Examples of Observations in GMP Compliance …

1 Examples of Observations inpGMP Compliance Inspections,and Related Problemsand Related Problems(Manufacturer/Market Authorization Holder/In-tC tk fMFEt)country Caretaker of MF, Etc.)Office of GMP/QMS inspection,Office of GMP/QMS inspection,Pharmaceuticals and Medical Devices AgencyCPhI J2013 CPhI Japan 2013 April 25, 2013 Tokyo Big Sight* The slides in Japanese are the official 's agendaToday s agenda21. Introduction (the main topic for today)2. Overview of GMP on-site inspections by the PMDApy3. Cases of non- Compliance in recent GMP Compliance inspectionsinspections4.

2 Examples of Observations in GMP on-site inspections5. Problems in GMP control(Marketing authorization holder/In-country caretaker of MF)MF)6. ConclusionsToday's agendaToday s agenda31. Introduction (the main topic for today)2. Overview of GMP on-site inspections by the PMDApy3. Cases of non- Compliance in recent GMP Compliance inspectionsinspections4. Examples of Observations in GMP on-site inspections5. Problems in GMP control(Marketing authorization holder/In-country caretaker of MF)MF)6. Conclusions1 Introduction (the main topic for today) (the main topic for today) High-quality drug products for patients (Safe products and stable supply) Marketing authorization holders, manufacturers (manufacturing sites) and representatives of manufacturers (trading companies, representatives making applications for accreditation of foreign manufacturers, in-country caretakers of MF, etc.

3 , regulatory authoritiesAppropriate GMP control (GQP control) Appropriate GMP control (GQP control) Smooth GMP Compliance inspectionsBoth inspectors and inspectees want reasonable collaboration and communication between aWhat is needed for reasonable itiClose collaboration and communication between a marketing authorization holder and the in-country caretakers of MF/manufacturers, understanding of Japanese pharmaceutical regulations and improvedinspections Non- Compliance cases/ Examples of Observations in recent GMP Compliance pharmaceutical regulations and improved knowledgeGMP Compliance inspections.

4 Responsibilities of manufacturers, marketing authorization holders, and in-country caretakers of 's agendaToday s agenda51. Introduction (the main topic for today)2. Overview of GMP on-site inspections by the PMDApy3. Cases of non- Compliance in recent GMP Compliance inspectionsinspections4. Examples of Observations in GMP on-site inspections5. Problems in GMP control(Marketing authorization holder/In-country caretaker of MF)MF)6. Conclusions2. Overview of GMP on-site inspections by the PMDA6 Inspections conducted by the PMDAI nspections conducted by the PMDAI nspection of Licenses for domestic facilities (for Inspection of facilities and equipmentsbiological products etc.

5 That require a license by the Minister accreditation of foreign manufacturersgGMP Compliance New drugs Biological products etc. Drug products manufactured at foreignTrends in the Japanese marketinspection Drug products manufactured at foreign manufacturing sitesp Of accredited foreign manufacturers: approximately 80% are Asian and frommajor Europeanpharmaceutical companies Import from major European pharmaceutical companies Manufacturing generic drugs in Asian countries2. Overview of GMP on-site inspections by the PMDA3 000[ accreditation of foreign manufacturers: Totals by fiscal year and area]Fiscal 2008 2012(As of November 1, 2012 )the PMDA72 4002,5002,6002,7002,8002,9003,000 ()Trends in the Japanese market: approximately 80% of accredited foreign manufactures are Asian and from major European pharmaceuticalfacturersQuasi drugsDrugs.

6 1,8001,9002,0002,1002,2002,3002,400 Import from major European pharmaceutical companies Manufacturing generic drugs in Asian countriesign manufPackaging/Labeling/StorageDrugs: General1,2001,3001,4001,5001,6001,700, dited foreiDrugs: Sterile drugsDrugs: Radiopharmaceti l5006007008009001,0001,100 r of accreduticalsDrugs: Biological products, * Numbers include sites closed afterNumbeaUAsalaUAsalaUAsalaUAsalaUAsal 20082009201020112012sites closed after accreditation (approximately 100) AsiaEUUSAO thers To taAsiaEUUSAO thers To taAsiaEUUSAO thers To taAsiaEUUSAO thers To taAsiaEUUSAO thers To ta2.

7 Overview of GMP on-site inspections by the PMDA(A il 2006the PMDA200[Number of domestic and foreign on-site inspections: Annual changes by area](April 2006 March 2012)8160180200 DomesticAsiaAfrica120140160 South AmericaNorth AmericaEurope801001203729492745406030202 006200720082009201020112. Overview of GMP on-site inspections by the PMDAthe PMDA9 Procedure for determining on-site inspection Outlines of product(s) subject to inspection: Form 1 Otlifdfti it(f ifti it)From application for inspection to commencing inspectionApplication for Outlines of drug manufacturing site ( foreign manufacturing site):Form 3 Risk assessmentDti tifitithdOn-site/Application for inspection On-site inspection.)

8 Arrangement of schedule Documents submitted in advance Determination of inspection methodInquiriesDocuments Documents submitted in advance Desk-top inspection: Documents for inspection by the PMDA On-site inspection: Issues Observations by the PMDA, grading themanufacturing siteImplementationof inspectionqthemanufacturing site Desktop inspection: Checking with inquiry-based documents Presence or absence of inconsistenciesof inspectionSelection of inspection sites according to risksPrior informationAttached documents at applicationRisk assessmentRisk assessment items Classification of the product (the drug) Manufacturing process Dosage form Hi tf itib fiAttached documents at application, etc.

9 (1) Information about the drug(Attachment 1)(2) Information on manufacturing site n of heet History of inspection by foreign regulatory authorities Previous GMP non- Compliance Previous recalls Previous inspection by the PMDA()gand history of inspection(Attachment 2 [domestic], Attachment 3 [ foreign ])Preparationelection sh Previous inspection by the PMDA Information about the manufacturing site (results of the last inspection) OthersPrevious on-site inspections(Profile of manufacturing site)(1) Grade of the manufacturing site(2) Checking each subsystemPsAccumulation of dataImplementationof inspectionInspection policy shall be determined the next month of of inspectionapplicationDesk-top inspectionOn-site inspectionNote.

10 For attached documents, see Notification dated October 27, cycle for inspection policyDecisionmaking cycle for inspection policy Ri kofetAttached documents submitted at application forDeterminationRiskassessmenteparation oection sheeInspectionAttached documents submitted at application for inspectionResults of previous on-site inspections (profile of manufacturing site)Information from Office of Review AdministrationI ftiffil tth itiDetermination of on-site inspectionPreseleInspectionplanInformati on from foreign regulatory authorities, documents submitted in advance and SOPs, and meeting with Office of Participation in PIC/S willOnsitePreparation of check sheet for key issues,gReview Administration for arrangement, in PIC/S will (hopefully)