Quality risk management of the chimeric antigen receptor T cell pharmaceutical circuit in one of the first qualified European centers

Autor: Eden Schwartz, Nicolas Boissel, Anne Brignier, Isabelle Madelaine, Nathalie Parquet, André Desproges, Sarah Mukenyi, Lorène Magdelonnette, Chloé Talarmin, Emmanuelle Lesprit, André Baruchel, Catherine Thieblemont, Steven Kerob, Jérôme Larghero, Miryam Mebarki, François Cartier
Přispěvatelé: Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Robert Debré, EFS, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CCSD, Accord Elsevier
Rok vydání: 2020
Předmět:
0301 basic medicine
Risk analysis
Cancer Research
CAR-T cells
Traceability
risk analysis
Computer science
[SDV]Life Sciences [q-bio]
media_common.quotation_subject
T-Lymphocytes
Immunology
Pharmacy
Transportation
Pharmacists
03 medical and health sciences
0302 clinical medicine
Backup
Immunology and Allergy
Humans
Quality (business)
Operations management
Hospital pharmacy
Genetics (clinical)
Risk management
media_common
Probability
Cryopreservation
Transplantation
Risk Management
Receptors
Chimeric Antigen
business.industry
Cell Biology
3. Good health
[SDV] Life Sciences [q-bio]
030104 developmental biology
Failure mode
effects
and criticality analysis
Oncology
Pharmaceutical Preparations
030220 oncology & carcinogenesis
Leukocytes
Mononuclear
advanced therapy medicinal product
cell therapy unit
France
pharmaceutical circuit
business
Zdroj: Cytotherapy
Cytotherapy, Elsevier, 2020, 22, pp.792-801. ⟨10.1016/j.jcyt.2020.06.009⟩
Cytotherapy, 2020, 22, pp.792-801. ⟨10.1016/j.jcyt.2020.06.009⟩
ISSN: 1477-2566
1465-3249
DOI: 10.1016/j.jcyt.2020.06.009⟩
Popis: International audience; Background aims: According to European Directive 2001/83/EC, chimeric antigen receptor T (CAR T) cells belong to a new class of medicines referred to as advanced therapy medicinal products (ATMPs). The specific features and complexity of these products require a total reorganization of the hospital circuit, from cell collection from the patient to administration of the final medicinal product. In France, at the cell stage, products are under the responsibility of a cell therapy unit (CTU) that controls, manipulates (if necessary) and ships cells to the manufacturing site. However, the final product is a medicinal product, and as with any other medicine, ATMPs have to be received, stored and further reconstituted for final distribution under the responsibility of the hospital pharmacy. The aim of our work was to perform a risk analysis of this circuit according to International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Q9 guidelines on quality risk management.Methods: We evaluated the activities carried out by the Saint-Louis Hospital CTU and pharmacy. Process mapping was established to trace all the steps of the circuit and to identify potential risks or failures. The risk analysis was performed according to failure mode, effects and criticality analysis. The criticality of each risk (minor [Mi], moderate [Mo], significant [S] or major [Ma]) was scored, and corrective actions or preventive actions (CAPAs) for Mo, S and Ma risks were proposed.Results: We identified five Mo, six S and no Ma risks for the CTU part of the process. The most frequent risk was traceability failure. To reduce its frequency, we developed and validated software dedicated to ATMP activities. Another S risk was non-compliance of CAR T cell-specific steps due to the significant variability between companies. Our CAPA process was to implement procedures and design information sheets specific to each CAR T-cell program. In addition, critical steps were added to the ATMP software. Our CAPA process allowed us to reduce the criticality of identified risks to one Mi, seven Mo and three S. For the pharmacy part of the process, five Mo, two S and one Ma risk were identified. The most critical risk was compromised integrity of the CAR T-cell bag at the time of thawing. In case of unavailability of a backup bag, we designed and validated a degraded mode of operation allowing product recovery. In this exceptional circumstance, an agreement has to be signed between the physician, pharmacy, CTU and sponsor or marketing authorization holder. The implemented CAPA process allowed us to reduce the criticality of risks to three Mi and five Mo.Conclusions: Our risk analysis identified several Mo and S risks but only one Ma risk. The implementation of the CAPA process allowed for controlling some risks by decreasing their frequency and/or criticality or by increasing their detectability. The close collaboration between the CTU and pharmacy allows complete traceability of the CAR T-cell circuit, which is essential to guarantee safe use.
Databáze: OpenAIRE
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