ABSTRACT

The importance of speed to clinic for medicines that may address unmet medical needs puts pressure on product development timelines. Historically, both toxicology and first-in-human clinical materials are generated using the same clonal-derived cells to ensure safety and minimize any development risks. However, cell line development with single cell cloning is time consuming, and aggravated by the time needed to screen for a lead clone based on cell line stability and manufacturability. In order to achieve faster timelines, we have used pools of up to six clones for earlier production of drug substance for regulatory filing-enabling toxicology studies, and then the final single clone was selected for production of clinical materials. This approach was enabled by using platform processes across all stages of early development, including expression vectors, host cell lines, media, and production processes. Through comprehensive cell culture and product quality analysis, we demonstrated that the toxicology material was representative of the clinical material for all six monoclonal antibody programs evaluated. Our extensive development experience further confirmed that using a pool of clones for toxicology material generation is a reliable approach to shorten the early development timeline.

摘要

对于可能解决未满足的医疗需求的药品而言，提高临床速度的重要性给产品开发时间表带来了压力。从历史上看，毒理学和人类首创的临床材料都是使用相同的克隆来源的细胞生成的，以确保安全性并最大程度地降低开发风险。然而，利用单细胞克隆进行细胞系发育是耗时的，并且由于基于细胞系稳定性和可制造性筛选前导克隆所需要的时间而加剧。为了实现更快的时间表，我们使用了多达六个克隆的库，用于更早地生产原料药，以进行监管文件启用毒理学研究，然后选择最终的单个克隆来生产临床材料。通过在早期开发的所有阶段使用平台流程来启用此方法，包括表达载体，宿主细胞系，培养基和生产过程。通过全面的细胞培养和产品质量分析，我们证明了所评估的所有六个单克隆抗体程序的毒理学材料都是临床材料的代表。我们丰富的开发经验进一步证实，使用克隆库进行毒理学物质生成是缩短早期开发时间的可靠方法。