Hu Zhilan, Hsu Wendy, Pynn Abby, Ng Domingos, Quicho Donna, Adem Yilma, Kwong Zephie, Mauger Brad, Joly John, Snedecor Bradley, Laird Michael W, Andersen Dana C, Shen Amy
Dept. of Early Stage Cell Culture, Genentech Inc., South San Francisco, CA, 94080.
Dept. of Purification Development, Genentech Inc., South San Francisco, CA, 94080.
Biotechnol Prog. 2017 Nov;33(6):1449-1455. doi: 10.1002/btpr.2467. Epub 2017 Apr 26.
In the biopharmaceutical industry, a clonally derived cell line is typically used to generate material for investigational new drug (IND)-enabling toxicology studies. The same cell line is then used to generate material for clinical studies. If a pool of clones can be used to produce material for IND-enabling toxicology studies (Pool for Tox (PFT) strategy) during the time a lead clone is being selected for clinical material production, the toxicology studies can be accelerated significantly (approximately 4 months at Genentech), leading to a potential acceleration of 4 months for the IND submission. We explored the feasibility of the PFT strategy with three antibodies-mAb1, mAb2, and mAb3-at the 2 L scale. For each antibody, two lead cell lines were identified that generated material with similar product quality to the material generated from the associated pool. For two antibody molecules, mAb1 and mAb2, the material generated by the lead cell lines from 2 L bioreactors was tested in an accelerated stability study and was shown to have stability comparable to the material generated by the associated pool. Additionally, we used this approach for two antibody molecules, mAb4 and mAb5, at Tox and GMP production. The materials from the Tox batch at 400 L scale and three GMP batches at 2000 L scale have comparable product quality attributes for both molecules. Our results demonstrate the feasibility of using a pool of clonally derived cell lines to generate material of similar product quality and stability for use in IND-enabling toxicology studies as was derived from the final production clone, which enabled significant acceleration of timelines into clinical development. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1449-1455, 2017.
在生物制药行业，通常使用克隆衍生的细胞系来生产用于支持研究性新药（IND）毒理学研究的材料。然后使用同一细胞系来生产用于临床研究的材料。如果在为临床材料生产选择主克隆的过程中，可以使用一组克隆来生产用于支持IND毒理学研究的材料（毒理学研究池（PFT）策略），则毒理学研究可以显著加速（在基因泰克大约可加速4个月），从而使IND提交时间可能提前4个月。我们在2L规模下，针对三种抗体——单克隆抗体1（mAb1）、单克隆抗体2（mAb2）和单克隆抗体3（mAb3），探索了PFT策略的可行性。对于每种抗体，鉴定出了两个主细胞系，它们产生的材料与相关细胞池产生的材料具有相似的产品质量。对于两种抗体分子mAb1和mAb2，对2L生物反应器中主细胞系产生的材料进行了加速稳定性研究，结果表明其稳定性与相关细胞池产生的材料相当。此外，我们在毒理学研究和GMP生产中，将这种方法用于两种抗体分子mAb4和mAb5。400L规模毒理学批次的材料以及2000L规模的三个GMP批次的材料，对于这两种分子都具有相当的产品质量属性。我们的结果证明了使用一组克隆衍生的细胞系来生产具有相似产品质量和稳定性的材料用于支持IND毒理学研究的可行性，这些材料与最终生产克隆产生的材料相同，这能够显著加速进入临床开发的时间表。© 2017美国化学工程师学会生物技术进展，33:1449 - 1455, 2017。
