Quality Standards for Chinese Medicine Intermediates in Three Drug Studies

1.Synthesis Process

The test items should be formulated according to the evaluation of the synthesis process. For example, palladium carbon is a commonly used catalyst in synthesis. We need to evaluate the residue of palladium in API. If only palladium is detected in API, there is a considerable risk of its qualification. When palladium carbon reduction is used, there should be a palladium removal strategy in the process. Whether this strategy is effective should be studied. The residual amount of palladium in an intermediate can be studied during the process optimization stage or even the pilot stage to ensure that the palladium in the finished product does not exceed the specified limit. After there is sufficient data to support the effective palladium removal strategy, the residual amount of palladium in the intermediate can no longer be detected, that is, the intermediate quality standard in the application data does not need to include palladium inspection.

2. Impurity control strategy
The "impurities" mentioned in this paragraph are impurities in a broad sense, that is, all components in the finished API except API are impurities, including related substances, isomers, inorganic salts, residual solvents, genotoxic impurities, metal catalysts, water, etc. The impurity control strategy in the synthesis process is not only the control strategy of related substances, but also the control strategy of all impurities. The quality standards of intermediates can help to improve the research contents of all impurity control strategies. For example, for organic solvents used in the process, an effective control strategy for residual solvents should be developed. If the strategy is not fully sure whether it is effective in the process, the residual amount of some solvents can be studied in the intermediate to ensure that the solvent residual limit of the finished product meets the requirements. The same as the palladium study above, if it is confirmed that the residual solvent control strategy is effective, the corresponding inspection items can be deleted from the intermediate quality standard.


3. Understanding of quality risk
Whether the impurity control strategy is effective does not necessarily need to be confirmed by testing, but should be judged according to the level of the impurity on the quality risk of finished products. Take the control of genotoxic impurities as an example. If acetyl chloride is used, the compound is particularly active. If the process involves water washing or salifying, the risk in API is very low, so it is not necessary to study it. The effectiveness and rationality of control can be described according to chemical properties and specific processes.

The same as the quality research process of starting materials, the quality research process of intermediates is also a risk management process, which is a dynamic process. As mentioned above in the study of palladium and residual solvents in intermediates, at the beginning of the process, we believe that the risk of finished products exceeding the standard is very high. However, with the process optimization and the analysis of multiple batches of data, the corresponding impurity control strategy is proved to be effective, and the risk of finished products exceeding the standard becomes very low, so the corresponding inspection items can be deleted from the quality standard of intermediates. It is also possible to discover previously unrecognized high-risk factors, such as the configuration change of chiral center in a certain step of reaction, and then add the isomer check item to the corresponding intermediate quality standard.