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1、GUIDELINE No.:HGB(1)T-1Technical Guideline for Making Post Approval Changes to Chemical DrugProducts(I)1April 20082Table of contentsI. Overview2II. Basic principles for performing studies post-approval changes to chemical drug products3III. Changes to Drug Substance Manufacturing Process6IV. Changes
2、 to excipients in a drug formulation14V. Changes to the manufacturing process for a drug product22VI. Changes to drug product strength and packaging size30VII. Changeto drug prodcugt specificication36VIII. Changes to the drug prodcut shelf-life (expiration dating period) and/or storage conditions41I
3、X. Changes to drug product packaging materials and the container closure syatem . 37X. Changes to the manufacturing site of an imported drug product51XI. Change to the manufacturing site of API used in an imported drug product and change to the manufacturing site of an imported API48XII. Changes in
4、the site of Manufacture for API used in a domestic drug product. Error! Bookmark not defined.Appendix I Basic methods for comparison investigation of drug dissolution/release36Appendix II General considerations for exemption of in vivo bioequivalence (BE waiver) 72Appendix III A partial list of of m
5、edicines with narrow therapeutic windowsError!Bookmark not defined.References77Glossary79Authors801I. OverviewThis guideline is primarily used to guide pharmaceutical manufacturers to carry out studies for post-approval changes (or changes) to chemical drug products. Changes here refer to the change
6、s that involve source, methods, control conditions with respect to the manufacture, quality-control and use condition and related areas for a drug product that has been approved for marketing. These changes may affect the products safety, efficacy and quality controllability. The change study here r
7、efers to the study and qualification work to support a proposed change.At present, the changes and change studies covered in this guidelines include the following areas: the changes to API/drug substance (DS) manufacturing process, excipient for pharmaceutical use in formulation and its manufacturin
8、g process, registered specifications, strengths, shelf life (expiration dating period), storage conditions , drug product packaging materials and container closure system, the imported drug product manufacturing site, manufacturing site of imported API/DS or API/DS used in import drug products, and
9、API manufacturing sites used in domestic drug products.This guideline describes from technical point of view the studies and qualifications that should be performed when changes are to be made to the products. Pharmaceutical manufacturers should perform change studies and qualifications in accordanc
10、e with the technical requirements of this guideline, and after the work is completed, submit supplemental application to appropriate food and drug regulatory authorities according to the requirements of Drug Registration Regulation (DRR).In order to control the potential impact of a change to the sa
11、fety, efficacy and quality controllability of the affected product, this guideline divides the all changes into 3 categories: Type I, minor changes that basically have no impact on the safety, efficacy and quality controllability of the affected product; Type II, moderate changes, for which studies
12、should be performed to demonstrate that the changes have no effect on the safety, effectiveness and quality controllability of the affected product ; Type III, major changes that need a series of studies to demonstrate that the changes have no negative impact on the safety, efficacy and quality cont
13、rollability of the affected product. The category of change types has taken into consideration the relevant regulation for supplemental application in of the current Drug Registration and Regulation (DRR) as well as relevant technical requirements of other countries in order to help the manufacturer
14、s to perform targeted change studies, summarize the study results into supporting information and make supplemental application to the regulatory agencies.2The changes referred to in this guideline are post approval changes aiming at marketed chemical drug products. Therefore, changes and change stu
15、dies should be based on the studies and cumulative data in the past from the drug registration stage and actual manufacturing processes. The more systematic and thorough the research work in registration phase was and the more sufficient the data were accumulated from the manufacturing processes, th
16、e more helpful it would be for the post-approval change study.For specific requirements in this guideline, please refer to the technical guidelines for chemical drug research and development or other relevant technical guidelines previously issued. If there are other scientific investigation results with sufficient evidence available to demonstrate that the changes hav
