Post-Approval Change Regulations in Japan

Transcription

1 Post-Approval Change Regulations in Japan Pharmaceuticals and Medical Devices Agency Office of Cellular and Tissue-based Products Futaba Honda, Ph.D.

2 Agenda Application Forms and attached documents for market approval of drugs in Japan Standard periods and procedures for a partial change approval application and a minor change notification A Partial change approved application and a minor change notification Manufacturing sites, Specifications and test methods, Period of validity, manufacturing methods Data requirement for a partial change approval application

3 Abbreviation a partial change approval application = PCA a minor change notification =MCN

4 M1: Administrative Information and Prescribing Information M2: Summaries 2.3 quality Overall Summary : : M3: Information on Quality M4: Nonclinical Study Reports Application Form for marketing approval M5: : Clinical Study Reports Brand Name Ingredients and Quantity Annex Specifications Manufacturing procedures Dosage and administration Indications Storage Conditions and Period of Validity Specifications and test methods Manufacturing Sites Any changes in the matters entered in the Application Form, shall be addressed in a PCA or a MCN.

5 M2 2.3.S.2 Manufacture 2.3.S.4 Control of DS 2.3.S.5 Reference Standards 2.3.S.6 Container Closure System 2.3.S.7 Stability M3 3.2.S.2.1 Manufacture 3.2.S.2.2 Manufacturing process and process controls 3.2.S.2.3 Control of materials 3.2.S.2.4 Controls of Critical Steps and Intermediates 3.2.S.4Control of DS 3.2.S.5 Reference Standards 3.2.S.6 Container Closure System 3.2.S.7 Stability 2.3.P.1Description and Composition of DP 2.3.P.3 Manufacture 2.3.P.4 Control of Excipients 3.2.P.3.1 Manufacture 2.3.P.5 Control of DP Application Forms 3.2.P.3.2 for Batch Marketing Formula Approval of Drugs 2.3.P.6 Reference Standards 3.2.P.3.3 Manufacturing process and process controls 2.3.P.7 Container Closure Ingredient System and Quantity 3.2.P.3.4 Controls of Critical Steps and Intermediates 2.3.P.8 Stability 3.2.P.4 Control of Excipients Annex Specifications 3.2.P.5 Control of DP Annex Specifications 3.2.P.6 Reference Standards 3.2.P.2.4 Container Closure System Manufacturing Procedures 3.2.P.8 Stability Specifications and Test methods Period of Validity and Storage condition Manufacturing sites

6 Standard Period and procedures for PCA and MCN Partial change approval application Approval application Application for GMP inspection Approval Six months Shipping One year Minor change notification Notification Next PCA, GMP periodic inspection Shipping Within 30 days

7 Approval and Notification in EU, US and Japan Approval Application EU Type II US Japan Major change Notification Before change EU Type IB Type IA US Partial change approval Moderate change After Change Japan Minor change notification Report US Annual Report

8 Standard Periods and procedures for a PCA and a MCN A MCN is not reviewed at the time. The matter is confirmed at the next PCA, but In the event that it is discovered in the GMP inspection that a MCN had been submitted concerning changes in manufacturing process that should not have originally been addressed in the MCN, the MCN becomes invalid, and there may be the possibility that the manufacturer may be accused of violating the Pharmaceutical Affairs Law.

9 What change is addressed in a PCA and a MCN? A general rule for Drugs A change other than listed below is addressed in a MCN (H yakushokuhatsu No ) Change of manufacturing procedures that affect quality, characteristics, efficacy and safety of the final products Deletions or changes of the item of specifications and test methods Change of the manufacturing processes concerns inactivation or elimination of pathogens Additions, changes or deletion of Dosage and administration, and Indications Any other change fear of being affected quality, efficacy or safety of the final products

10 What change is addressed in a PCA and a MCN? Biological Products (H yakushokushinsahatu No Attachment 3) As changes in the matters entered in the Manufacturing Method column require adequate change control, they shall therefore be addressed in a PCA, in principle.

11 What change is addressed in a PCA and a MCN? It is difficult to uniformly specify the matters to be addressed in a MCN for biological drugs. Biological drugs are produced by utilizing biosynthesis processes in biological bodies, it may be possible that materials that are inhomogeneous in molecular structure are produced. Some changes in the higher structure of the molecule are difficult to be determined by physicochemical analyses can affect biological activity, evaluation of the impact by changes in the manufacturing method on the quality safety. Biological drugs consist of various kinds of materials such as proteins, glycoproteins, polypeptides, and their derivatives, and their controls also vary.

12 What change is addressed in a PCA and a MCN? Change of manufacturing sites Since change in manufacturing sites require adequate change control, they shall be, in principle, addressed in a PCA for matters that have been approved. However, for changes that are related to facilities for inspection and testing, it shall be addressed in a MCN.

13 What change is addressed in a PCA and a MCN? Specifications and test methods They shall be, in principle, addressed in a PCA Changing strictly an acceptance criteria without changing the substance of the item of specifications, it can be addressed in a MCN Period of validity They shall be, in principle, addressed in a PCA

14 Description of the manufacturing method column in the application form The processes required to ensure the quality of the drug shall be described appropriate implementation of process management by GMP For clarifying the operation of the whole process, the manufacturing method shall be described follow the manufacturing process.

15 Description of the manufacturing method column in the application form Raw materials reagents Critical processes Major equipment Critical process parameters In-process control tests Key intermediates The applicant personally distinguish and establish in advance the matters to be addressed in a PCA, and the matters to be addressed in the MCN. Storing conditions and duration, in-process control test Testing items, analytical methods, acceptance criteria

16 Process parameters or none MCN <<PCA>> Description Validation Data Design of Experiments Risk Management Prior Knowledge M2 M3

17 Target value/ Set value MCN Target values/set values may be included in operating conditions, etc. If a target value/set value is set, the reference value shall be enclosed in or, and at the same time, an allowable range for the target value/set value must be established in the product master formula or SOPs. However, if these parameters are set for parametric release, or if the parameters can affect the quality significantly, it is necessary to specify an allowable range on the approval application form, and they must not be made a target value/set value PCA

18 The matter addressed in a MCN on Biological Products In the event that it is evident that there is an extremely low possibility of the change having an adverse impact on the quality/ safety of the final product, and in the following confirmed cases, a MCN may be applicable. Based on the type of drug and the type of change in the manufacturing method, a MCN may be applicable. For the applicable cases, the applicant may make such a proposal when submitting an approval application; the proposal will be judged during the review as to whether it can be accepted. As an example of applicable case, the allowable range for process parameters, etc. that is proposed at the time of application may be changed during the review for approval or on the occasion of the actual production results.

19 Changes in manufacturing method For changes in the manufacturing method of drugs, etc., adequate validation and change control, etc. shall be conducted as a prerequisite for changes in either a PCA or a MCN, regardless of the magnitude of the impact on quality. That is, a change shall be made based on the judgment that the change imposes no obvious impact on the quality though change control as performed under GMP.

20 Necessary data for a PCA Manufacturing Sites Process validation data and lot analysis data at a new manufacturing site, comparability data, etc. Specifications and test methods Validation data, comparability data, etc. Period of Validity a real-time/real-temperature stability data Manufacturing procedures Process validation data, comparability data (characteristics, specifications, stability etc.), etc. The Necessity of data may be depend upon degree or substance of the change

21 Change of the matter addressed in a PCA to a MCN a MCN to a PCA Minor change notification a PCA to a MCN Partial change approval application

22 Thank you for your attention! 22