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An important amount of cytotoxic drug may accumulate in the workplace following the breakage of a vial containing an anticancer drug. Thanks to the monthly monitoring of the surface contamination in our compounding unit, a strong increase of cyclophosphamide contamination was highlighted in the storage area following the breakage of the vial, despite application of the emergency procedure. This study presents an analysis of chemical decontamination in the context of massive contamination. Samples were taken on the floor and on the caster of a storage shelf where the vial broke. The residual contamination was measured with a liquid chromatography–mass spectrometry/mass spectrometry method. An admixture of 10−2 M sodium dodecyl sulfate and 70% isopropanol (SDS/IPA 8:2) was selected as the decontamination solution. High amounts of cyclophosphamide were retrieved. The initial contamination on the floor was over 20 ng/cm2. Three decontaminations with SDS/IPA were carried out at Day 61, Day 68, and Day 71. The amount of cyclophosphamide decreased to 0.45 ng/cm2 at D134. However, high values were still measured on the caster despite successive decontaminations, with a maximal value of 19.78 ng/cm2 observed at Day 106. Continuous monitoring in our unit led us to highlight the inefficiency of our emergency procedure to eliminate high cyclophosphamide contamination. The procedure involving the SDS/IPA admixture was more efficient on the floor compared to the caster, which is a different surface type and porosity. This work highlights the importance of improving the procedures of incident management using contamination monitoring and repeated decontamination procedures adapted to different contaminants and surfaces.

The extraordinary and unexpected success of cellular immunotherapy using genetically engineered T-cells to express a chimeric antigen receptor (CAR) targeting CD19, in the treatment of refractory or relapsing B-hematological malignancies, has provided a real therapeutic hope. Indeed, remission rates reach more than 80 % in patients at a stage, without any other possibilities of treatment, notably in the child's acute lymphoblastic leukemia. These results, initially resulting from academic research, led to Food and Drug accreditation for market access of two innovative autologous therapy drugs, Kimryah® and Yescarta®. Based on the impressive clinical results, mainly so far in hematological malignancies (LAL, MM, LBDGC, etc.), the development of several types of cells expressing a CAR receptor suggests a wide range of future applications, particularly in the field of solid tumors. However, while the development of CAR-T cells now appears to be in the hands of private pharmaceuticals companies, the logistical constraints, the cryopreservation and the very high cost of these personalized medicines may ultimately limit their use. The development of academic productions by CAR-T cells could bypass some of these disadvantages. The strong innovation capacity of healthcare institutions associated with research units allows them to identify the ideal tumor target and efficient performing cells. Thus, authorized production platforms could allow for shorter administration times and reasonable production costs for national health systems. The aim of this workshop is to identify the requirements for the academic production of CAR-T cells, while respecting the research standards useful to establish proof of concept, but also at the preclinical development stage, leading in fine to the manufacture, through an authorized pharmaceutical establishment, of the innovative therapy drug, and in accordance with Good Manufacturing Practice (GMP). The ultimate goal is to make these innovative and high-performance medicines available to as many patients as possible.

CAR T-cells are autologous or allogeneic human lymphocytes that are genetically engineered to express a chimeric antigen receptor targeting an antigen expressed on tumor cells such as CD19. CAR T-cells represent a new class of medicinal products, and belong to the broad category of Advanced Therapy Medicinal Products (ATMPs), as defined by EC Regulation 2007-1394. Specifically, they are categorized as gene therapy medicinal products. Although CAR T-cells are cellular therapies, the organization for manufacturing and delivery is far different from the one used to deliver hematopoietic cell grafts, for different reasons including their classification as medicinal products. Currently available clinical observations were mostly produced in the context of trials conducted either in the USA or in China. They demonstrate remarkable efficacy for patients presenting advanced or poor-prognosis hematological malignancies, however with severe side effects in a significant proportion of patients. Toxicities can and must be anticipated and dealt with in the context of a full coordination between the clinical cell therapy ward in charge of the patient, and the neighboring intensive care unit. The present workshop aimed at identifying prerequisites to be met in order for French hospitals to get efficiently organized and fulfill sponsors' expectations before initiation of clinical trials designed to investigate CAR T-cells.

The extraordinary and unexpected success of cellular immunotherapy using genetically engineered T-cells to express a chimeric antigen receptor (CAR) targeting CD19, in the treatment of refractory or relapsing B-hematological malignancies, has provided a real therapeutic hope. Indeed, remission rates reach more than 80 % in patients at a stage, without any other possibilities of treatment, notably in the child's acute lymphoblastic leukemia. These results, initially resulting from academic research, led to Food and Drug accreditation for market access of two innovative autologous therapy drugs, Kimryah® and Yescarta®. Based on the impressive clinical results, mainly so far in hematological malignancies (LAL, MM, LBDGC, etc.), the development of several types of cells expressing a CAR receptor suggests a wide range of future applications, particularly in the field of solid tumors. However, while the development of CAR-T cells now appears to be in the hands of private pharmaceuticals companies, the logistical constraints, the cryopreservation and the very high cost of these personalized medicines may ultimately limit their use. The development of academic productions by CAR-T cells could bypass some of these disadvantages. The strong innovation capacity of healthcare institutions associated with research units allows them to identify the ideal tumor target and efficient performing cells. Thus, authorized production platforms could allow for shorter administration times and reasonable production costs for national health systems. The aim of this workshop is to identify the requirements for the academic production of CAR-T cells, while respecting the research standards useful to establish proof of concept, but also at the preclinical development stage, leading in fine to the manufacture, through an authorized pharmaceutical establishment, of the innovative therapy drug, and in accordance with Good Manufacturing Practice (GMP). The ultimate goal is to make these innovative and high-performance medicines available to as many patients as possible.

International audience; Chimeric Antigen Receptor T-cells (CART) belongs to a new class of medicine, Advanced Therapy Medicinal Product, such as define by the European Regulation 1394/2007, and more exactly to the category of gene therapy medicinal product. Their status of medicine, as well as genetically modified organisms, imposes a particular circuit at hospital while maintaining a way over the Hospital Pharmacy. The manipulation of genetically modified cells is not usual in pharmacy. It requires, besides the acquisition of new skills, a not insignificant reorganization of the teams and the rooms of the pharmacy as well as an adapted training of the staff. A good communication is essential between the various actors of the circuit. The hospital pharmacist plays a key role in the implementation of a circuit adapted to this new type of medicine. This article aims to identify the roles of the hospital pharmacist and more generally of the pharmacy in the management of CART. We shall detail the specificities of this type of medicine in every stage of the circuit and the adaptations necessary to realize to guarantee the quality and the safety of the treatment by CART. Beyond the implementation of the circuit in the hospital, the pharmacist has an important role to be played in the follow-up of the patients after administration in view of the complexity of the side effects and a certain role in the training of the teams to this new medicine.; Les lymphocytes T exprimant un Récepteur Chimérique à l’Antigène (CART) appartiennent à une nouvelle classe de médicaments, les médicaments de thérapies innovantes, tels que définis par le règlement Européen 1394/2007, et plus précisément à la catégorie des médicaments de thérapie génique. Leur statut de médicament ainsi que d’organismes génétiquement modifiés impose un circuit particulier à l’hôpital tout en maintenant un passage par la Pharmacie à Usage Intérieur du Centre Hospitalier. La manipulation de cellules génétiquement modifiées n’est pas habituelle en pharmacie. Elle nécessite, en plus de l’acquisition de nouvelles compétences, une réorganisation non négligeable des équipes et des locaux de la pharmacie ainsi qu’une formation adaptée du personnel. Une bonne communication est indispensable entre les différents intervenants du circuit. Le pharmacien hospitalier joue un rôle primordial dans la mise en place d’un circuit adapté à ce nouveau type de médicament. Le présent article a pour but d’identifier les rôles du pharmacien hospitalier et plus généralement de la pharmacie à usage intérieur dans la prise en charge des CART. Nous détaillerons les spécificités de ce type de médicament à chaque étape du circuit et les adaptations nécessaires à réaliser afin de garantir la qualité et la sécurité du traitement par CART. Au-delà de la mise en place du circuit au sein de l’hôpital, le pharmacien a un rôle important à jouer dans le suivi des patients après administration au vu de la complexité des effets secondaires et un rôle certain dans la formation des équipes à ce nouveau médicament.

CAR T-cells are autologous or allogeneic human lymphocytes that are genetically engineered to express a chimeric antigen receptor targeting an antigen expressed on tumor cells such as CD19. CAR T-cells represent a new class of medicinal products, and belong to the broad category of Advanced Therapy Medicinal Products (ATMPs), as defined by EC Regulation 2007-1394. Specifically, they are categorized as gene therapy medicinal products. Although CAR T-cells are cellular therapies, the organization for manufacturing and delivery is far different from the one used to deliver hematopoietic cell grafts, for different reasons including their classification as medicinal products. Currently available clinical observations were mostly produced in the context of trials conducted either in the USA or in China. They demonstrate remarkable efficacy for patients presenting advanced or poor-prognosis hematological malignancies, however with severe side effects in a significant proportion of patients. Toxicities can and must be anticipated and dealt with in the context of a full coordination between the clinical cell therapy ward in charge of the patient, and the neighboring intensive care unit. The present workshop aimed at identifying prerequisites to be met in order for French hospitals to get efficiently organized and fulfill sponsors' expectations before initiation of clinical trials designed to investigate CAR T-cells.

International audience; BACKGROUND: The objective of this randomized, prospective and controlled study was to investigate the ability of a closed-system transfer device (CSTD; BD-Phaseal) to reduce the occupational exposure of two isolators to 10 cytotoxic drugs and compare to standard compounding devices. METHODS AND FINDINGS: The 6-month study started with the opening of a new compounding unit. Two isolators were set up with 2 workstations each, one to compound with standard devices (needles and spikes) and the other using the Phaseal system. Drugs were alternatively compounded in each isolator. Sampling involved wiping three surfaces (gloves, window, worktop), before and after a cleaning process. Exposure to ten antineoplastic drugs (cyclophosphamide, ifosfamide, dacarbazine, 5-FU, methotrexate, gemcitabine, cytarabine, irinotecan, doxorubicine and ganciclovir) was assessed on wipes by LC-MS/MS analysis. Contamination rates were compared using a Chi2 test and drug amounts by a Mann-Whitney test. Significance was defined for p