Post-approval Variations

Transcription

1 Post-approval Variations JPMA Perspective JPMA Biopharmaceutical Committee Subcommittee on Technological issues Takao Kojima (Takeda Pharmaceutical Company Limited) CASSS CMC Strategy Forum Japan 2013

2 Outline 1. Current status of administrative regulatory procedures related to the quality Regulations in Japan Case of Post-approval Variations 2. Proposals on administrative regulatory procedures based on the Questionnaire results 3. Opinion Exchange on the post approval variations between Regulatory Authorities and Industry (JPMA, PhRMA, EFPIA) 4. Vision 1

3 Outline 1. Current status of administrative regulatory procedures related to the quality Regulations in Japan Case of Post-approval Variations 2. Proposals on administrative regulatory procedures based on the Questionnaire results 3. Opinion Exchange on the post approval variations between Regulatory Authorities and Industry (JPMA, PhRMA, EFPIA) 4. Vision 2

4 Approval Letter First page of Application form Product Name Ingredient and Contents Manufacturing Process Dosage and Administration Indications Storage and Shelf life Specification and Testing Method These are commitment to MHLW. Almost all parts are CMC contents. 3

5 Submission Type NDA (new drug application) New API New API strength New dosage form New brand name PCA (partial change application) Other changes ingredients other than the active ingredient, their contents dosage and administration Indications manufacturing methods specifications and test methods storage condition and expiration date etc. MCN (minor change notification) changes other than specified in the following items : 1.Changes in the manufacturing Process, etc. which affect the nature, properties, performance and/or safety of the product 2.Deletion of items concerning specifications and test methods as well as concerning changes in the specifications 3.Change in the methods of inactivating or eliminating pathogenic factors 4.All other changes that may affect the quality, efficacy or safety of the product (The Article 47 of the Enforcement Regulations of the PAL stipulates ) 4

6 Submission Timing PCA (partial change application) 1. Prior to the change 2. Regulatory review 3. Data required (basically) (US : PAS, EU : Type II ) MCN (minor change notification) days after the change 2. Reviewed at next PCA 3. No data submitted (US : CBE, EU : Type IA) prior 12M 30 days after PCA Regulatory review! Change occur MCN 5

7 Example Biotechnology products PCA (partial change application) 1. Package form change/addition 2. Site change/addition (DS, DP, storage, package) 3. Ingredients prescription change 4. Manufacturing Process change 5. Testing method change MCN (Minor Change notification) 1. Site change/addition (test) 2. Manufacturing Process change (allowed part* : marked ) Synthetic products PCA (partial change application) 1. Package form change/addition 2. Site change/addition (DS, DP) 3. Ingredients prescription change 4. Manufacturing Process change 5. Testing method change * Identified in the application form Justification provided in the CTD MCN (Minor Change notification) 1. Site elimination (one of several sites) 2. Site addition (storage/package/test) 3. Manufacturing Process change (allowed part* : marked ) 6

8 Outline 1. Current status of administrative regulatory procedures related to the quality Regulations in Japan Case of Post-approval Variations 2. Proposals on administrative regulatory procedures based on the Questionnaire results 3. Opinion Exchange on the post approval variations between Regulatory Authorities and Industry (JPMA, PhRMA, EFPIA) 4. Vision 7

9 Questionnaire about Biotechnology Products Purpose Extraction of Issues relevant to Post-approval Variations Improvement of administrative regulatory procedures May 30 th ~June 24 th, companies (JPMA biopharmaceutical Committee) Response rate : 89%(32/36) (Domestic: 21, Foreign : 11) Further analysis based on 99 variations and 43 proposals. (Detailed information was provided by 18 companies) 8

10 Types of Biotechnology products animal cell culture products (Excl. recombinant) recombinant vaccine mammalian cell culture products 35 recombinant microorganism Questionnaire result 9

11 Type of post approval change The number of cases MCN: Minor Change Notification PCA: Partial Change Application Ingredient and Contents Manufacturing Process Specification and Testing Method (drug substance) Specification and Testing Method (drug product) Storage and Shelf life Type of post approval change Manufacturing site(s) Others Questionnaire result 10

12 PCA (partial change application) / MCN (minor change notification) PCA : 81 No answer : 1 MCN : 17 Manufacturing Process : 7 cell culture process : 2 cell culture/purification process : 1 purification process : 1 manufacturing process for drug product : 3 Specification and Testing Method : 1 amendment of misdescriptions : 1 Manufacturing site(s) : 6 storage/package/testing site : 2 testing site : 3 update of FMA* number : 1 *FMA: Foreign Manufacturer Accreditation Others : 3 Questionnaire result 11

13 Comparison of administrative regulatory procedures US Japan PCA MCN Annual Report CBE CBE PAS No answer EU Japan PCA MCN Type IA Type IB Type II Extension Appl No answer # of submission at Questionnaire result 12

14 Outline 1. Current status of administrative regulatory procedures related to the quality Regulations in Japan Case of Post-approval Variations 2. Proposals on administrative regulatory procedures based on the Questionnaire results 3. Opinion Exchange on the post approval variations between Regulatory Authorities and Industry (JPMA, PhRMA, EFPIA) 4. Vision 13

15 Proposals on administrative regulatory procedures for post-approval changes 32 companies Others Setting of shelf life Clarification of administrative procedures 8 12 Simplification of administrative procedures Questionnaire result 14

16 1. Setting of shelf life Manufacturing process changes of drug substance Based on appropriate comparison of relevant quality attributes, pre- and post-change product are highly similar and considered comparable Shelf life of post-change drug products is set up based on the shelf life of pre-change drug products. Result of stability studies on the post-change drug products is not for submission (but for in-house data). OR Shelf life of post-change drug products is set up based on the result of stability studies on the post-change drug products. Shelf life of post-change drug products is extended by MCN (minor change notification) based on the result of commitment stability studies. 15

17 Comparison of administrative regulatory procedures (extension of shelf life) In case of variation about extension of shelf life, administrative procedures have a large difference between Japan and US/EU. Unlikely US/EU, PCA is mandatory in Japan. US EU Japan categories review periods Annual report Type IB PCA - 30d 12M Different timing of approval could impact a stable global supply of Biotechnology drugs Questionnaire result 16

18 1. Setting of shelf life Site change / addition Pre- and post-manufacturing processes are highly similar Shelf life of drug products manufactured at a new site is set up based on the shelf life of drug products manufactured at a old site. Result of stability studies on the drug products manufactured at a new site is not for submission (but for in-house data). 17

19 2. Simplification of administrative regulatory procedures for post-approval changes Expansion of the scope of MCN (minor change notification) in a manufacturing process No influence of the quality on the end products by performing proper change management. The same administrative regulatory procedures as a Synthetic products 18

20 Comparison of administrative regulatory procedures (manufacturing process) Manufacturing site(s), manufacturing process, manufacturing scale Basically, all of these changes should be in PCA in Japan. Japan has only two categories, PCA and MCN. US and EU have Intermediate categories CBE-30 and Type IB, respectively. It is possible to lower categories in US when the comparability protocol is submitted to FDA in advance, and approved. Questionnaire result 19

21 Outline 1. Current status of administrative regulatory procedures related to the quality Regulations in Japan Case of Post-approval Variations 2. Proposals on administrative regulatory procedures based on the Questionnaire results 3. Opinion Exchange on the post approval variations between Regulatory Authorities and Industry (JPMA, PhRMA, EFPIA) 4. Vision 20

22 Background Variations are handled on a case-by-case basis Under the current administrative regulatory procedures related to the quality of Biotechnology products, variations are handled on a case-by-case basis. Accumulation of knowledge /experience In recent years, experiences in development of biotechnology products (Industry) and review (Regulatory Authorities) has increased. Clarification/ Improvement Clarification and Improvement of administrative regulatory procedures are necessary 21

23 Discussion between PMDA and Industry 1 st meeting Authorities : MHLW, PMDA Industry : JPMA(biopharmaceutical Committee, Regulatory Affairs Committee) 2 nd meeting Authorities : PMDA Industry : JPMA(biopharmaceutical Committee, Regulatory Affairs Committee), PhRMA EFPIA These meetings were very fruitful and productive. 22

24 Outline 1. Current status of administrative regulatory procedures related to the quality Regulations in Japan Case of Post-approval Variations 2. Proposals on administrative regulatory procedures based on the Questionnaire results 3. Opinion Exchange on the post approval variations between Regulatory Authorities and Industry (JPMA, PhRMA, EFPIA) 4. Vision 23

25 For facilitating the development of Biotechnology products in Japan As an expert committee of Biotechnology products in Japan, Build foundations for development of biotechnology products Facilitate development of Biotechnology products Continue to cooperate with the Regulatory Authorities to improve and clarify the administrative regulatory procedures. 24