Trevor Deeks, Karen Ginsburyand Susan Schniepp

Editors

PHARMACEUTICALOUTSOURCING:

QUALITY MANAGEMENTAND PROJECT DELIVERY

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CONTENTS

Preface

1 OVERVIEW OF OUTSOURCED OPERATIONSSusan SchnieppReferencesAbout the Author

2 LEGAL ASPECTS OFCONTRACT MANUFACTURINGPaul RansonIntroductionKey Background Legal Issues in Manufacture OutsourcingAgreements

Intellectual Property (IP)IntroductionPatentsConfidential informationTrade marks

Copyright

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DesignsProduct liability

IntroductionThe Directive and negligenceDefences under the Act

Preliminary DocumentationIntroductionConfidentiality agreementsLetters of intent/recording understandingsTerm sheets and heads of termsPreferred provider agreements

The Contract AgreementThe role and structure of the contract

IntroductionMaster agreementsService level agreements

Terms in outsourcing agreementsThe partiesRecitalsDefinitionsAppointmentTechnical transferManufacturing methods and supplyOrders and forecastsPerformance termsAcceptance/rejection of compound/productand failure to supplyObligations of the clientObligations of the service providerConfidentialityOwnership of data, inventions and rightsWarranties and indemnificationPublicationRelationship of the partiesWarranties, indemnities and insuranceDuration and terminationForce majeureAssignment and sub-contractingGoverning law, dispute resolution and jurisdictionTechnical (or quality) agreement

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3 POINTSTO CONSIDER FORTHE OUTSOURCINGOF HIGHVALUE MANUFACTURING A CUSTOMERS PERSPECTIVEKevin OTooleIntroductionBackground The Basics of Biological Manufacture

Upstream processingPrimary recovery and downstream processingSecondary manufactureAnalytical requirementsThe rapidly evolving market place for biologicalcontract manufactureOutsource drivers

CMO Identification, Screening and SelectionScope of outsourcingIdentifying potential CMOsScreening CMOs to produce a short-listfor evaluationEvaluating the short-listed CMOsDesigning an RFI for contractor selectionQuality/reputationTechnical fitPrevious experience of the contractorCapacityGood working relationshipProject management/business philosophyCostGeographyValue adding servicesMaking the decision choosing the best CMO

Establishing the Services AgreementFinalising the Services Agreement Problem Areas

Liability and indemnityPrice and payment scheduleIP generated during the projectDelivery schedule/timelinesWarrantiesTermination and cancellation terms and feesWork-scope interpretationOthers

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Finally The Concept of TrustworthinessCredibilityReliabilityIntimacySelf-interestQuantifying trustworthiness

ReferencesAbout the Author

4 BEST PRACTICES IN IMPLEMENTINGQUALITY AGREEMENTSKen DrostIntroduction

Why have quality agreements?What exactly is a quality agreement?Types of quality agreements

20 Best Practices for Implementing Quality AgreementsNumber 20 Review your quality agreement annuallyNumber 19 Define who is responsible for regulatory issuesNumber 18 Dont out-think yourself by getting too creativeNumber 17 Review the quality agreement for conflictswith the supply agreementNumber 16 Create shorter and simpler quality agreementsfor earlier phase projectsNumber 15 Start with a template but dont be afraidto customize based on needNumber 14 Quality agreements should be flexibleand practicalNumber 13 Have oversight and knowledge ofsupply chain securityNumber 12 Quality agreements must allow for auditsand site visitsNumber 11 Contract giver should make sure the qualityagreement is followedNumber 10 Ensure quality agreement calls for dailycommunication during regulatory inspectionsNumber 9 Have an issue resolution pathwayNumber 8 Have general management oversight provisionsNumber 7 Ensure firms have aligned values

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Number 6 Setup and have heavily involved teamsNumber 5 Perform due diligenceNumber 4 If you dont trust your partner,get out as soon as possibleNumber 3 Have clearly defined roles and responsibilitiesfor change controlNumber 2 If an application is involved, the applicationholder is responsibleDo not start any work prior to having a signed agreement

About the Author

5 MANAGEMENT OF OUTSOURCED OPERATIONS:A CONTRACT PROVIDERS PERSPECTIVEJane RasmussenIntroductionSimilarities between Industries whenWorking with OutsourcingCommon Practice and Pitfalls Regardless of IndustryMistakes to avoid

Do not neglect your responsibility for the outsourcedactivityCommunicationShare your goalsThe grass is not greener on the other side

Sharing Better PracticesOur Journey in Dealing with Outsourced Manufacturing

in the Pharma IndustryInternal Company Alignment on Roles and ResponsibilitiesJoint Lean InitiativesJoint Knowledge Sharing and DevelopmentUse of Process Flows and Maps to Identify the Scope and

Limitations of the Outsourced OperationRisk Management: Identification of Critical Control Points

on the Process Flows and Design of ControlsRisk CommunicationDefinition of Milestones for the ProjectOngoing Management once an Operation becomes RoutineConclusionAbout the Author

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6 QUALITY MANAGEMENT SYSTEMFOR OUTSOURCED OPERATIONSE.J. BrandrethUs vs.ThemCMOQuality SystemClient AuditsExpectationsTrainingLot ReleaseConclusionReferencesAbout the Author

7 OUTSOURCED SERVICES:AVIRTUAL COMPANY PERSPECTIVETrevor DeeksIntroductionWhat is a Virtual Company?What is the Business Model?What Impact does this have on the Company?

Manufacturing and the manufacturing platformAnalytical developmentProcess developmentcGMP manufacturing

What can the Company do to Protect Itself to Ensurethat its Needs are Met?

Project ManagementConclusions

The final selection processCommunication with and involvement of the project team

ReferencesAbout the Author

8 OUTSOURCING PROCESS DEVELOPMENTSpencer OliverIntroductionGeneral ConsiderationsRationales for Outsourcing

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Basic Process for Selecting an Outsource PD Service ProviderIn-house project teamStrategy and planShort-listing, requirements, site visits, selectionCommercial/agreement/IP/legal considerationsQuality agreementSummary of selection process

Process Development Requirements(Targets and Deliverables etc)

Technical process considerationsNature of the Product and Expression SystemComplexity of the Process and Impurities

Analytical and characterizationOngoing project management, progress reviews, problem solving

ConclusionAppendix 1 General Process Development FlowAppendix 2 Simple Biological Process OutlineReferencesAbout the Author

9 OUTSOURCING ANALYTICAL METHODSSusan Schniepp and Trevor DeeksIntroductionWhat are the Choices for the Sponsor?The Importance of the Quality AgreementOOS InvestigationsCommunicationsOutsourcing Specialized Analytical MethodsSummaryReferencesAbout the Authors

10 CMOs FOR EARLY PHASE BIOLOGICALSPRODUCTION: PROCESSANDANALYTICALDEVELOPMENTJonathan Mitschelen, John Lightholder and Rabi PrustiIndustry OverviewPreparing a Contract

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Execution of the ContractFactors Affecting the CMO Project PlanExpression of Recombinant Protein ProductsBioreactor Design and Process DecisionsAnalytical Development and Analytical Supportfor Process Development

Analytical development planStatus of analytical development: preliminary reference standard

Analytical support for PDSummaryReferencesAbout the Authors

11 CMOs FOR EARLY PHASE BIOLOGICALSPRODUCTION: CONTRACT MANUFACTURINGAND CONTROLJohn Conner, Rabi Prusti and Bill MinshallCharacter of Desired Contract Manufacturing Organization

(CMO) RelationshipClinical Development Plan: Production StrategiesResearch, Pilot, Non-GMP and GMP Manufacture of ProductProject ManagementTechnology Transfer

Transfer raw materials: bill of materialsTransfer of an established MCBTransfer of established analytical protocols and methodsTransfer of established production batch recordsTransfer of production historyTransfer of well-developed PD processTransfer of Standard Operating ProceduresTransfer of development reports and notebooksTransfer of a Research Cell Bank (RCB)

Manufacturing PlanProduction capabilities

Production of Pre-clinical SuppliesMCB productionMCB testing strategy for bio-safety and characterization

Strategy

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Typically detailed MCB testing, release and storage planGMP Production Documentation

Bach record preparationMaterials and product specificationsRaw materialsContainer closure: process intermediates, drugsubstance and final drug productEngineering run materials

GMP production materialsSampling plan: process intermediates, viral clearanceand releaseEnd of production cell bankFill/finish materials

Manufacturing ReadinessExecuting the Manufacturing PlanAnalytical Processes

Analytical protocols/SOPTransfer of qualified/validated analytical proceduresEvaluation and qualification of transferred researchanalytical proceduresDevelopment and qualification of assays for productquantitation, characterization and product release

Reference Standard Preparation and CharacterizationReference Standard LotsDrug Substance and Drug Product Stability StudiesGeneral Regulatory ConsiderationsDrug Product StabilityEnd of GMP Manufacturing CampaignReferencesAbout the Authors

12 CONTRACT MANUFACTURE OF ACOMMERCIAL BIOLOGICAL PRODUCTIan ElvinsDeviations

NotificationInvestigationsReview and approval

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Product dispositionChange controlFacility and engineeringQuality control (testing)Warehousing and shipmentRegulatory submissionsContract giver auditsRegulatory inspections

About the Author

13 AUDITING THE CMOThomas L.Thorpe and Jessica K. WalkerIntroductionTypes of Audit TeamsTiming and Scope of AuditAuditing Standards (cGMP, ISO, EU, FDA, Clinical Trial,

NDA, etc.)Before the Audit The CustomerBefore the Audit The CMOThe Audit AgendaThe Audit DayCommunication is KeyFacility TourKey IndicatorsOff-limitsIrritating Practices by AuditorsIrritating Practices by Audit HostsCloseout meetingAudit Report and Follow-upClassifying ObservationsRisk AssessmentAWord about Quality AgreementsFinallyAbout the Author

14 OUTSOURCED QUALIFICATION,VALIDATION, CALIBRATION,ANDMAINTENANCE ACTIVITIES

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Jeanne MoldenhauerIntroductionContractsService AgreementsUnderstanding the Type of Service Provider NeededChoosing the Right Consultants/Service ProvidersQualification andValidation Services

Installation qualification (IQ)Operational qualification (OQ)Performance qualification (PQ)Process Validation (PV) and/or ProcessPerformance Qualification (PPQ)

Contracted Calibration ServicesThe standards laboratoryCalibration controlsDocumentationAudit support

Contracted Maintenance ServicesCleaning operationsClean room operations

In House SMEsConclusionReferencesAbout the Author

15 OUTSOURCING IT SERVICES AND CONSULTING:BENEFITS AND PITFALLSSiegfried SchmittIntroductionThe User Requirements (Specifications)/Terms of ReferenceGood IT Service PracticesManaging the Outsourced Service or ApplicationSummary and OutlookAbout the Author

16 TOOLS FOR THE MANAGEMENTOF OUTSOURCED OPERATIONSTrevor DeeksIntroduction

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Tools for Identifying and Selecting Outsourcing PartnersEnthusiasmCultural FitGeographic LocationProject ManagementTrustworthinessTools for Managing Outsourcing DecisionsThe Final Selection ProcessCommunication with and Involvement of the Project TeamReferencesAbout the Author

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