The residue of solvent in APIs is one of the key issues to be mindful of during drug manufacturing. When solvent residue exists in the APIs or formulations, it may have adverse effects on the stability, purity, and efficacy of the drugs. Overcoming the difficulties of solvent residue in APIs involves multiple aspects, such as selecting appropriate solvents, optimizing synthesis conditions, and employing effective methods for solvent removal. At the same time, it is essential to employ scientific testing methods to monitor and ensure that solvent residues are within acceptable limits. Establishing highly sensitive and accurate analytical detection methods is indispensable to meet international standards for residual solvent detection, thus safeguarding the safety and efficacy of medication for patients.
Medicilon Cloud Lecture invites the head of the Process Analysis Department, Maodun Xie to share with us the challenges and solutions regarding solvent residue in APIs during preclinical operations.
Q: Benzene is used in the second to last step of the starting material. My synthesis process for the API consists of four steps. Benzene should be able to be removed in subsequent steps of the process, resulting in a low possibility of residue in the API. Does this mean further research is unnecessary?
Maodun Xie: Whether further research is required depends on whether the manufacturer of the raw materials you purchase has conducted relevant studies. If the manufacturer has conducted research according to the standards for APIs, then you may not need to conduct further research. But if the manufacturer has not conducted relevant research, then it is still necessary to study the possibility of residue. Generally, purchased raw materials are essentially reagent-grade, and they are rarely studied for benzene residue according to API standards. Therefore, it is highly likely that research in this area will be necessary.
Q: If the process only involves 3 types of solvents, can we directly use the method of drying and weighing loss for detection?
Maodun Xie: Whether to use the method of drying and weighing loss for sample detection mainly depends on whether the sample is thermally stable. If it’s a solid sample, it’s more likely to be thermally stable. In ICH-Q3C, drying and weighing loss can be used for detection, with a limit requirement of less than 0.5%. However, it is recommended to choose the methods with stronger specificity and higher accuracy for confirmation. If the results from testing representative batches are similar to the results from drying and weighing loss, then drying and weighing loss can be used for testing in subsequent production.
Q: Can LD50 be used to calculate limits?
Maodun Xie: This is not possible. The National Medical Products Administration stated clearly in 2022 that LD50 values cannot be used in limit setting. LD50 represents the median lethal dose, indicating high toxicity and therefore cannot be used to calculate safe limits.
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