University of Minnesota University of Minnesota Facility DesignFacility Design

Diane Kadidlo MT(ASCP), SBB Diane Kadidlo MT(ASCP), SBB Operations ManagerOperations Manager

University of MinnesotaUniversity of MinnesotaMolecular and Cellular TherapeuticsMolecular and Cellular Therapeutics

Molecular and Cellular Therapeutics University of Minnesota

OverviewOverviewFacility Facility –– 40,000 square feet40,000 square feet

ISO Class Production Clean Rooms ISO Class Production Clean Rooms –– 2020

Total Operational Staff Total Operational Staff –– 3737

Major Therapeutic Product Classes Supported Major Therapeutic Product Classes Supported –– 44

18 INDs (14 internal; 4 external)18 INDs (14 internal; 4 external)

Over 900 products produced annuallyOver 900 products produced annually

Value of Production Value of Production -- $5MM$5MM

Our MissionOur Mission

To Provide WorldTo Provide World--Class Development and Class Development and Production of Therapeutic Products, for Production of Therapeutic Products, for University of Minnesota Investigators, external University of Minnesota Investigators, external institutions, and startinstitutions, and start--up firmsup firms

Molecular and Cellular Therapeutics Molecular and Cellular Therapeutics (MCT) (MCT) Est.1992Est.1992

Translate basic discovery to clinical trials, across a wide Translate basic discovery to clinical trials, across a wide array or therapeutic classesarray or therapeutic classes

Develop and manufacture therapeutic products meeting Develop and manufacture therapeutic products meeting Good Manufacturing Practices (cGMPs) and current Good Good Manufacturing Practices (cGMPs) and current Good Tissue Practices (cGTPs)Tissue Practices (cGTPs)

Support Phase I/II/III clinical trials of molecular and Support Phase I/II/III clinical trials of molecular and advanced celladvanced cell--, tissue, tissue--, gene, gene--based, protein, drug based, protein, drug therapies for researchers and external contracts therapies for researchers and external contracts

Manufacturing Units Manufacturing Units –– Cell Therapy, Protein Production Cell Therapy, Protein Production Pancreatic Islet Transplant, and Pharmaceutical SynthesisPancreatic Islet Transplant, and Pharmaceutical Synthesis

Production CapabilitiesProduction Capabilities

Hematopoietic TransplantHematopoietic TransplantPancreatic Islet TransplantPancreatic Islet TransplantImmunoadoptive TherapiesImmunoadoptive TherapiesCardiac RepairCardiac RepairMonoclonal Antibodies/ProteinsMonoclonal Antibodies/ProteinsActive Pharmaceutical Ingredients (API)Active Pharmaceutical Ingredients (API)Xeno (Porcine) Pancreatic Islet Transplant Xeno (Porcine) Pancreatic Islet Transplant (1)(1)

(1) (1) -- Planned for 2009Planned for 2009

Upper Level (10,000 sq ft.) Upper Level (10,000 sq ft.) 5500 sq ft Clean Space5500 sq ft Clean Space

MCT Renovation PlanMCT Renovation Plan

Core ActivitiesCore ActivitiesQuality and ComplianceQuality and ComplianceOperations/Quality/Materials ManagementOperations/Quality/Materials ManagementControl of Critical SystemsControl of Critical SystemsProgram Budgets/Forecasts/Cost AccountingProgram Budgets/Forecasts/Cost AccountingBusiness Plan DevelopmentBusiness Plan DevelopmentProject ManagementProject ManagementEquipment ManagementEquipment ManagementDocument Change ControlDocument Change ControlProcess Process Development/Qualification/ValidationDevelopment/Qualification/Validation

MCT Organizational StructureMCT Organizational StructureScientific Director Scientific Director

Dr. John Wagner, MDDr. John Wagner, MDFacility DirectorFacility Director

Randy TlachacRandy TlachacFacility Medical DirectorFacility Medical Director

Dr. David McKenna, MDDr. David McKenna, MDDirector of IND/IDE Assistance ProgramDirector of IND/IDE Assistance Program

Harvey Arbit, PhDHarvey Arbit, PhDManagersManagers

Quality AssuranceQuality AssuranceFacility & MaterialsFacility & MaterialsOperationsOperationsFinanceFinance

•• Limited Access Limited Access –– Electronic Card KeyElectronic Card Key•• Controlled Environment Areas (ISO Class 5 and 7)Controlled Environment Areas (ISO Class 5 and 7)

•• Single pass, isolated differential air pressure rooms, negative Single pass, isolated differential air pressure rooms, negative pressure pressure capabilitiescapabilities

•• Defined Personnel and Process FlowDefined Personnel and Process Flow•• Product/Process SegregationProduct/Process Segregation

•• Central Alarm Monitoring Critical SystemsCentral Alarm Monitoring Critical Systems•• Materials and Inventory ManagementMaterials and Inventory Management•• Equipment Equipment

•• Calibration & Preventative maintenanceCalibration & Preventative maintenance•• IQ/OQ/PQIQ/OQ/PQ

•• Document Control Document Control •• Product DevelopmentProduct Development

•• Project ManagementProject Management•• Regulatory Oversight and GuidanceRegulatory Oversight and Guidance

•• Facility (Type V) Master FileFacility (Type V) Master File•• CMC Quality IndicesCMC Quality Indices

Facilities and Services AttributesFacilities and Services Attributes

LOWER LEVEL LOWER LEVEL 7,000 Sq ft Clean Space7,000 Sq ft Clean Space

University of Minnesota Medical Center, FairviewUniversity of Minnesota Medical Center, FairviewClinical Cell Therapy LaboratoryClinical Cell Therapy Laboratory

Established 1979 in support of the Blood and Marrow Established 1979 in support of the Blood and Marrow Transplant Program at the University of Minnesota. Moved to Transplant Program at the University of Minnesota. Moved to MCT Facility 1996MCT Facility 1996

Processes more than 1500 human bone marrow, peripheral Processes more than 1500 human bone marrow, peripheral blood, umbilical cord blood and tissues annuallyblood, umbilical cord blood and tissues annually

Provide translational development expertise for bringing novel Provide translational development expertise for bringing novel cell engineering techniques from research to clinical cell engineering techniques from research to clinical applicationsapplications

UMMC Cell Therapy Lab UMMC Cell Therapy Lab Clinical Operations Clinical Operations --GTP ProductionGTP Production

3300 sq ft, separate air handling system3300 sq ft, separate air handling systemUnclassified space meets the requirements for Unclassified space meets the requirements for Class 100,000Class 100,000Clinical production not requiring extensive Clinical production not requiring extensive manipulation. manipulation. Processes: cryopreservation, positive and Processes: cryopreservation, positive and negative selection.negative selection.

Auto/Allo PB, CB & Bone MarrowAuto/Allo PB, CB & Bone Marrow

Closed system processes Closed system processes –– products in bags; products in bags; biological safety cabinetsbiological safety cabinets

GMP Production

Production Area CharacteristicsProduction Area Characteristics

Class 10,000 (ISO 7) Clean Suite Class 10,000 (ISO 7) Clean Suite ISO 5 Biological Safety CabinetsISO 5 Biological Safety CabinetsSingle pass, isolated differential air pressure Single pass, isolated differential air pressure rooms, negative pressure capabilitiesrooms, negative pressure capabilitiesTerminal HEPA Filtration, 20Terminal HEPA Filtration, 20--70 Air Changes/Hr 70 Air Changes/Hr Clean Room surfaces, epoxy liquid flooring Clean Room surfaces, epoxy liquid flooring coved base, reinforced resinous wall surfacing, coved base, reinforced resinous wall surfacing, and epoxy painted veneer plaster ceilings and epoxy painted veneer plaster ceilings

PersonnelMaterialsProductWaste

••UniUni--directional directional workflow workflow

••Production in Production in biosafety cabinets or biosafety cabinets or within closed within closed systems. systems.

••Personnel and Personnel and product exit through product exit through the degowning the degowning rooms.rooms.

Process FlowProcess Flow

Environmental ControlsEnvironmental Controls

SanitizationSanitizationContract for janitorial services Contract for janitorial services (non Class 10,000)(non Class 10,000)Programs cleans production suitesPrograms cleans production suites

Environmental MonitoringEnvironmental MonitoringWeekly surface testingWeekly surface testingMonthly viable particlesMonthly viable particlesQuarterly mold and nonQuarterly mold and non--viable particlesviable particles

GMP Product ManufacturingGMP Product ManufacturingPancreatic Islet CellsPancreatic Islet Cells

AutologousAutologousAllogeneic Phase I/II/IIIAllogeneic Phase I/II/III

Hematopoietic Stem CellsHematopoietic Stem CellsMultipotent stem cellsMultipotent stem cells

Immunoadoptive TherapyImmunoadoptive TherapyAllogeneic Natural Killer CellsAllogeneic Natural Killer CellsT Regulatory CellsT Regulatory CellsMesenchymalMesenchymal Stem CellsStem CellsLarge Multivalent Large Multivalent ImmunogenImmunogen VaccineVaccineDonor Lymphocyte InfusionsDonor Lymphocyte Infusions

Cardiac RepairCardiac RepairBM derived MNCBM derived MNCCardiac derived stem cellsCardiac derived stem cells

Monoclonal Antibodies/ProteinsMonoclonal Antibodies/Proteins