthetic drugs is generally longer and the influencing factors are also more, the specific and detailed operation steps and process conditions are the basis for evaluating the rationality of the process and the feasibility of quality research methods. The control of intermediate processes includes: control of intermediates and control of process conditions.

The quality control of intermediates is an important measure to ensure the stability of the production process and the controllability of product quality, which requires full attention. The FDA summarizes the main intermediates as: pivot intermediates (intermediates that can be synthesized by different methods), key intermediates (usually intermediates formed for the first time in important parts of the molecule, such as intermediates with stereoisomeric molecules that first introduce chiral atoms), and final intermediates (that is, the previous step in the final reaction of API synthesis), emphasizing the importance of controlling the quality of these intermediates to ensure the quality of APIs.

4 Organic Solvent Residues Should Be Detected Locally

Residual solvents in drugs refer to organic volatile compounds used in the production of APIs, excipients and formulations that cannot be completely eliminated in the process, and residual solvents are unavoidable components in drugs.

5 Process Research Should Emphasize Optimization And Amplification

The research on the production process of APIs should include two parts: laboratory stage and pilot scale-up, and after the small trial production in the laboratory stage is stable, it should be gradually enlarged to the pilot test. Pilot production is an indispensable link in the transition from laboratory to industrial production, which is a bridge between the two, and is also of great significance for evaluating the materiality and stability of the process route. Clarify the main tasks of pilot scale-up; It is necessary to attach importance to the evaluation of the pilot scale; It should be clear that process optimization is a dynamic process; Pay attention to the analysis and research of impurities.