【正文】 hetic process without changing their quality have no effect on drug9substance quality, and thus no study or qualification is required (See Table 31).2. Enhancement of the specifications of reagents, starting materials or intermediatesThese changes include adding new qualitycontrol tests for reagents, starting materials or intermediates, tightening the original qualitycontrol test limits, switching to analytical methods with better sensitivity and specificity, etc.This type of changes actually increases the qualitycontrol requirements for reagents, starting materials or intermediates. Therefore, the focus should be on the methodological study and qualification of the analytical method for the change (see Table 31)Table 31 Changes to drug substance manufacturing process (Type IChanges)Changes0 Changes to the source of reagents or Prerequisites Studies and Qualifications 1,2,6 1starting materials0 Enhancement of the specifications of2 1,3,4,5,6 the reagents, starting materials or drugsubstance intermediatesPrerequisites1 Quality of reagents or starting materials is not lowered.2 If changes to acceptance criteria in a specification are involved, the changes should be implemented within the limits of the original specification.Studies and Qualifications1 Explain the reasons for making changes.2 List the new source pany and analysis report3 List the new and original specifications.4 Conduct methodological study and qualification of the new analytical methods5 Provide the analysis report and chromatograms for the reagents, starting materials or intermediates, both pre and postspecification change.106 Test three consecutive batches of drug substance by the postchange process.(3) Type II Changes1. Changes to specifications of starting material, solvents, reagents and intermediates Specific change and prerequisitesThis type of changes includes: reducing the qualitycontrol testing for starting materials, solvents, reagents or intermediates, or broadening the limits, or replacing the existing methods with new methods without improved specificity or sensitivity. For example, the change may involve deleting an unnecessary or redundant test, ., deleting a particular impurity test if the impurity no longer exists due to the change of the suppliers。 deleting a boiling point test for a solvent because its content is tested using a chromatographic method. This type of changes reduces the qualitycontrol testing for starting materials, solvents, reagents, or intermediates without promising the drug substance quality, ., changes should not have any negative impact on the quality of intermediates (or drug substance) involved. The impurity profile of the pre and postchange intermediates (or drug substance) involved should be equivalent. These are the prerequisites for this type of changes. For example, if the assay of a starting material is changed from 98%102% to 90%102%, the intermediates or drug substance manufactured using the starting material near the lower limit (90%) should be tested to demonstrate that the quality is equivalent before and after the change. If it is not equivalent, the change cannot be categorized as a Type II change. It needs to be tested prehensively according to the requirement for a Type III change. Without sufficient rationale, normally this type of changes is not encouraged. Studies and qualificationComparison of the pre and postchange reaction products from a particular step or drug substance should be performed according to the basic thinking and methodology described in Overall Considerations in the guideline (See Table 32).For studies that focus on the reaction product from a particular step, if the pre and postchange impurity profile is equivalent, no further study of the drug substance is required.If parison is done on the drug substance, the impurity profile and physical properties of the drug substance that are related to the quality of the drug11product dosage form should be examined.Table 32 Changes to drug substance manufacturing process (Type IIChanges)Changes0 Change the specifications of starting material, solvents, Prerequisites Studies and Qualificationsreagents and intermediates 1,2 1,2,3Prerequisites1 The intermediate of the last step of reaction is not involved2 The drug substance quality is not promised.Studies and Qualifications1 Explain the reasons and the rationale for the change.2 Establish new specifications and test, record related spectrums and chromatograms.3 Compare the quality of the pre and postchange reaction products or drug substance.4 Test three consecutive batches of postchange drug substance.(4) Type III changesThis type of changes is fairly plicated and is generally considered to have significant impact on the quality of the drug substance or drug product. It includes changes to reaction conditions, changes to one or several reaction steps or even the whole synthetic route. A change involving redesignation of an intermediate in the original synthetic route as the new starting material also falls into this category.Overall, this type of changes should not promise the drug substance quality. If study shows that the drug substance quality has been promised after a change, such as increased levels of impurities, sufficient evidence should be provided to prove that the change will not promise the product safety and justify the necessity for this process change. Additionally, stability of the pre and postchange drug substances should pared prehensively.12This type of changes morally warrants prehensive study and qualification. The study can be carried out according to the basic thinking and methodology described in Overall Consideration in this guideline. Specifically,1. Explain the reasons for the change. Describe in detail the synthetic routes, operating conditions, key steps and quality control methods for th