December 4, 2008 1 Implementation of 2005 Pharmaceutical Affairs Law and ICH Q8-Q10 in Japan Yukio HIYAMA Yukio HIYAMA Chief, 3 Chief, 3 rd rd Section, Division of Drugs Section, Division of Drugs National Institute of Health Sciences, National Institute of Health Sciences, Ministry of Health, Ministry of Health, Labour Labour and Welfare and Welfare , , JAPAN JCCT workshop on Q8/Q9/Q10 Beijing
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Implementation of 2005 Pharmaceutical Affairs Law … · Under the Japanese environment, ... Assurance for Drugs, Quasi-Drugs, Cosmetics and ... New GMP standards 2005
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December 4, 2008 1
Implementation of 2005 Pharmaceutical Affairs Law and ICH Q8-Q10 in Japan
Yukio HIYAMAYukio HIYAMAChief, 3Chief, 3rdrd Section, Division of DrugsSection, Division of Drugs
National Institute of Health Sciences,National Institute of Health Sciences,Ministry of Health, Ministry of Health, LabourLabour and Welfare and Welfare , , JAPAN
JCCT workshop on Q8/Q9/Q10 Beijing
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Presentation OutlinePresentation Outline
20052005 Pharmaceutical Affairs Law (PAL)Pharmaceutical Affairs Law (PAL)Regulations under the 2005 PALRegulations under the 2005 PALGQP, Manufacturing Process as Approval Matters, GQP, Manufacturing Process as Approval Matters, Drug master file, GMP positioning, GMP standards
Challenges under the 2005 PAL and in Challenges under the 2005 PAL and in Implementation of ICH Q8Implementation of ICH Q8--Q10Q10
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Pharmaceutical Affairs Law (PAL)Pharmaceutical Affairs Law (PAL)
Points on 2002 revision of the PAL (effective 2005)Points on 2002 revision of the PAL (effective 2005)
Business impact: Manufacturing may be contracted Business impact: Manufacturing may be contracted
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Revision of the Quality RegulationsRevision of the Quality Regulations(Effective April 2005)(Effective April 2005)
11.. MAHMAH’’ss** responsibility for the Quality responsibility for the Quality managementmanagement : : GQPGQP **MarketingMarketing AuthorizationAuthorization HolderHolder
2. Requirement Changes in Approval Matters 2. Requirement Changes in Approval Matters manufacturing process commitmentmanufacturing process commitment
3.3. Drug Master File system to support CTD Drug Master File system to support CTD based applicationbased application
4.4. Consolidation of the Legal Positioning of Consolidation of the Legal Positioning of GMPGMP
5.5. Revision and Consolidation of GMP standardsRevision and Consolidation of GMP standards
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MAH
Manufacturer A(API)
Manufacturer B(bulk product)
Manufacturer C(packaging, label)
ExternalTesting laboratory
Responsibility of MAH based on GQPResponsibility of MAH based on GQP
Supervise and manage the manufacturers Ensure proper release to market
MarketRelease
Total responsibility!
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2. 2. Manufacturing Process Commitment Manufacturing Process Commitment Application Form and Approval MattersApplication Form and Approval Matters--
A Unique SystemA Unique System
Contents provided in the NDA application Contents provided in the NDA application form are dealt with as form are dealt with as ““matters subject to matters subject to approvalapproval..””
Contents described in approval letter are Contents described in approval letter are ““legal bindinglegal binding”” approval matters.approval matters.
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Application Form after the Enforcement of Application Form after the Enforcement of Revised Pharmaceutical Affairs LawRevised Pharmaceutical Affairs Law
Application form
Module 3
Partial Change(application)
Minor change(notification)
Possibility that changesaffect drug quality
Low
Quality Information
Batch Data etc
Batch Data etc
Module 2
GAIYO
Approval Matter
OLD APPLICATIONManufacturing Application
CTD-BASED APPLICATIONMarketing Application
(Specification)
Specification+Manufacturing
(Process Control)
High
Quality Information
Requires regulatory actions
Key review document
December 4, 2008 8
Revision of the Quality RegulationsRevision of the Quality Regulations(Effective April 2005)(Effective April 2005)
11.. MAHMAH’’ss** responsibility for the Quality responsibility for the Quality managementmanagement **MarketingMarketing AuthorizationAuthorization HolderHolder
2. Requirement Changes in Approval Matters 2. Requirement Changes in Approval Matters manufacturing process commitmentmanufacturing process commitment
3.3. Drug Master File system to support CTD Drug Master File system to support CTD based applicationbased application
4.4. Consolidation of the Legal Positioning of Consolidation of the Legal Positioning of GMPGMP
5.5. Revision and Consolidation of GMP standardsRevision and Consolidation of GMP standards
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Became a Became a requirementrequirement for product approvalfor product approval
GMP inspection GMP inspection prior to approval (new prior to approval (new product application and product application and partial change (prepartial change (pre--approval ) of the approval mattersapproval ) of the approval matters,, and and periodical GMP inspection in postperiodical GMP inspection in post--marketing marketing phasephase
GMP inspection GMP inspection at foreign sitesat foreign sites
4. Consolidation of the Legal 4. Consolidation of the Legal Positioning of GMPPositioning of GMP
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Revision of the Quality RegulationsRevision of the Quality Regulations(Effective April 2005)(Effective April 2005)
11.. MAHMAH’’ss** responsibility for the Quality management responsibility for the Quality management **MarketingMarketing AuthorizationAuthorization HolderHolder
2. Requirement Changes in Approval Matters 2. Requirement Changes in Approval Matters manufacturing process commitmentmanufacturing process commitment
3.3. Drug Master File system to support CTD based applicationDrug Master File system to support CTD based application4.4. Consolidation of the Legal Positioning of GMPConsolidation of the Legal Positioning of GMP
5.5. Revision and Consolidation of GMP Revision and Consolidation of GMP standardsstandardsProduct Release by Quality Control DepartmentProduct Release by Quality Control Department
Change Control and Deviation ControlChange Control and Deviation Control
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Challenges under the 2005 PALChallenges under the 2005 PAL
Understanding of the new regulationsUnderstanding of the new regulationsMeeting GQP expectations varies Meeting GQP expectations varies
Manufacturing process descriptionManufacturing process descriptionDrug Master FileDrug Master File
Foreign GMP inspectionsForeign GMP inspections
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Approval Matters PolicyApproval Matters PolicyNotification from Director of Evaluation and licensing Notification from Director of Evaluation and licensing
division, 0210001 February 10, 2005division, 0210001 February 10, 2005
Manufacturing Process: Principles and end points Manufacturing Process: Principles and end points of the critical manufacturing steps with key of the critical manufacturing steps with key operational parameters of operational parameters of commercial scalecommercial scale are are approval matters. approval matters. Principle and quality end point Principle and quality end point for each manufacturing stepfor each manufacturing step are subject to preare subject to pre--approval review. approval review.
InIn--process procedure is preprocess procedure is pre--approval matter if it approval matter if it replaces final specification test.replaces final specification test.
A pilot scale manufacturing processes may be A pilot scale manufacturing processes may be submitted at Application. submitted at Application.
The commercial scale processes will be subject The commercial scale processes will be subject to Preto Pre--approval GMP inspection and the approval GMP inspection and the commercial scale must be described in the commercial scale must be described in the approval. approval.
PrePre--approval vs. notification classification may approval vs. notification classification may be determined through the review processbe determined through the review process
JCCT workshop on Q8/Q9/Q10 Beijing
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The Role of Pharmaceutical Development(P2) sectionThe Role of Pharmaceutical Development(P2) section--Science and Risk basedScience and Risk based--
in reviewing NDA under revised PALin reviewing NDA under revised PAL
Matters describedin Module3
Matters not subject to approval
Matters subject to approval
*Partial change approval application matters
*Minor changenotification matters
P2
P2
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Implementation issues of Q10 in JapanImplementation issues of Q10 in Japan
Very important ICH guidance for PQS for every Very important ICH guidance for PQS for every pharmaceutical industrypharmaceutical industry-- Is this recognized well?Is this recognized well?Q10 says Q10 says ““ICH Q10 is not intended to create any new ICH Q10 is not intended to create any new
expectations beyond current regulatory requirements. expectations beyond current regulatory requirements. Consequently, Consequently, the content of ICH Q10 that is the content of ICH Q10 that is additional to current regional GMP requirements is additional to current regional GMP requirements is optional.optional.”” Under the Japanese environment, it should Under the Japanese environment, it should read read ““ICH Q10 is not intended to create any new ICH Q10 is not intended to create any new expectations beyond current regulatory requirements. expectations beyond current regulatory requirements. Consequently, Consequently, the content of ICH Q10 that is the content of ICH Q10 that is additional to GMP additional to GMP and pharmaceutical GQPand pharmaceutical GQPrequirements is optionalrequirements is optional..””
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Implementation issues of Q10 in JapanImplementation issues of Q10 in Japan--continuedcontinued
Is that optional? Much of ICH Q10 expectations are Is that optional? Much of ICH Q10 expectations are covered by GMP and by GQP. All the four elements in covered by GMP and by GQP. All the four elements in Q10 are requirements based on PAL, GMP and GQP Q10 are requirements based on PAL, GMP and GQP (while continual improvement is not required by the (while continual improvement is not required by the regulations. ) regulations. ) Understood well?Understood well?
Variety of MA holders under GQPVariety of MA holders under GQPSelf contained, Self contained, Large international companiesLarge international companiesPreviously importation licenseesPreviously importation licensees
Is more rigorous GQP inspection needed?Is more rigorous GQP inspection needed?
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Ministerial Ministerial OrdinaceOrdinace on Standards for Quality on Standards for Quality Assurance for Drugs, QuasiAssurance for Drugs, Quasi--Drugs, Cosmetics and Drugs, Cosmetics and
Medical Devices No136, 2004 (GQP)Medical Devices No136, 2004 (GQP)Self inspections)Self inspections)Article 13 Article 13 The marketing The marketing authorisationauthorisation holder of drugs shallholder of drugs shall, in accordance with the quality , in accordance with the quality
assurance duty procedure documents, etc., have the person designassurance duty procedure documents, etc., have the person designated beforehand ated beforehand conduct the following duties.conduct the following duties.
(1)(1) To conduct the To conduct the selfself--inspections periodicallyinspections periodically on the quality assurance duties and to on the quality assurance duties and to establish records of the results, andestablish records of the results, and
(2)(2) …………2. The marketing 2. The marketing authorisationauthorisation holder of drugs, in case where important improvements are holder of drugs, in case where important improvements are
necessary based on the results of the selfnecessary based on the results of the self--inspections, shall have the quality assurance inspections, shall have the quality assurance manager take necessary actions, establish records of the actionsmanager take necessary actions, establish records of the actions and report in writing the and report in writing the results of the actions to the general marketing manager.results of the actions to the general marketing manager.
(contract with Manufacturers, etc)(contract with Manufacturers, etc)Article 7 Article 7 The marketing The marketing authorisationauthorisation holder of drugs shall conclude a contractholder of drugs shall conclude a contract for the for the
following items with manufacturers, etc. of the products and desfollowing items with manufacturers, etc. of the products and describe the details of the cribe the details of the agreement in the quality assurance duty procedure documents, etcagreement in the quality assurance duty procedure documents, etc. to ensure that the . to ensure that the manufacturing control and quality control are conducted properlymanufacturing control and quality control are conducted properly and efficiently by the and efficiently by the manufacturers, etc.manufacturers, etc.
(3) The nature and extent of (3) The nature and extent of the periodical verification, by the marketing the periodical verification, by the marketing authorisationauthorisation holderholder, , of the of the thethe manufacturing duties that they are conducted under the proper amanufacturing duties that they are conducted under the proper and efficient nd efficient manufacturing control and quality controlmanufacturing control and quality control
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Working relation with foreign manufacturing site Working relation with foreign manufacturing site GQPGQP・・GMPGMP
Inadequate or no contract between MAH and site
•Large international companies are NOT willing to write Supply/Quality Agreement between its manufacturing site and MAH(??)
•If size of purchase/supply is small, vendors are unwilling to write contract(??)
Importers keep information from MAH•In the case of Heparin, most of MAHs did not have information required by the PAL and GQP.
The regulation requires a contract with manufacturers of the products and describe the details of the agreement in the quality assurance duty procedure documents the periodical verification, by the marketing authorisation holder.
With or without contract manufacturing, proper control must be in place.
•“Because we use foreign manufacturers, it is difficult to obtain necessary information”---This is Serious PAL violation
GMP/QMS* inspection for foreignGMP/QMS* inspection for foreign manufacturingmanufacturingfacilitiesfacilities startedstarted sincesince April, 2005. April, 2005.
MRA*:MRA*: Document basedDocument based for pharmaceuticalsfor pharmaceuticals except except sterile products and biologics sterile products and biologics MOU*:MOU*: Document basedDocument based for Pharmaceuticalsfor Pharmaceuticals
QMS*:QMS*: Standards for Manufacturing Control and Quality Control for MedStandards for Manufacturing Control and Quality Control for Medical Devices and ical Devices and InIn--vitro Diagnostic Reagentsvitro Diagnostic Reagents; ; MRA* JapanMRA* Japan--EU MutualEU Mutual Recognition Agreement (API: out Recognition Agreement (API: out of scope); MOU* Memorandum of Understanding betweenof scope); MOU* Memorandum of Understanding between Japan and Japan and Australia, Australia, GermanyGermanySweden, Switzerland)Sweden, Switzerland)
TotalTotalOthersOthersAsiaAsiaCentral Central and South and South AmericaAmerica
North North AmericaAmerica
EUEUCategoryCategory
On site On site GMPGMP inspectionsinspectionsfor foreign facilitiesfor foreign facilities
Apr.2005-Sep.2008
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Problems experienced in foreign on Problems experienced in foreign on site inspectionsite inspection
Discrepancy between Japanese Application file Discrepancy between Japanese Application file and actual operations in the manufacturing siteand actual operations in the manufacturing siteNonconformity to the Japanese Standards for Nonconformity to the Japanese Standards for Biological ingredientsBiological ingredients
→→Insufficient concern of Japanese marketing Insufficient concern of Japanese marketing approval holder in control of manufacturer on approval holder in control of manufacturer on foreign siteforeign site
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Pharmaceutical Affairs Law(PAL), ICH Q8/Q9/Q10 Pharmaceutical Affairs Law(PAL), ICH Q8/Q9/Q10 and MHLW Grant and MHLW Grant Regulatory ScienceRegulatory Science StudiesStudies
GMP for IP (clinical supply)GMP for IP (clinical supply)
CTD mock
Approval matters
GMP guidelinesInspection Policy
Skip Test guidanceInspection Checklist
P2 /application mock
Change management system
GMP for IP
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Summary and ConclusionsSummary and Conclusions
Overview of the 2005 PAL regulation changes Overview of the 2005 PAL regulation changes presented. presented. Challenges for implementation of the PAL with Challenges for implementation of the PAL with ICH guideline presentedICH guideline presentedChallenges we face are mostly common worldChallenges we face are mostly common world--wide. Hope to solve the problems with more work wide. Hope to solve the problems with more work and international collaboration.and international collaboration.