AP-HP, Hôpital Saint-Louis, Unité de Thérapie Cellulaire, Paris, France.
AP-HP, Hôpital Saint-Louis, Pharmacie à Usage Intérieur, Paris, France.
Cytotherapy. 2020 Dec;22(12):792-801. doi: 10.1016/j.jcyt.2020.06.009. Epub 2020 Jul 27.
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.
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.
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.
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.
根据欧洲指令 2001/83/EC，嵌合抗原受体 T（CAR T）细胞属于被称为先进治疗药物产品（ATMP）的新型药物类别。这些产品的特定特征和复杂性要求对医院的整个循环进行全面重组，从从患者采集细胞到最后药物的给药。在法国，在细胞阶段，产品由细胞治疗单位（CTU）负责，该单位控制、操作（如有必要）并将细胞运输到制造地点。然而，最终产品是一种药物，与任何其他药物一样，ATMP 必须在医院药房的负责下接收、储存和进一步重新配制以供最终分发。我们工作的目的是根据人用药品技术要求国际协调理事会关于质量风险管理的 Q9 指南对该循环进行风险分析。
我们评估了圣路易医院 CTU 和药房开展的活动。我们建立了流程映射以追踪循环的所有步骤，并识别潜在的风险或故障。风险分析是根据失效模式、影响和关键性分析进行的。对每个风险（轻微[Mi]、中等[Mo]、显著[S]或主要[Ma]）的关键性进行评分，并为 Mo、S 和 Ma 风险提出纠正和预防措施（CAPA）。
我们确定了 CTU 部分流程的五个 Mo、六个 S 和零个 Ma 风险。最常见的风险是可追溯性失败。为了降低其频率，我们开发并验证了专门用于 ATMP 活动的软件。另一个 S 风险是由于公司之间存在显著差异，CAR T 细胞特定步骤的不合规。我们的 CAPA 流程是实施针对每个 CAR T 细胞计划的程序和设计信息表。此外，在 ATMP 软件中添加了关键步骤。我们的 CAPA 流程使我们能够将确定的风险的关键性降低到一个 Mi、七个 Mo 和三个 S。对于药房部分流程，我们确定了五个 Mo、两个 S 和一个 Ma 风险。最关键的风险是解冻时 CAR T 细胞袋的完整性受损。在没有备用袋的情况下，我们设计并验证了一种降级操作模式，允许产品回收。在这种特殊情况下，医生、药房、CTU 和赞助商或上市许可持有人之间必须签署协议。实施的 CAPA 流程使我们能够将风险的关键性降低到三个 Mi 和五个 Mo。
我们的风险分析确定了几个 Mo 和 S 风险，但只有一个 Ma 风险。CAPA 流程的实施通过降低其频率和/或关键性或提高其可检测性来控制一些风险。CTU 和药房之间的密切合作允许对 CAR T 细胞循环进行完整的追溯，这对于保证安全使用至关重要。
