STUDIO DI ANALISI DEL RISCHIO E CONVALIDA DEI PROCESSI DI PRODUZIONE DI FARMACI INIETTABILI PER LE TERAPIE AVANZATE

Advanced therapies include gene therapy products, cellular and tissue engineering. These "products" contain living cells or complex parts of them appropriately manipulated to "alter" the genetic, physiological or biological tissue / organ treated. The work, performed during the PhD, was addressed to risk assessment and validation of production processes of two advanced therapy products. The products consist of mesenchymal stem cells for the treatment of bone defects and stem cells from a deceased donor organ. The mesenchymal stem cell approach is a patient-specific therapy and is aimed at patients suffering from conditions that do not allow spontaneous healing of bone lesions. Preliminary data confirm that the use of mesenchymal stem cells favours revascularization of damaged bone tissue, thus avoiding autoplastic implants. The development of this product for advanced therapies was preceded by the execution of some expansion tests during which the qualified staff of Rizzoli Orthopedic Institute carried out a transfer of technology to operators of Areta through coaching. The tests were used to develop the expansion procedure, to prepare the worksheet needed to perform the subsequent expansion and to develop analytical tests used to control the process and the finished product. After the transfer of technology, it has been possible to perform the risk assessment considering all the information related to the production process, facility and operators. After the hazard identification, we adopted procedures to reduce it to a lower value. After the production of validation batches, all results were compliant with established specifications, and two batches for clinical use have been produced and released. In order to evaluate the feasibility of production of tissue stem cells from a Master Cell Bank, some expansions were performed in the preliminary stages of the project, by the qualified personnel of the sponsor that transferred the technology to the Areta operators. The feasibility of the process was performed in unclassified area research labs of Areta, and it allowed to develop the expansion procedures, the tests for quality control and edited the worksheet of the preparation of the Master cell Bank. Furthermore, it was possible to conduct the assessment of risk, considering all the information related to the production process, facility and operators. After careful evaluation, procedures were adopted to minimize risk and reduce it to a lower value. In addition, as requested by law, being this a heterologus therapy, it was necessary to conduct a complete characterization of the cell bank, focused mainly on the detection of human viruses such as: HIV 1 and 2 - Anti-HIV 1 and 2, Hepatitis B HBsAg - Anti-HBc, Hepatitis C - Anti-HCV Ab, syphilis. In the characterization phase, viral and bacterial contaminations have not been identified, so the cell bank has been released. In addition, all quality control tests performed were complying with the results obtained for lots of feasibility. Future steps of this project will be the validation of the aseptic process by three media fill, and the risk assessment for the production of batches for clinical trials. After production of the three validation batches it will be possible to produce clinical batches.