【正文】 may lead to changes to drug product specifications。. Overall, a Type III change on excipient may have more significant impact on the drug product safety, efficiency and quality controllability, relevant biological studies could be required.III. Changes to Drug Substance Manufacturing ProcessIn this guideline, changes to a drug substance manufacturing process refer to those for a chemically synthesized drug substance including changes to sources of reagents and starting materials, changes to specifications of reagents, intermediates and starting materials, changes to reaction conditions, and changes to synthetic routes (including shortening synthetic routes and changing reagents and starting materials), etc. Changes to a manufacturing process may involve one or several of the changes mentioned above. In the latter case, studies relevant to each change need to be considered and performed. In principle, for a change to a synthetic route, the number of6chemical reaction steps to synthesize a chemical drug substance should be at least more than one (excluding saltformation and purification steps).In short, changes to a drug substance manufacturing process should not adversely affect the safety, efficacy and quality of drugs.(1) Overall considerationsAfter changes to a drug substance manufacturing process is made, a prehensive analysis of its impact on the drug structure, quality and stability should be performed. Changes to a drug substance manufacturing process may result in changes in the types and contents of impurities as well as the physical properties of the drug substance that may negatively affect the quality of the drug product. It is generally believed that the closer a change is to the final step of a synthesis route, the more likely it is to affect the quality of the drug substance. Because changes to a manufacturing process before the final reaction step generally do not affect the physical properties of a drug substance, the degree of the effect of the process changes on drug substance quality is normally judged by whether those changes occur before the final reaction step.The emphasis of such studies should be placed to evaluate the consistency of the drug substance quality before and after a change is made. There are mainly two aspects about the quality parison: one is about the impurity profile (including types and levels of impurities), and the other is about the physical properties of the drug substance. In certain special cases, however, other factors may be important and require parison studies as well. For example, in the case where a drug substance is a mixture of bioactive stereoisomers or analogs, after a change is made, the ratio of the stereoisomers or its analogs should be examined for its conformity with the requirement in the specifications. If there is no specified ratio in the specifications, it should fall within the range of measurements from multiple batches of drug substance produced by the original manufacturing process. In some cases, more attention should be paid to whether there are changes to the structure and the stability of drug substance. Additionally, a slight change to drug substance manufacturing process, such as an increase in the heavy metal content, may affect the stability of a drug product, and therefore, attention to drug product stability may be also needed during the study.1. Impurity profileThe study should primarily assess if there are changes to existent known impurities and if there emerge any new impurities. At the same time, levels of residual solvents and inorganic impurities should be examined according to specific changes to a manufacturing process.7For the study of impurities after a change is made to a manufacturing process, it is very important to determine the reaction step from which the examination of changes to impurities should be started and a proper impurity test method should be established.It is most ideal that the intermediate is isolated from the reaction step subject to changes, and its impurity profile is assessed. If the impurity profile is found to be the same, it can be concluded that the impurity level of the drug substance is unaffected by this change. If the impurity profile is different, the impurities of the intermediates from the subsequent reaction steps should be examined. However, it is usually difficult to implement this ideal scenario. due to various reasons, . the lack of suitable test methods for the impurities of intermediates, the lack of impurity data from the original process with which can be pared, or the difficulty in isolating intermediates for study, etc. Under these circumstances, the consistency of impurity profile may be demonstrated by testing the impurities in the drug substance. Therefore, the equivalency of the pre and postchange impurity profile can be demonstrated by paring the impurity profiles of either the intermediates or the drug substances. However, when it is not possible to isolate intermediate from a multistep reaction mixture, it is not possible to prove that the pre and postchange impurity profile is consistent by studying the impurities of intermediates. The impurity test method to be used should be able to effectively separate and test both existing and new impurities. For a newlyestablished impurity test method, a detailed method evaluation should be performed. A parison of the pre and postchange impurity profiles should be carried out in the same manner. In general, at least three consecutive postchange batches should be tested and pared with at least three prechange batches. The pre and postchange impurity profiles can be considered consistent if the results meet the following requirements: (1). no new impurity at more than % are detected in the postchange intermediates, or new impurities in the drug substance are within the specification limits prescribed by “Technical Guideline for Study of Impurities in Chemical Drugs