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首页> 外文会议>Conference on single-use technologies III >MANUFACTURING HUMAN MESENCHYMAL STEM CELLS AT CLINICAL SCALE: PROCESS AND REGULATORY CHALLENGES
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MANUFACTURING HUMAN MESENCHYMAL STEM CELLS AT CLINICAL SCALE: PROCESS AND REGULATORY CHALLENGES

机译：在临床规模中制造人间充质干细胞：过程和监管挑战

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There is an obvious increasing interest in human mesenchymal stem cell (hMSC)-based therapies for regenerative medicine (e.g. neurology, cardiology, immunology, orthopaedics). At the beginning of May 2018, there were 253 registered clinical trials using hMSCs (www.clinicaltrials.gov). Despite the large number of current clinical studies, only 13 hMSC-based products have received regulatory approval. In order to efficiently manufacture hMSC-based products, not only must the targeted cell quantity and quality be taken into account, but the production costs must also be considered. In general, autologous and allogeneic stem cell products are characterized by similar upstream processing (USP), downstream processing (DSP), formulation, and fill & finish operations. Typical USP operations are manufacturing of the Master Cell Bank (MCB) and the Working Cell Bank (WCB), seed cell production, and subsequent cell expansion. The DSP steps include cell harvesting, cell detachment, cell separation, washing and concentration procedures, and medium exchange. However, before hMSCs can be administered as an Advanced Therapeutic Medicinal Product (ATMP), additional formulation, and fill and finish steps have to be carried out. The main differences between allogeneic and autologous manufacturing approaches are the number of therapeutic doses generated in each batch and the number of patients treated. Therefore, it is unsurprising that allogeneic therapies are the more cost-effective method in terms of hMSC production. Furthermore, various economic studies have demonstrated that USP and in particular, hMSC expansion, represent the main cost drivers when examining the entire manufacturing process. In order to achieve the high cell numbers of up to 10~(13) cells per batch needed in allogeneic hMSC manufacturing processes, manufacturers have to move away from traditional planar cultivation systems. Many reports over the last years have shown that instrumented, single-use bioreactors in combination with microcarriers are promising systems for this task. Even though different procedures and equipment for USP and DSP are already available and established for allogeneic production of hMSCs, various challenges still exist. Therefore, the authors intend to highlight the current state of the art of allogeneic hMSC manufacturing and show the current main process and regulatory challenges for USP and DSP operations.
机译：对人间充质干细胞（HMSC）的疗法具有明显的兴趣，用于再生药物（例如神经内科，心脏病学，免疫学，骨科）。在2018年5月初，使用HMSCS（www.clinicaltrials.gov）有253项注册的临床试验。尽管目前的临床研究有大量，但只有13个基于HMSC的产品获得了监管批准。为了有效地制造基于HMSC的产品，不仅必须考虑到有针对性的细胞数量和质量，而且还必须考虑生产成本。通常，自体和同种异体干细胞产物的特征在于类似上游加工（USP），下游加工（DSP），配方和填充和填充操作。典型的USP操作是制造主细胞库（MCB）和工作细胞库（WCB），种子细胞生产和随后的细胞扩张。 DSP步骤包括细胞收集，细胞脱离，细胞分离，洗涤和浓缩程序和中等交换。然而，在HMSCs可以作为先进的治疗药品（ATMP），另外的配方和填充和填充物之前，必须进行填充和完成步骤。同种异体和自体制造方法之间的主要差异是每批中产生的治疗剂量的数量和治疗的患者的数量。因此，由于HMSC生产方面，异构疗法是更具成本效益的方法是不成熟的。此外，各种经济研究表明，USP尤其是HMSC扩展，代表了在检查整个制造过程时的主要成本司机。为了在同种异体的HMSC制造工艺中获得每批批次最多10〜（13）个细胞的高细胞数，制造商必须远离传统的平面栽培系统。在过去几年的许多报告表明，仪器化的单使用生物反应器与微载体结合使用的是这项任务的有希望的系统。尽管USP和DSP的不同程序和设备已经可用并为同种异体生产的HMSCs生产，但仍存在各种挑战。因此，提交人打算突出同种式化合物HMSC制造的当前状态，并展示了USP和DSP操作的当前主要过程和监管挑战。

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