Implementation of 2005 Pharmaceutical Affairs Law … · Under the Japanese environment, ... Assurance for Drugs, Quasi-Drugs, Cosmetics and ... New GMP standards 2005

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

December 4, 2008 2

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


December 4, 2008 3

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)

PostPost--marketing safety measuresmarketing safety measures

Concept of Marketing Approval Holder (MAH)Concept of Marketing Approval Holder (MAH)

Revision of the approval and licensing systemRevision of the approval and licensing system

““Marketing ApprovalMarketing Approval”” rather than rather than

““Manufacturing/Importing ApprovalManufacturing/Importing Approval””

Business impact: Manufacturing may be contracted Business impact: Manufacturing may be contracted


December 4, 2008 4

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


December 4, 2008 5

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!


December 4, 2008 6

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.


December 4, 2008 7

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


11.. MAHMAH’’ss＊＊ responsibility for the Quality responsibility for the Quality managementmanagement ＊＊MarketingMarketing AuthorizationAuthorization HolderHolder


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


December 4, 2008 9

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


December 4, 2008 10


11.. MAHMAH’’ss＊＊ responsibility for the Quality management responsibility for the Quality management ＊＊MarketingMarketing AuthorizationAuthorization HolderHolder


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


December 4, 2008 11

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

Missing Quality agreements, Periodical quality assuranceMissing Quality agreements, Periodical quality assurance

Manufacturing process descriptionManufacturing process descriptionDrug Master FileDrug Master File

Foreign GMP inspectionsForeign GMP inspections


December 4, 2008 12

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.


December 4, 2008 13

Approval Matters Policy (continued)Approval Matters Policy (continued)

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


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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

December 4, 2008 15

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..””


December 4, 2008 16

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?


December 4, 2008 17

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


18

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

December 4, 2008 19

GMP/QMS InspectionGMP/QMS Inspectionfor Foreignfor Foreign SitesSites

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

NNumberumber of facilities inspectedof facilities inspected (~(~September,September, 2008)2008)Pharmaceuticals:Pharmaceuticals: 144144Medical devices:Medical devices: 3939

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)


December 4, 2008 20

1144441121213364645555TotalTotal

1212000000111111Packaging Packaging site,site, testing testing

labslabs

52521115153310102323API API (chemicals)(chemicals)

1414003300101011Solid productsSolid products

666600330033333030Sterile drugs, Sterile drugs, BiologicsBiologics

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


December 4, 2008 21

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

22

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

Regulatory science groupsRegulatory science groups20022002

QS/GMP guidanceQS/GMP guidance20032003

Approval mattersApproval mattersInspection PolicyInspection Policy

20042004

20052005

20062006--20082008

ICH discussionICH discussion20022002

CTD Q&ACTD Q&A20032003

GMP workshop in GMP workshop in BrusselsBrussels

Q8 and Q9 startedQ8 and Q9 started20042004

Q8 reached step 2Q8 reached step 220052005

Q9 reached step 2Q9 reached step 2Q8 / Q9 reached step4Q8 / Q9 reached step420072007

Q10 /Q8R1 reached step Q10 /Q8R1 reached step 2220082008

Q10 /Q8R1 reached step4Q10 /Q8R1 reached step4

PAL regulation PAL regulation changeschanges2002 2002

Revised PAL publishedRevised PAL published

20042004

PMDA established PMDA established New GMP standardsNew GMP standards20052005

Approval matters policyApproval matters policyRevised PAL enforcedRevised PAL enforced

Inspection policy publishedInspection policy published20062006

Product GMP guidanceProduct GMP guidance

20082008

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

December 4, 2008 23

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.


Documents

Implementation of 2005 Pharmaceutical Affairs Law … · Under the Japanese environment, ... Assurance for Drugs, Quasi-Drugs, Cosmetics and ... New GMP standards 2005