Thurman-Newell Jamie A, Petzing Jon N, Williams David J
Healthcare Engineering Group, Centre for Biological Engineering, Holywell Park, Loughborough University, Loughborough, UK.
Healthcare Engineering Group, Centre for Biological Engineering, Holywell Park, Loughborough University, Loughborough, UK.
Cytotherapy. 2016 May;18(5):686-94. doi: 10.1016/j.jcyt.2016.01.011.
Currently cellular therapies, such as hematopoietic stem cell transplantation (HSCT), are produced at a small scale on a case-by-case basis, usually in a clinical or near-clinical setting. Meeting the demand for future cellular therapies will require a robust and scalable manufacturing process that is either designed around or controls the variation associated with biological starting materials. Understanding variation requires both a measure of the allowable variation (that does not negatively affect patient outcome) and the achievable variation (with current technology). The prevalence of HSCT makes it an ideal case study to prepare for more complex biological manufacturing with more challenging regulatory classifications. A systematic meta-analysis of the medical literature surrounding HSCT has been completed of which the key outcomes are the following: (i) the range of transplanted CD34+ cells/kg can be up to six orders of magnitude around the median for allogeneic procedures and four orders of magnitude for autologous procedures, (ii) there is no improvement in variation encountered over a period of 30 years and (iii) as study size increases, the amount of variation encountered also increases. A more detailed, stratified source from a controlled single-site clinical center is required to further define a control strategy for the manufacture of biologics.
目前，细胞疗法，如造血干细胞移植（HSCT），通常是在临床或接近临床的环境中，根据具体情况小规模生产。满足未来细胞疗法的需求将需要一个强大且可扩展的制造工艺，该工艺要么围绕生物起始材料相关的变异进行设计，要么对其进行控制。了解变异既需要衡量允许的变异（不会对患者预后产生负面影响），也需要了解可实现的变异（利用当前技术）。HSCT的普遍性使其成为一个理想的案例研究，可为更复杂的生物制造以及更具挑战性的监管分类做好准备。围绕HSCT的医学文献已完成一项系统的荟萃分析，其主要结果如下：（i）对于同种异体程序，每千克移植的CD34+细胞数量范围在中位数周围可达六个数量级，对于自体程序则为四个数量级；（ii）在30年的时间里，变异情况没有改善；（iii）随着研究规模的增加，所遇到的变异量也会增加。需要来自受控单中心临床中心的更详细、分层的来源，以进一步确定生物制品制造的控制策略。
