Production of Adeno-Associated Virus vectors for gene therapy

Thesis: S.M., Massachusetts Institute of Technology, Department of Chemical Engineering, 2016. In conjunction with the Leaders for Global Operations Program at MIT.Thesis: M.B.A., Massachusetts Institute of Technology, Sloan School of Management, 2016. In conjunction with the Leaders for Global Operations Program at MIT.Cataloged from PDF version of thesis.Includes bibliographical references (pages 51-56).Gene therapy is a promising modality for the potential treatment of rare Mendelian diseases. To date a number of high profile proof-of-concept studies within the industry have demonstrated the significant disease-correcting promise of this therapeutic strategy. One of the major hurdles that remains for the commercialization of gene therapies is the lack of efficient manufacturing capabilities for the production of clinical-grade drug substance/drug product. The primary goals for this project were to decrease the biological contamination and cross-contamination risk associated with the biologic manufacturing process for viral gene therapy vectors and to adjust the process in order to optimize commercial profit. The project also included documenting the different existing processes for AAV production and developing a competitive analysis using information from ongoing clinical trials in the industry pipeline. The following process design steps were followed in order to fulfill the project objectives: (1) Define product specifications, analytical needs and market size, (2) Select production platform/process, (3) Collect data and create process flow diagram, (4) Perform material and energy balances, (5) Calculate costs: equipment and consumables, (6) Model the process in a spreadsheet, (7) Carry out sensitivity analyses, (8) Assess cost-effectiveness and risk, and (9) Develop recommendations. Five different AAV production platforms were identified and an AAV gene therapy landscape was generated. Also, the current process that Pfizer is planning to use was documented and an initial market sizing was performed. Finally, all the data necessary to model the process was collected and the cost-effectiveness and biological contamination and cross-contamination risk assessment were completed. This project confirmed that the use of a scalable line of single-use high cell density bioreactors for the production of AAV is cost-effective. This implies that sufficient AAV quantities can be manufactured for preclinical and clinical trials, using the process developed by Pfizer.by Diego Rodríguez Pinhao Miessner.S.M.M.B.A