Preparing For Commercial GMP Manufacture; Areas For . - Catapult Centres
Preparing for commercialGMP manufacture; areasfor considerationDaria Popova, Lead Technical ScientistGina Basman, Validation ManagerDoli Patel, Head of Quality Control
Preparing for GMPmanufactureDaria Popova, Lead Technical Scientist
CGT Catapult manufacturing centreThe centre provides access to theexpertise, skills, facilities and equipmentas the stepping stone needed fororganisations to develop newtechnologies and systems forlarge scale manufacturing.Managed warehouse with deliveryto your manufacturing spaceFlexible quality control optionsQuality controlQualified personsOperating policiesWarehouse managementDevelopment assistance3
Collaborating companies“CGT Catapult’s unique operational model allows us togrow our manufacturing capacity, while accessing a rangeof services provided by the centre.” Jim Faulkner, SVPand Head of Product Delivery“CGT Catapult’s unique operational model allows“We are delighted to establish this collaboration for ourusto grow our manufacturing capacity, whilenext generation AAV gene therapy platform for chronicaccessinga rangeof Thirkettle,services providedsystemic disease.”JanChief by thecentre”.Jim Faulkner,SVP and Head ofDevelopmentOfficerProduct Delivery“We are looking forward to an important collaborationwith CGT Catapult scaling-up GMP manufacturing“Weare delightedto establishthisGreggcollaborationstrategiesfor commercialproduction.”Sando,CEOforour next generation AAV gene therapyplatform for chronic systemic disease”. JanThirkettle, Chief Development Officer“We are looking forward to an importantcollaboration with CGT Catapult scaling-up GMPmanufacturing strategies for commercialproduction”. Gregg Sando, CEO“With our own vector manufacturing capability atthe Catapult facility, we will extend vector supplycapacity beyond 2020”. James Noble, CEO“With our own vector manufacturing capability at theCatapult facility, we will extend vector supply capacitybeyond 2020.” James Noble, CEO“The agreement with CGT Catapult enables us to meet ourimmediate clinical trials needs and have the flexibility ofboth our own dedicated manufacturing space” GarryMenzel, Ph.D., President and CEO4
Preparing for GMP manufactureCleanroom Design & Set up ConsiderationsPath to GMP Readiness: Operational PerspectiveScheduling & Planning ChallengeWaste Management ChallengeSummary5
Design considerationsConsumablesWaste ConsumablesReagentsWaste LiquidsPatient/Starting MaterialProductEquipmentRejected Product/StartingMaterials6
Process mapping and mass/volume balanceBuffer A (8 L)Drug Substance (1L)Product (1 L)Buffer B (1 L)UnitOperation(Equipment)Waste Liquid (9L)EquipmentListWaste ConsumableConsumable SetVisual ToolExcel/Calculation Tools7
Equipment placement-HVAC type & supply-Utility provisionPower supply(UPS/generator/nonessential)Gas supplyChilling capacity-Environmental monitoringConnectionCabling route-Identify clear zonesair outletsequipment access routesMaterial, product & peoplemovement routesOperational Considerations-Segregation of unit operations- Space & movement of auxiliary materialse.g., buffers/medium/weldingstations/mobile equipmentOperational qualityProcess efficiencyProcess robustnessOperator safetyCross- containmentContamination riskCross- contamination riskOperator errorUnnecessary movement8
Material, product and people flowMaximiseCleanroom Area43% increase in productionareaMaximiseThroughputAutologous: up to 25% throughput increase9
Material, product and people flowSegregated SmallProduction Areawith dedicatedaccessMaximiseThroughputEnables use of area as a QC lab,segregated seed train oradditional segregatedproductionViral Vector: up to 6 fold throughput increase10
Material, product and people flowSegregatedMaterial, Sampleand ProductTransferMaterialsClean DownMaximiseThroughputIncreased efficiency incontrolled transfer from CNCthrough to return corridorOptimiseFlowsMaterialsClean DownDirect MaterialTransfer via CNCCorridorReduces need for staging ofmaterials in shared areas.Enables delivery directly tomodule.11
Material, product and people flowMaterialsClean er forMaterial TransferImproved cross-containmentmeasureUp to 150k annual efficiencysaving in labour costDecreaseLabour12
Path to GMP readiness: Operational perspectiveGap analysisRisk assessmentMitigationstrategyDesign of projectplanImplementationof project planSuccessfulOn-boardingFacility as-built OQPreparation of example ModuleExample Module at-rest OQQMS DevelopmentBuilding handover1. Equipment6 Quality Control2. Facility Adjustment/Modifications7. EHS3. Supply Chain & Logistics8 Operations-boardingExample Module in operation PQMHRA Inspection– licence grantCollaborator Module at-rest OQQMS DevPreparation of Collaborator Module4. ValidationCollaborator Module in operationPQMIA, MIA(IMP), MS variation to add Collaborator5. Quality Assurance13
Path to GMP readiness: Operational perspectiveGap analysisRisk assessmentMitigationstrategyDesign of projectplanImplementationof project planSuccessfulOn-boardingFacility as-built OQPreparation of example ModuleExample Module at-rest OQQMS DevelopmentBuilding handover1. Equipment6 Quality Control2. Facility Adjustment/Modifications7. EHS3. Supply Chain & Logistics8 Operations-boardingExample Module in operation PQMHRA Inspection– licence grant Collaborator Module at-rest OQQMS DevPreparation of Collaborator Module4. ValidationCollaborator Module in operationPQMIA, MIA(IMP), MS variation to add Collaborator5. Quality Assurance14
Path to GMP readiness: Operational perspectiveProcess UnderstandingEquipment PurchaseEquipmentQualificationFacility AdjustmentActivitiesWorkplace& ITEHSQCQASupply-Chain & eering RunsProcess ActivitiesTeam TrainingProcess DocumentationPQ1PQ2PQ3Year 1Year 215
Scheduling and planning challengeMaterial/productmovementEMModule 3Cleaning TeamWarehouseDocumentationWaste movementModule agementCleaningRegimenModule 2Module tyAssuranceModule 1Product process
Scheduling tool Modules and MC common areas Rules Maps Activities Accessible to all facility teams
Scheduling tool: Process specificDetailed process schedule automated tool example Automated calendars for each piece of equipmentIn-built process step lengthDefined process step sequence to allow for automatedschedule generationVisual and numerical outputsAllow to determine rules for maximum capacity scheduleReduce operational riskAssist scheduling and decision making in detailed andhigh level planning18
Waste management challenge1. Brainstorm2. Options Analysis3. Risk Assessment19
Waste management challengeCollection Tank Movement OutInner TankCollection TankDrainAdvantaPass20
Inactivation of biological process waste streamsPreliminary studyAssess:VolumesCompositionConditionsWork tocomponentlevel of detailConsider AgentInhibitory Factors:- Temperatureconditions- pH- Salt concentration- Buffering capacity- Protein contentInactivationAgent CandidatePanelConsider:- Waste Removal Route- Waste Contractor- Suitability for Drain- Handleability- Efficacy (available data)- Need for pre-treatmentprior to disposal- Acceptance criteriaRepresentativeMatricesConsider:- Contaminated stream(bacterial & fungal)- Range of inhibitory materials- Range of operatingconditions- Worst case vs DoE approach- Matrix stabilityDesignExperimentConsider:- Contracting out vs inhouse- Type of study - validation vsinformative package- One vs multiple studies- Order of experiments- TimelineDevelop appropriate rationale for acceptance criteria: e.g., EN 1447621
Inactivation agent selection InactivationAgentConcentrationInactivationTime (h)Pass/FailVirkon3%6 hoursPassNaOH0.1M6 hoursPassPeracetic Acid1% v/v6 hoursPassAdditional considerations include: Practical handling of reagents Storage, use and disposal Cost and supply reliability Compatibility with trade effluent consent limits22
SummaryProcess mapping and varying complexity of design tools areavailable to aid cleanroom design and fit out.Quality, operations and project management collaborativeapproach is key to timely delivery of GMP readiness.Activity scheduling can be a challenge during operational set up,the solution needs to be appropriate for the level of planningrequired.Inactivation studies take time and effort. Not all waste can godown the drain.23
AcknowledgementsMarcia MataMajahar SayedMoira FrancoisIris ValeroAlexia ToufexiRyan McCoyVicky AdamsHusnah HusseinStephen ShapkaKay BusseyKen MurfittJingjing LiZulekha SaiyadKasia AverallJulie KerbyKwok PangJon HallingJames Biggins24
ValidationconsiderationsEstablishing a cell and genetherapy manufacturing centreGina Basman, Validation Manager
Validation Considerations
Validation ConsiderationsUser RequirementSpecificationValidation MasterPlanDesign QualificationRegulatory expectation: “The manufacturer, or- as appropriate- the sponsor ormarketing authorisation holder should define the specifications for the premises andequipment.” Define scope, and deliverables for quality, engineering, IT and business complianceCommissioning,Offsite (FAT) / OnSite (SAT) Testing
Validation ConsiderationsUser RequirementSpecificationValidation MasterPlanDesign QualificationRegulatory expectation: “The key elements of the site qualification andvalidation programme should be clearly defined and documented in a validationmaster plan (VMP).” Validation Scope and Strategy Deliverables Roles and Responsibilities System Criticality AssessmentCommissioning,Offsite (FAT) / OnSite (SAT) Testing
Validation ConsiderationsUser RequirementSpecificationValidation MasterPlanRegulatory expectation: “Compliance with userrequirements should be demonstrated.” Design Specifications Design Review Design Freeze Change Management Design Qualification ProtocolDesign QualificationCommissioning,Offsite (FAT) / OnSite (SAT) Testing
Validation ConsiderationsUser RequirementSpecificationValidation MasterPlanRegulatory expectation: “Equipment, especially ifincorporating novel or complex technology, may be evaluated,if applicable, at the vendor prior to delivery.” Good Engineering Practices Agree inspection test plans Commissioning Master Plan Leveraging Matrix Documented Inspections Acceptance of pre-qualification activities FAT, SAT, Commissioning HandoverDesignQualificationCommissioning,Offsite (FAT) / OnSite (SAT) Testing
Validation QualificationRegulatory expectation: “The manufacturer or- as appropriatethe sponsor or marketing authorisation holder should verify that thepremises/equipment comply with the user specifications and are inline with GMP requirements.” Validation Protocols Verification of Installation and Functionality Leveraged Tests as per Plan Establishing ProceduresPerformanceQualificationValidation Sign Off
Validation QualificationRegulatory expectation: “The suitability of the premisesand equipment to operate consistently in accordance with therequirements of the intended manufacturing process (assumingworst case conditions) should be tested. A test with surrogatematerials or simulated product is acceptable.” Verification of Performance Training Cleaning Qualification (where applicable)PerformanceQualificationValidation Sign Off
Validation QualificationPerformanceQualificationRegulatory expectation: “A formal release for the next stage in thequalification and validation process should be authorised by the relevantresponsible personnel either as part of the validation report approval or as aseparate summary document.” Validation Sign Off Quality Approval Regulatory ApprovalValidation Sign Off
Validation ConsiderationsProcess / EquipmentQualificationProcess ValidationValidated StatePeriodic EvaluationRegulatory expectation: “Equipment used in production or control operations should be suitable for its intendedpurpose and it should not present any hazard to the product.” Process Equipment Qualification Data Collection , Critical Process Parameters Process Development / OptimisationRegulatory expectation: “The validation of analytical methods is intended to ensure the suitability of the analyticalmethods for the intended purpose.” QC Equipment Qualification Analytical Test Method Validation
Validation ConsiderationsProcess Prequalification RunsProcess ValidationValidated StateRegulatory expectation: “The aim of the process validation for ATMPs is todemonstrate that the finished product characteristics are within a given range(in compliance with the terms of the marketing authorisation).” Validation Protocol Strategy to Process Validation Critical Process Parameters Critical Quality AttributesPeriodic Evaluation
Validation ConsiderationsProcess Prequalification RunsProcess ValidationValidated StateRegulatory expectation: “Manufacturers should monitor productquality to ensure that a state of control is maintained throughout theproduct lifecycle with the relevant process trends evaluated.” Product Process Monitoring Environmental Monitoring Calibration Program Preventative Maintenance Program Change Control Management Non Conformance ProcessPeriodic Evaluation
Validation ConsiderationsProcess Prequalification RunsProcess ValidationRegulatory Expectation: “Equipment, facilities, utilities andsystems should be evaluated at an appropriatefrequency to confirm that they remain in a state of control.” Periodic Review Schedule (risk based) Periodic Qualification Tests Temperature Mapping DecommissioningValidated StatePeriodic Evaluation
Key Points Validation is a lifecycle that begins with a conceptual design of the manufacturing process or facility andends with system retirement. Validation activities and requirements are taken into account at the earliest stages of the design process. Risk-based approach where supplier testing is leveraged and used to reduce repetitive validation testing. Activities that support the manufacturing process such as analytical methods, and computer systems areadequately validated. The need for periodic reviews, changes to the validated system and revalidation activities are adequatelyaddressed.
References1. The principles of Orange Guide ‘Rules and Guidance for Pharmaceutical Manufacturers andDistributors’ (MHRA)2. EU EudraLex Vol 4 Annex 15: Qualification & Validation Annex 1: Manufacture of Sterile Medicinal Products Annex 11: Computerised Systems Part 4: GMP Requirements for Advanced Therapy Medicinal Products3. International Conference on Harmonisation (ICH) Q9 Quality Risk Management andQ10 Pharmaceutical Quality Systems guides will be used to support the validation studies.4. International standards, such as ISO 146445. ISPE GAMP 5 : Compliant GxP Computerised Systems6. ISPE Baseline Guide Vol 5: Commissioning and Qualification7. The Genetically Modified Organisms (Contained Use) Regulations 2018. FDA Guidance for Industry Process validation: General Principles and Practices
Quality controlconsiderationsDoli Patel, Head of Quality Control
Quality Control Considerations
QC load Vs. Process Model
QC provision Approximately half of all cell therapy products under clinical development areautologous therapies Product release - several complex assays manual and time consuming Each individual patient treatment is a separate batch that requires productrelease Significant strain on its way for a QC facility - can limit the number of productsthat can be releasedAs companies strive to improve manufacturing processes to increasethroughput the ability to release products will become an industrybottleneck
QC profiling
Quality Control – Strategy and Delivery
QC delivery – Building an affordable model Date integritypurchase Staff AvailabilityRequalify/PPM Capital aringCostvalidateproceduralizeMaintain Assay life cycles ModernizationCROQualify Validation cycles Staff TrainingINHOUSEuse
References1. The principles of Orange Guide ‘Rules and Guidance for Pharmaceutical Manufacturers and Distributors’(MHRA)2. EU EudraLex Vol 4 Annex 15: Qualification & ValidationAnnex 1: Manufacture of Sterile Medicinal ProductsAnnex 11: Computerised SystemsPart 4: GMP Requirements for Advanced Therapy Medicinal Products3. International Conference on Harmonisation (ICH)Q2 Validation of Analytical ProceduresQ9 Quality Risk ManagementQ10 Pharmaceutical Quality Systems guides will be used to support the validationstudies.4. The Genetically Modified Organisms (Contained Use) Regulations 20145. European Pharmacopoeia
12th Floor Tower WingGuy’s HospitalGreat Maze PondLondon SE1 9RTCell and Gene Therapy Catapult is committed to ensuring high standards of research integrity andresearch best practice in the activities we carry out. We subscribe to the principles described inthe UK concordat to support research kTwitter: @CGTCatapultCell and Gene Therapy Catapult is a trading name of Cell Therapy Catapult Limited, registered in England and Wales under company number07964711, with registered office at 12th Floor Tower Wing, Guy’s Hospital, Great Maze Pond, London, SE1 9RT. VAT number 154 4214 33.48
Installation Qualification Operational Qualification Performance Qualification Validation Sign Off. Validation Considerations Regulatory expectation: "A formal release for the next stage in the qualification and validation process should be authorised by the relevant
EU GMP Guide-Annex 15 Qualification & Validation draft released In February 2014, a draft of the revised Annex 15 was released by the European Commission (EC) for public comment. The draft version is based on an EMA Concept Paper, published in November 2012 which outlined various reasons for the revision of Annex 15.File Size: 553KBPage Count: 17Explore furtherEU GMP Annex 15: Qualification and Validation - ECA Acad www.gmp-compliance.orgEU GMP Annex 15 Revisions: Improving Qualification and .www.cleanroomtechnology.c GUIDELINES ON VALIDATION APPENDIX 6 VALIDATION O www.who.intGuideline on Process Validationwww.ema.europa.euEudraLex - Volume 4 - Good Manufacturing Practice (GMP .ec.europa.euRecommended to you b
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