differences in the interpretation of the glp requirements ... · differences in the interpretation...

OECD OECD EventEvent , Villa , Villa TuscolanaTuscolana , Frascati (Roma), , Frascati (Roma), ItalyItaly , , AprilApril 10 10 –– 11,11, 2008 2008

DifferencesDifferences in the in the InterpretationInterpretationof the GLP of the GLP RequirementsRequirements by OECD by OECD

Monitoring Monitoring AuthoritiesAuthorities : The point of : The point of viewviewfromfrom the Pharmaceutical the Pharmaceutical IndustryIndustry

Dr. Dr. R.K.R.K. LowingLowingAssociate Vice Associate Vice PresidentPresident

QualityQuality & & ComplianceCompliance GLPGLPSanofiSanofi--Aventis Aventis R&DR&D

MassyMassy, , FranceFrance


Global GLP:Global GLP:WhatWhat isis ourour ExperienceExperience

– Global R&D Organization• 12 R&D sites located in 7 countries in 3

Regions (US, Europe, Japan)• Having received around 15 inspections in the

last 18 months • 80% of studies multi-site and many multi-

country• Observing different expectations /

interpretations from their respective local Monitoring Authorities


Global GLP:Global GLP:The ChallengeThe Challenge

• Submission for Authorization of one dossier– Containing study reports from different countries

with different GLP interpretations – Each Study Report could be Submitted in 3

Regions (US, Europe, Japan) having different expectations / interpretations

– Locally address all National Requirements from Monitoring Authorities from routine inspections.

Better chance of ensuring good quality

if the same process is always used


•• OECD Principles & consensus documentsOECD Principles & consensus documents•• FDA, European, Japanese or other National FDA, European, Japanese or other National GLPsGLPs•• National National ““ GuidelinesGuidelines ””•• National Question & Answer sessionsNational Question & Answer sessions•• Conference presentations (Crystal City, Red Conference presentations (Crystal City, Red

Apple etc.)Apple etc.)•• Inspection outcomes (FDA 483s, Inspection Inspection outcomes (FDA 483s, Inspection

reportsreports ……))

WhichWhich «« GLPGLP ReferencesReferences »»


What Variations in Interpretation have been noted between Monitoring Authorities

AndWhat Questions Remain Unanswered


•• Definition of a multiDefinition of a multi --site studysite study– Doesn’t exist in all countries– Different interpretations between countries

• Several sites from same company: Mono-site or multi-si te? • Different phases - different studies

•• Definition of Test Facility ManagementDefinition of Test Facility Management– One person or Management team

•• Roles and responsibilities of Principal Roles and responsibilities of Principal Investigators and Study DirectorsInvestigators and Study Directors– How to demonstrate the independence of the PI in th e

finalization of his phase report?– Who determines impact of deviations?

MultiMulti --site studies site studies


•• Phase plan requirementsPhase plan requirements– Not mandatory in GLPs– Required or refused in different countries– Formal phase plan to be signed before final study p lan– Detailed content specified – Phase plans as appendices to the study plan.



•• Variable expectations concerning the number of Variable expectations concerning the number of PIs per Test SitePIs per Test Site

•• Signed contributing scientist reports required by Signed contributing scientist reports required by FDAFDA



•• PI Phase PI Phase ““ reportsreports ”” not required by OECDnot required by OECD•• Expectations for phase report content Expectations for phase report content

continuously increasingcontinuously increasing•• Communication challenges and required Communication challenges and required

documentationdocumentation– Signed document from Lead QA to Test Site QA statin g

that they agree with the “Content of the Study Plan ”



•• Study report contentStudy report content– Specific expectations not required by GLPs nor

receiving authorities

Study Reports Study Reports


•• Verification/ Check of BalancesVerification/ Check of Balances– Use of “standards” linked to National Standards even

for daily checks – separate set required in each laboratory

– Specific requirements on how to store automatic manual pipettes

•• Metrology by SubMetrology by Sub --contractorscontractors– Requirements to audit suppliers that perform routin e

equipment metrology for the company even if performed off-site

– QA must audit the contracts with the companies performing metrology

– Endorsement / Knowledge of SOPs of subcontractor performing metrology

MetrologyMetrology


•• Definition of Raw DataDefinition of Raw Data– Different countries have different requirements for

definition of raw data (paper or electronic) when u sing the same computerized system

•• Global Validation for Global Computerized SystemGlobal Validation for Global Computerized System– Different requirements on availability of documenta tion

supporting validation at different sites.

•• E.DataE.Data ArchivingArchiving– Specific country requirement to produce additional CDs

of data for archiving even when full network archiv ing system is in place

– How long to archive e.Raw Data (native format)?

Computer Related SystemsComputer Related Systems


•• Who is responsible for updating the Master Who is responsible for updating the Master Schedule, who keeps a copy?Schedule, who keeps a copy?

•• Format Format – Electronic or paper?

•• ContentContent– GLP and Non-GLP?– Country content specificities e.g. archiving date

Master ScheduleMaster Schedule


•• Study specific audits and process auditsStudy specific audits and process audits– FDA Regulation requires each study to be

inspected– OECD permit process audits under certain

conditions– Japan requires:

• audit of finalized, signed study report • and one specified, designated auditor by study

Quality Assurance Quality Assurance Program and ResponsibilitiesProgram and Responsibilities


•• Test Item analysisTest Item analysis–– Europe accept the high standards required by GMP

which ensure patient safety– FDA and Japan require GLP

Analysis of Test Item Analysis of Test Item


•• Scope:Scope:– How to add new GLP work to a given study once the

report has been finalized

•• OptionsOptions– To amend the initial study plan and after the work

amend the final study report or

– New study with reference to the first study

Complementary InformationComplementary Informationto a finalized Studyto a finalized Study


•• What type of report is required?What type of report is required?•• QA involvementQA involvement•• Downgrading from GLP to nonDowngrading from GLP to non --GLPGLP

– Prohibited by FDA, – accepted by some Authorities, – whereas some other Authorities request to do so.

Is it the same decision tree if development is Is it the same decision tree if development is stopped before going into manstopped before going into man

Terminated Compounds Terminated Compounds


BioanalysisBioanalysis

•• MethodMethod ValidationValidation– Official full validation report signed before any

dosage using a validated method?

•• Satellite Satellite WorkWork PlanPlan– Sometimes required, sometimes tolerated,

sometimes not accepted….

•• Content of the Content of the «« Phase ReportPhase Report »»– Details of the method, QCs, re-analysed

samples…


•• Health & Safety Legislation / Health & Safety Legislation / GLPsGLPs•• Control of environment for test system housingControl of environment for test system housing

OECD The inspectors should verify: OECD The inspectors should verify: ““ The equipment for maintaining the environmental The equipment for maintaining the environmental

conditions required for each test system is conditions required for each test system is adequate, well maintained and effectiveadequate, well maintained and effective ””

Some veterinary inspectors require that dogs Some veterinary inspectors require that dogs actually have the possibility to go outside in open actually have the possibility to go outside in open air pens. So how can we standardize and controlair pens. So how can we standardize and control

Differences Between GLP Differences Between GLP and Other Legislationsand Other Legislations


•• What is globally required to be GLP and what is What is globally required to be GLP and what is requested locally?requested locally?– Pre-clinical PK & metabolism studies?– Clinical bio-equivalence studies?– Clinical PK and metabolism?– Method validations?– Test article characterization?– Non-core dossier safety pharmacology studies?– Biotechnology compounds – Release safety studies?

Scope of Application Scope of Application of of GLPsGLPs


•• Clinical bioClinical bio --equivalence studies equivalence studies – GLP – To be or not to be, that is the question– Inspected or not?– By whom?– Using what guidelines, GLP or GCP?– QA statement or not?

•• BioBio --analysis in clinical studiesanalysis in clinical studies– What are the real requirements?

Scope of Application Scope of Application of of GLPsGLPs –– Clinical MPKClinical MPK


•• Position of MPK QCs and validation of runs Position of MPK QCs and validation of runs •• Verification of MPK sample stability by reVerification of MPK sample stability by re --

analysis of real samples during subsequent runs analysis of real samples during subsequent runs (Incurred samples FDA)(Incurred samples FDA)

•• Requiring report content which reviewers have Requiring report content which reviewers have never requested nor criticizednever requested nor criticized

Should QA be checking for good science, good Should QA be checking for good science, good quality or only compliance?quality or only compliance?

Science or compliance Science or compliance --Conference PositionsConference Positions


•• What is supposed to be the role of GLP QAWhat is supposed to be the role of GLP QA– Quality Control or Quality Assurance– Preventing fraud or improving quality– Improving science– Or simply ensuring compliance

ConclusionConclusion


Conclusion (Conclusion ( contcont .).)

•• The challenges are large but very interestingThe challenges are large but very interesting•• The challenges are not unThe challenges are not un --surmountablesurmountable•• Being successful has enormous benefits to the Being successful has enormous benefits to the

industry and also to the Regulatorsindustry and also to the Regulators•• Requires lots of discussions with external and Requires lots of discussions with external and

internal partnersinternal partners•• Be logical and pragmaticBe logical and pragmatic

• BE PATIENT

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