Establishing how to effectively manufacture cell therapies is an industry-level problem. Decentralised manufacturing is of increasing importance, and its challenges are recognised by healthcare regulators with deviations and comparability issues receiving specific attention from them. This paper is the first to report the deviations and other risks encountered when implementing the expansion of human pluripotent stem cells (hPSCs) in an automated three international site-decentralised manufacturing setting. An experimental demonstrator project expanded a human embryonal carcinoma cell line (2102Ep) at three development sites in France, Germany and the UK using the CompacT SelecT (Sartorius Stedim, Royston, UK) automated cell culture platform. Anticipated variations between sites spanned material input, features of the process itself and production system details including different quality management systems and personnel. Where possible, these were pre-addressed by implementing strategies including standardisation, cell bank mycoplasma testing and specific engineering and process improvements. However, despite such measures, unexpected deviations occurred between sites including software incompatibility and machine/process errors together with uncharacteristic contaminations. Many only became apparent during process proving or during the process run. Further, parameters including growth rate and viability discrepancies could only be determined post-run, preventing 'live' corrective measures. The work confirms the critical nature of approaches usually taken in Good Manufacturing Practice (GMP) manufacturing settings and especially emphasises the requirement for monitoring steps to be included within the production system. Real-time process monitoring coupled with carefully structured quality systems is essential for multiple site working including clarity of decision-making roles. Additionally, an over-reliance upon post-process visual microscopic comparisons has major limitations; it is difficult for non-experts to detect deleterious culture changes and such detection is slow.

中文翻译：

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多能干细胞产品的分布式自动化制造。

确定如何有效地制造细胞疗法是一个行业层面的问题。分散式制造变得越来越重要，其挑战得到了医疗监管机构的认可，偏差和可比性问题受到了他们的特别关注。本文首次报告了在自动化的三个国际站点分散制造环境中实施人类多能干细胞 (hPSC) 扩增时遇到的偏差和其他风险。一个实验性示范项目使用 CompacT SelecT (Sartorius Stedim, Royston, UK) 自动化细胞培养平台在法国、德国和英国的三个开发地点扩展了人类胚胎癌细胞系 (2102Ep)。站点之间的预期变化跨越材料输入，过程本身的特征和生产系统的细节，包括不同的质量管理系统和人员。在可能的情况下，通过实施包括标准化、细胞库支原体检测以及特定工程和工艺改进在内的策略来预先解决这些问题。然而，尽管采取了这些措施，但站点之间还是出现了意想不到的偏差，包括软件不兼容和机器/过程错误以及异常污染。许多仅在过程证明或过程运行期间变得明显。此外，包括生长速率和生存力差异在内的参数只能在运行后确定，从而阻止“实时”纠正措施。这项工作证实了在良好生产规范 (GMP) 制造环境中通常采用的方法的关键性质，并特别强调了将监控步骤包含在生产系统中的要求。实时过程监控以及精心构建的质量系统对于多站点工作（包括明确的决策角色）至关重要。此外，过度依赖后处理视觉显微镜比较有很大的局限性。非专家很难检测到有害的文化变化，而且这种检测速度很慢。过度依赖后处理视觉显微镜比较有很大的局限性；非专家很难检测到有害的文化变化，而且这种检测速度很慢。过度依赖后处理视觉显微镜比较有很大的局限性；非专家很难检测到有害的文化变化，而且这种检测速度很慢。