Purity, Potency and Safety: Quality Management Reports (QMR) as the Basis for An Effective Continuous Process Improvement System in An Academic Gene Therapy Program.

Abstract 1417

Poster Board I-440

Gene-modified cellular products (GMCP) hold great promise for the management of numerous disease indications but are considered high-risk biological agents and are derived through extremely complex design and manufacturing processes. Thus, a robust Quality Management System (QMS) is essential for safe production of GMCP for clinical investigation. Development of a QMS that ensures compliance with current Good Manufacturing Practices (cGMP) and current Good Tissue Practices (cGTP) is particularly challenging in an academic setting where basic researchers, clinical investigators, regulatory, administrative, facilities and manufacturing personnel are all involved in the realization of a single GMCP. Following an ISO9001-based gap analysis of the Cellular Therapeutics program at the City of Hope, we implemented Quality Management Reports (QMR) as a tool for capturing data related to GMCP manufacturing. The QMR system was used to document and facilitate corrective and preventative actions (CAPA) as required following protocol deviation and/or Out of Specification (OOS) analyses. QMR data is captured in real-time and includes a detailed description of the event, impact analysis, root cause investigation, action plan and effectiveness analysis for resulting interventions. QMRs are documented using the Labware^® (Wilmington, DE) Laboratory Information Management System (LIMS) that is available in real-time to authorized participants in GMCP production. A key aspect in the development of this on-line system was creation of links between the QMRs, OOS and CAPA documentation and investigation. The investigation database contains a series of templates: CAPA, SOP deviations, OOS and QMR that are designed to fully capture any events that impact or have the potential to impact quality, safety or efficient realization of a GMCP. The QMR process was applied to 2 manufacturing campaigns: a lentiviral vector-transfected CD34 GMCP for autologous transplantation in patients with AIDS lymphoma and a Master Cell Bank that was created for the treatment of patients with recurrent Glioblastoma Multiforme based upon an oligoclonal allogeneic T-cell product that contained both a chimeric antigen T-cell receptor and a zinc finger disrupted glucocorticoid receptor genomic sequence. Between May 2008-June 2009, 22 QMRs were generated related to product/reagent transfer, reagent quality/storage, equipment malfunction/OOS, product/environmental sterility, biological reagent OOS and Quality Control specifications for product release. Seventeen of 22 QMRs were resolved and closed. The average time to closing a QMR was 82 days (range 4-198 days). QMR findings lead to a revision of the program organizational chart, lead to the development and implementation of a new standard operating procedure (SOP) for Root Cause Analysis (RCA) investigations, development of new forms (GMP Equipment Approval Forms, a Quality Systems Project Proposal Form and Quality Assurance Customer Satisfactions Survey Forms), revisions to the SOP for CAPA and retraining of manufacturing staff as part of the resultant CAPA investigations to prevent repeat occurrences. Based upon QMR findings, 2 multidisciplinary RCAs were performed and resulted in revisions to documentation for CD34-cell selection and a major revision to the use of RODI water and manufacturing flow during GMCP production campaigns. Only 1 of 22 QMR-captured events has recurred (failure of an equipment monitoring system) and no events have re-occurred that might have had an impact upon product quality or safety. User satisfaction surveys performed by QA following the completion of a multidisciplinary RCA investigation indicate that the QMR process was viewed as fair, unbiased and transparent by a majority of the users (86% were either “Extremely Satisfied” or “Satisfied” with the experience). The QMR process is a powerful tool for the safe realization of GMCP and allows for real-time capture and multidisciplinary communication of complex events, including OOS that either individually or in aggregate may impact the purity, potency or safety of manufactured GMCP. These are often events that would not be routinely captured either as part of a batch record or merit CAPA. Because effectiveness analysis is included as part of the QMR process, it provides a key mechanism for continuous process improvement.