ISLET ISLET TRANSPLANTATION:TRANSPLANTATION:

FOCUS ON FOCUS ON MANUFACTURINGMANUFACTURING

UNIVERSITY OF CHICAGOUNIVERSITY OF CHICAGO

ANDAND

cGMP, Co.cGMP, Co.

Michael Millis, M.D.

GOALGOAL

Develop a Islet Transplant Program that Develop a Islet Transplant Program that would withstand the anticipated regulatory would withstand the anticipated regulatory requirementsrequirements

Practical for an academic institution’s Practical for an academic institution’s financial constraintsfinancial constraints

University of Chicago cGMP, Co

University of Chicago cGMP, Co

cGMP, Co

•Procedure that encompasses cGMP for the manufacture of biologics •BLA ready•Reimbursable

• Standard Laboratory Practice• 2000 Reminder letter that FDA regulates Islet Transplantation• 3/02 Guidance regarding validation of processing human tissues for transplantation

Principles for Biologic Principles for Biologic Manufacturing Manufacturing

Control and Validation of Control and Validation of FacilityFacility ProcessProcess

Goal: Make cellular (Islet) Goal: Make cellular (Islet) isolation conform to the isolation conform to the Principles of Biologic Principles of Biologic ManufacturingManufacturing

University of Chicago cGMP, Co

FacilityFacility

Early planning matching existing Early planning matching existing institutional assets with anticipated institutional assets with anticipated regulatory compliance- form a good planregulatory compliance- form a good plan

Define robust process that when modified Define robust process that when modified does not effect integrity of facility does not effect integrity of facility (validated)(validated)

Early planning to control costsEarly planning to control costs

University of Chicago cGMP, Co

ProcessProcess

Control the critical process environment to Control the critical process environment to assure product safety and repeatabilityassure product safety and repeatability TemperatureTemperature Bio-burdenBio-burden Cross-contaminationCross-contamination

Eliminate all equipment that cannot be validated Eliminate all equipment that cannot be validated to assure absence of contamination/cross to assure absence of contamination/cross contaminationcontaminationEliminate all components that require the use of Eliminate all components that require the use of undesirable substratesundesirable substratesEarly training of staff to assure aseptic transfer Early training of staff to assure aseptic transfer of product (SOPs, training, QA/QC)of product (SOPs, training, QA/QC)

University of Chicago cGMP, Co

Temperature Controlled COBE 2991Chilled by Refrigerant Unit that also chills other equipment

University of Chicago cGMP, Co

Temperature of bath and productdetermines depth of immersion

University of Chicago cGMP, Co

Bag being placed in heating device made for the bag

University of Chicago cGMP, Co

Bag being placed in cooling

device made for the bag

University of Chicago cGMP, Co

SummarySummary

Islet Isolation can be performed under Islet Isolation can be performed under conditions that adhere to BLA conditions that adhere to BLA requirementsrequirements

It requires expertise in pharmaceutical It requires expertise in pharmaceutical standards for laboratory and process standards for laboratory and process developmentdevelopment

University of Chicago cGMP, Co

AcknowledgmentsAcknowledgments

Jonathan LakeyJonathan Lakey

Camillo RicordiCamillo Ricordi

Benhard HeringBenhard Hering

James ShapiroJames Shapiro

State of IllinoisState of Illinois Tom CrossTom Cross

JDRFJDRF

University of ChicagoUniversity of Chicago Diane OstregaDiane Ostrega Marc GarfinkleMarc Garfinkle TechniciansTechnicians

cGMP, Co.cGMP, Co. Phil LasarskyPhil Lasarsky John JaroszJohn Jarosz

Gambro/COBEGambro/COBE

Additional InformationAdditional Information

cGMP, Co.cGMP, Co.Phil LasarskyPhil Lasarsky312 543-5523312 543-5523

University of ChicagoUniversity of ChicagoMichael Millis, M.D.Michael Millis, M.D.773 702 – 6319773 702 – 6319