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

17、 with sufficient evidence available to demonstrate that the changes have no negative impact on the drugs safety, efficacy and quality controllability, it is unnecessary to perform the change studies by following this guideline.II. Basic principles for the studies in support of post-approval changes

18、to chemical drug productsThe studies for post approval changes (or changes) referred in this guideline are those performed to support changes to chemical drug products that have been approved for marketing. Research and development work in the studies should generally follow the principles below:(1)

19、 Pharmaceutical manufacturers should drive the change studies and self-assessment of the study results.Based on the needs in manufacturing, etc., pharmaceutical manufacturers propose changes and perform relevant studies. Pharmaceutical manufacturers should have a comprehensive and accurate understan

20、ding of the research & development work, manufacturing and properties of their products. They should clearly understand the reason for the proposed change, extent of the change to the products and the impact of the change to the product when a change is being consideration. Hence, changes to a chemi

21、cal drug product should be driven by pharmaceutical manufacturers.Pharmaceutical manufacturers should carry out a comprehensive study for the products quality, stability and biological properties before and after a change. Pharmaceutical manufacturers should also carefully analyze the study results

22、and evaluate the impact of the proposed change to product quality, i.e., whether the products quality is the same and therapeutic effect is equivalent before and after the change. Self-assessment for the study results is specifically emphasized.3(2) A complete and comprehensive evaluation for the im

23、pact of change to the safety, efficacy and quality controllability of the drug product.Because drug research & development work and manufacturing processes are closely related, changes to manufacturing process, excipient with pharmaceutical application in the drug product formulation or quality stan

24、dards etc., could affect the overall safety, efficiency and quality controllability of the drug product. If in-vitro studies can not accurately determine how a change affects the product, it is necessary to perform more in-depth studies, comprehensive evaluation for the impact of the change to the s

25、afety, efficacy and quality controllability of the drug product. This is also the starting point for the change study.Generally, a change study should take into consideration of the following aspects:1. Evaluation of Impact of Changes on Drug ProductsWhen a change was made to a product, a study shou

26、ld be carried out to evaluate and assess the impact of the change to the safety, efficacy and quality controllability of the drug product, including evaluation of changes to product chemistry, physics, microbiology, biology, biological equivalence, and/or stability. The study should be designed base

27、d upon a comprehensive consideration about the specifics and type of the change, drug substance and /or dosage forms, and degree of impact of the change to the drug product, etc. For example, to evaluate any change of impurities in a drug product prior to and post a change, it is appropriate to firs

28、t select or establish a suitable chromatographic method, and then perform a comparative analysis of the impurity profiles (types and amount of impurities) prior to and post a change. If new impurities appear after a change, or if levels of existing impurities exceed the established limits, then it i

29、s necessary to determine whether the impurity levels are acceptable or not with rationales according to the Appendix 1 or 2 of “Technical Guideline for Study of Impurities in Chemical Drug Products”； If it is not acceptable, then a decision tree should be referenced to decide the subsequent step of

30、work including consideration for carrying out any needed toxicology studies.In addition to the studies suggested under each change type in this guideline, it is also necessary to perform other selected important studies by taking into consideration of the characteristics and specifics of the change.

31、 For example, for some changes to a tablet manufacturing process, besides comparing dissolution/release performances, it is also necessary to assess if there are any changes to other physical parameters.2. Evaluation of Sameness or Equivalence prior to and post Change4Strictly speaking, it is unnece

32、ssary for a product to remain completely identical before and after a change, however, the product must keep the sameness and equivalence, namely, the product must have the same quality and clinical equivalence.Based on the study and qualification about the chemistry, physics, microbiology, biology,

33、 biology equivalence and stability of a product, comprehensive analysis should be carried out to evaluate how a change would impact drug safety, efficacy and quality controllability. In general, by comparing and analyzing of the results before and after a change, it can be determined whether the res

34、ults pre- and post change are equivalent. The comparison studies include dissolution and release as well as a thorough comparative analysis of a property, such as drug product stability, etc.In some cases, however, the products are unable to retain the same equality or equivalence after the change,

35、i.e., the change may have affected the product safety, efficacy and quality controllability. If a pharmaceutical manufacturer still wishes to implement the change, it must prove that the change will not negatively impact the product quality through a series of pharmacological and biological studies.

36、 For example, if the studies found that certain manufacturing process changes could result in new degradation products. However, further study shows that the degradation products will not raise concerns about the drug safety. Therefore, this change still can be implemented.3. Considerations about th

37、e samples used for studiesIf a change occurs at the manufacturing phase after a drug product has been approved for marketing, samples used for change studies and qualification should come from manufacturing at a scale greater than the pilot scale.In general, quality comparison studies (e.g., dissolu

38、tion, release comparison experiments) for a drug product in support of a change are performed using samples from 3 production batches prior to the proposed change and from 1-3 batches manufactured with the proposed changes incorporated.Post change drug product stability study is usually performed us

39、ing samples from 13 batches stored for 36 months under an accelerated and a long-term storage conditions. The stability results are compared with that of the 3 batches obtained from the manufacturing scale prior to the change. Specifics on the number of batches and testing duration should be determi

40、ned based on the level of impact caused by the change to the product quality and stability. As for major change, or products with test results revealing a poorer product stability, it is suggested that more samples batches be selected and extended testing duration be adopted. With respect to a chang

41、e for an injection product,5stability sample batches and testing duration should be in accordance with the relevant technical requirements.4. Related ChangesA change required to a product seldom occurs alone. For example, manufacturing site change may occur in parallel with changes to manufacturing

42、equipments and processes; a change to a pharmaceutical excipient in a formulation may lead to changes to drug product specifications; or may result in changing packaging materials at the same time. In this guideline, changes paralleled to or consequential to another change are called Related Changes

43、With respect to Related Changes, studies can be performed according to the guiding principles for various types of changes in this guideline. Because these changes may affect the products safety, efficacy and quality controllability to different extents, i.e., related changes may be classified to di

44、fferent change types in this guideline, and studies may be carried out according to the respective technical requirements; however, the overall studies should be carried out to meet the higher technical requirements. For example: a change to an excipient in a drugs tablet formulation is within the s

45、cope of Type III change per this guideline; while making the change to the excipient, there is a need to add an HPLC test in the drug product specifications, and the latter change falls into Type I change for changing drug product registration specifications in this guideline. For the abovementioned

46、 related changes, change studies should follow the requirements for Type III changes for excipient and Type I changes for drug product specifications, respectively;. Overall, a Type III change on excipient may have more significant impact on the drug product safety, efficiency and quality controllab

47、ility, 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, ch

48、anges 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 c

49、hanges 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 salt-formation a

50、nd 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 comprehensive analysis of its impact on the drug struc

51、ture, 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 believ

52、ed 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 e

53、ffect 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 aspe

54、cts about the quality comparison: 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 comparison studies as well. For example,

55、 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 sho

56、uld 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 subs

57、tance 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

58、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 t

59、o 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 subst