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Introduction
The Clinical Cell and Vaccine Production Facility (CVPF) is a core facility within the Abramson Cancer Center of the University of Pennsylvania that can perform processing of a variety of cell types in support of adoptive cell therapy clinical trials. A variety of cell-based therapies involving bone marrow derived cells such as lymphocytes, dendritic and stem cells are currently ongoing or in development. In addition, non-marrow derived cells such as neural stem cells, islet cells and myoblasts can be processed in the CVPF. Processing includes isolation/enrichment of particular cell lineages, cryopreservation and storage of cells and tissues, RNA isolation from tumor, growth and expansion of cells, and transduction (insertion) of experimental therapeutic genes into cells.
The Facility is in continuous development and improvement of procedures and instituting policies to become compliant with the standards of the Foundation for the Accreditation of Cellular Therapy (FACT). The International Society for Cellular Therapy (ISCT) and the American Association of Blood Banks (AABB) have jointly developed these standards in response to guidance offered by the Food and Drug Administration.
CVPF Mission
The overall mission of the Clinical Cell and Vaccine Production Facility is to help trnslate insights into novel cellular therapies. Other important missions include:
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To activate and/or gene transduce cells for allogeneic or autologous cell based cancer therapies |
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To answer questions relative to the effectiveness of cell and gene therapy by analysis of patient samples |
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To develop new and improved methods of ex vivo cell culture and gene transduction |
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To maintain a knowledge of regulatory requirements and guidelines and provide expertise to Penn investigators and collaborators |
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To increase the impact of potential novel cellular therapies by facilitating wide application of the techniques developed |
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CVPF Manufacturing Suite: Expansion to Maloney Building, Hospital of the University of Pennsylvania |
The Facility
Since establishment of the CVPF at Penn, there has been a steady growth in the demand on this facility as new clinical trials have opened and the number of cellular vaccines produced has steadily increased. In order to address the wider needs of the Penn Medical Center and CVPF collaborators to produce the required number of vaccines for the numerous ongoing and proposed clinical trials, the School of Medicine awarded the CVPF space in the Hospital of the University of Pennsylvania on the 6th floor of the Maloney Building . The CVPF relocated to this renovated and larger space in April 2005. The renovations included replacing the Heating Ventilation and Air Conditioning supply air handler, upgrading to a 24/7/365 Rees monitoring and alarm system for critical equipment, and equipping the facility with state-of-the-art equipment for cell processing processes.
The new CVPF space is comprised of ten rooms: five rooms dedicated to T-cell or dendritic cell vaccine production, two rooms for equipment and freezer storage, and three rooms for reagent preparation, flow cytometry, and quality control testing. The CVPF has been designed and is operated in a manner that completely isolates cell and vaccine processing from any contact with other Maloney building areas, utilities and activities and is BL3 compliant. The CVPF has also undergone a wide array of testing, calibration and validation of equipment, environmental and alarm controls and process validation, and have had a number of regulatory audits to assess current Good Manufacturing Practices (cGMP) compliance.
Renovations will include:
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replacement of existing air handler |
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replacement of existing HVAC control and monitoring system |
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replacement of the current wire hung ceiling with an upgraded rod hung sealed ceiling with access ports |
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replacement of HEPA filters |
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floor and wall finishes patched and sealed |
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upgraded Reese monitoring system installed |
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new equipment to fully outfit facility for maximum use of processing rooms |
Renovations are anticipated to begin in 2Q 2004 and be completed in 4Q 2004. Click here to view a movie of the Maloney 6 Facility prior to renovations.
Quality Program
Quality Management Plan: Quality in its simplest form in relation to engineered cells and vaccines refers to the quality control testing performed on a product prior to release to the patient in a clinical trial. The Clinical Cell and Vaccine Production Facility has developed a comprehensive Quality Management Plan that is an integrated program of quality assessment, assurance, control, and improvement that covers all aspects of the operations, equipment, and personnel of the Facility. The Quality Plan provides the overall framework and philosophy that will result in cellular vaccine products of consistent, predictable composition.
| Elements of Good Manufacturing Practices |
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Say What you Do |
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- SOP's, procedures for equipment, supplies, facilities |
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Do What You Say |
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- Training, proficiency, competency, process controls |
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Prove It |
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- Validation, records, audits |
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Improve It |
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- Monitor and act on deficiencies |
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A Quality Plan is essential to meet the expectations of principal investigators administering the components and complying with regulatory requirements of current Good Manufacturing Practices as specified in Title 21 of the Code of Federal Regulations Parts 210 and 211. The following key elements of cGMPs were used in formulating the plan: Say What you Do - Standard Operating Procedures, procedures for equipment, supplies, facilities; Do What You Say - Training, proficiency, competency, process controls; Prove It - Validation, records, audits; and 4) Improve It - Monitor and act on deficiencies.
External standards of professional organizations, such as the Foundation for Accreditation of Cellular Therapy and the American Association of Blood Banks (AABB), were consulted in formulating the Quality Management Plan. There are currently over 130 approved Standard Operation Procedures (SOPs) representing thousands of hours of development time that cover various aspects of cell processing, equipment and policies. The Quality Plan enables a consistent manufacturing pathway that is designed to reduce variability in product purity and potency. The program is modeled after the AABB Quality System Essentials and was developed to be consistent with ISO 9000 Standards and the FDA "Guidelines for Quality Assurance in Blood Establishments." The ten Quality System Essentials and Clinical Cell and Vaccine Production Facility initiatives are identified as:
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Organization. The Quality Program includes an external Quality Assurance consultant, an internal Quality Manager, and a Clinical Trials Manager. The University's Office of Human Research provides regulatory support. |
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Personnel Management and Training. The Facility has a Standard Operating Procedure (SOP)-based training program. Following review of an SOP, a staff member first observes a procedure performed by senior staff, then performs the procedure with guidance from senior staff, and finally performs the procedure independently. Training is documented so that procedures performed on cells destined for infusion to humans are always performed by trained and certified staff. |
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Equipment. There is an SOP for Equipment Qualification of all new equipment which includes selection, installation qualification, operational qualification, and performance qualification (IQ/OQ/PQ). |
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Supply Issues. All incoming reagents/supplies are visually inspected for integrity. All Certificates of Analysis (when available) are reviewed and filed. All critical reagents are quality tested prior to release. All lot numbers are recorded. All expired reagents/supplies are removed from stock. |
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Process Control and Final Inspection. Each process is controlled by an approved SOP and documented. Deviations from approved procedures are recorded and tracked. Processing data is compiled and analyzed for expected outcomes and acceptance criteria. QA is responsible for final release of product. All release assays are reviewed by two individuals before submission to QA. Internal Quality Management reviews all clinical patient books. |
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Documents and Records. A database tracks current versions and revisions for all SOPs and accompanying forms. Other official documents include clinical patient notebooks, training records and validation study records. SOPs are in place for issuance, review, storage, and archival of all clinically relevant forms. |
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Incidents, Errors and Accidents. There is an SOP to document all deviating events regarding clinical product processing. Quality Management reviews all events and performs follow-up actions and root cause analysis, as necessary. This system is subject to annual audit. |
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Assessments. Quality Management compiles and trends processing data and performs internal audits on a predetermined schedule. These audits include deviations, equipment records, training files, reagent preparation records, and freezer inventory system. Quality Management/Assurance notifies the Office of Human Research or the Cancer Center's Data Safety Monitoring Board if it is felt that a quality issue is not being addressed appropriately. Quality Management also maintains a file on customer feedback that can be used to improve operations and service. External Quality Assurance has the ability to perform audits as deemed appropriate. The Cancer Center Data and Safety Monitoring Committee and the University Office of Human Research also perform periodic audits of Facility operations. |
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Process Improvement. Senior staff meet regularly to discuss improvement initiatives. Data from tracking and trending and new protocols submitted by investigators may lead to validation studies for improved or novel techniques. |
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Facilities and Safety. Several SOPs outline procedures to protect employees from potential harm. These procedures include biohazard and chemical disposal, personnel gowning requirements and follow-up for accidental exposure. An environmental monitoring plan is in place to document viable and non-viable particles in the facility as an aid towards maintaining a clean facility. |
Staff
Bruce Levine, Ph.D., Scientific Director (215) 573-6788
Anne Chew, Ph.D., Director, Research Operations (215) 615-1603
Julio Cotte, Technical Director (215) 746-5548
Lori Landgrebe, Quality Management (215) 898-8794
Zhaohui Zheng, Senior Clinical Applications Scientist (215) 746-5552
Andrea Cannon, Senior Clinical Applications Scientist (215) 746-5549
Hong Huynh, Cell Processing (215) 615-4708
David Dobrzynski, Cell Processing (215) 615-4671
Ursula Koldovsky, Dendritic Cell Processing
Elaine Huang, Validation Scientist (215) 615-4705
Morgan DeCaul, Validation Scientist (215) 615 4675
Naeemah Alston, Facilities Manager (215) 615-4709
How you can help
To direct a donation to the CVPF, contact Tricia Bruning, Gifts Officer, Abramson Cancer Center 215-898-0578, tbruning@ben.dev.upenn.edu. |
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