The CVPF is a unit within the Division of Transfusion Medicine and Therapeutic Pathology in the Department of Pathology and Laboratory Medicine at the University of Pennsylvania. The CVPF is accredited by the Foundation for the Accreditation of Cellular Therapy (FACT). The CVPF is a university shared-core resource that supports cellular therapy clinical trials which include manufacture of activated and expanded T lymphocytes, dendritic cells, mesenchymal stem cells, and lentiviral vector and RNA gene-modified T lymphocytes, among others to support investigators at UPenn and collaborating institutions.
Two Designated Manufacturing Facilities
CVPF consists of two manufacturing facilities: Ravdin and the Center for Advanced Cellular Therapies (CACT). The two manufacturing spaces share the same Quality Control Laboratory unit, and the Quality Assurance unit, who leads the CVPF Quality Management System and releases all manufactured products at CVPF. The CVPF manufacturing facilities are designed to maximize isolation of the cell and vaccine processing from other building areas, utilities, and activities. Access to the CVPF cleanroom areas is restricted via card-access and/or key lock access leading to a dedicated gown-in entrance. The Air Handler Units (AHU) serving each facility provide 100% outdoor air filtered by high efficiency particulate air (HEPA) filters. They operate as constant supply air-volume systems to maintain constant airflow to the spaces in the manufacturing suites, and to maintain cleanroom classifications.
The Ravdin Facility of CVPF is located in approximately 2,000 ft2 of space on the third floor of the Ravdin Pavilion at HUP. CVPF-Ravdin is in direct proximity to the apheresis cell collection and infusion unit, the autologous and allogeneic blood donor center, the blood bank, and the stem cell processing facility that supports the clinical transplantation service. The facility consists of seven processing rooms, a gown-in/gown-out room, a media preparation and storage room. The interior hallway and common areas are class 100,000 (ISO 8) and the individual cell processing rooms are class 10,000 (ISO 7). Processing is performed in class 100 (ISO 5) BSCs.
The CACT Facility of CVPF is the newest manufacturing facility, opened in July 2016 and located on the ninth floor in the newly built South Tower building, adjacent to the Smilow Translational Research Center on the University of Pennsylvania’s campus. The CVPF-CACT cleanroom manufacturing space consists of eight processing cleanrooms, an automation room, a media prep room, and gown-in/gown-out rooms. The interior hallway and common areas are class 100,000 (ISO 8) and the individual cell processing rooms are class 10,000 (ISO 7). The CVPF-CACT footprint of the clean room manufacturing area is approximately 4,500 ft2. Processing is performed in class 100 (ISO 5) BSCs.
The CVPF-CACT facility also contains the Quality Control (QC) laboratory space that also serves Ravdin. The QC lab supports investigational product scale up, validation, and clinical manufacturing by qualifiying critical reagents including media to release for use in clinical manufacturing and performs analytical testing for in process and product release requirements that include sample characterization via FACS analysis, testing for mycoplasma and endotoxin, and sterility testing.
Critical equipment in the CVPF is monitored continuously by the Rees Centron Environmental Monitoring System that is password protected and can be accessed remotely to provide information on the status of critical equipment, for example, incubators and freezers. The Rees sensors record parameters once every 15 minutes and will alarm if these parameters reach conditions outside of the pre-established acceptance criteria. Both facilities are cleaned at predetermined frequencies by trained staff, according to approved internal procedures. Critical cell processing equipment, such as Biological Safety Cabinets, is disinfected before and after each use, and ancillary equipment is cleaned after use, such as scales, and water baths. Common processing equipment is stored in a cleanroom central area and brought into culture rooms as needed. Single use disposable tubing sets are utilized to process the cells to reduce the risk of cross-contamination. Closed system processing steps are used whenever technically feasible. Finally, viable and non-viable Environmental Monitoring is performed at both facilities.
|Name of equipment||Name of equipment|
|20/50 EHT Bioreactor||Freezer, -40°C|
|4' laminar flow hood||Freezer, -80°C|
|5' laminar flow hood||Freezer, Controlled Rate|
|6' laminar flow hood||Haemonetics Cell Saver 5 Autologous Blood Recovery System|
|Airtest BioSampler SAS||Hamilton Fluid Dispenser|
|BACTEC© 9050 Blood Culturing System||HEPA filtered CO2 incubator|
|BACTEC© FX Blood Culture System||Labnet Lab Roller II|
|Baxter MaxSep Magnetic Separator||LN2 Freezer|
|Centrifuge, Microcentrifuge||LN2 Manifold Changeover|
|Centrifuge, Sorvall Biofuge Primo R||LUNA Cell Counter|
|Centrifuge, Sorvall Legend RT||MaxCyte Flow Transfection System|
|Centrifuge, Sorvall Legend XTR||Microscope, Inverted|
|Centrifuge, Sorvall RC3B-plus||Miltenyi CliniMACS Magnetic Separator|
|Climet Particle Analyzer Counter||Plate Washer|
|Coulter M3 Cell Counter/Sizer||REES monitoring system, server based|
|Coulter M4 Cell Counter/Sizer||Refrigerator|
|Counterflow Centrifugation Elutriator||Sebra Heat Sealer|
|CO2 Mixer||Table top CO2 incubators|
|Digital balance||Terumo Elutriator Elutra|
|Endotoxin Analyzer||Terumo Sterile Connect Device|
|Floor Scales||ThawStar Cell Thawing|
|Flow cytometer, BD LSRFortessa||Waterbath|
|Flow cytometer, FACS Calibur with Cellquest software||WAVE 2/10 Bioreactor|
III. Quality Management
The CVPF Quality Management Plan is modeled in accordance with the standards and practices jointly developed by the International Society for Cellular Therapy (ISCT), the American Association of Blood Banks (AABB), and FACT. The CVPF Quality Management Plan is an integrated program of quality assessment, quality assurance & control, and continuous improvement that governs all areas of operations in the CVPF, such as personnel, equipment, facilities maintenance, and processing procedures. The main purpose of the Quality Management Plan is to provide a consistent manufacturing pathway to reduce variability in product purity and quality, resulting in cellular products of predictable composition. The eleven Quality System essentials which enable the CVPF to function efficiently and effectively include organization, personnel management and training, equipment management, materials management, change management, process control, final inspection and handling, documents and records, incidents and deviations, internal inspections and assessments, continuous improvement, and facilities, safety and environmental monitoring.