Process-related impurities (PRIs) derived from manufacturing process should be minimized in final drug product. ICH Q3A provides a regulatory road map for PRIs but excludes biologic drugs like monoclonal antibodies (mAbs) that contain biological PRIs (e.g. host cell proteins and DNA) and low molecular weight (LMW) PRIs (e.g., fermentation media components and downstream chemical reagents). Risks from the former PRIs are typically addressed by routine tests to meet regulatory expectations, while a similar routine-testing strategy is unrealistic and unnecessary for LMW PRIs, and thus a risk-assessment-guided testing strategy is often utilized. In this report, we discuss a safety risk management strategy including categorization, risk assessment, testing strategy, and its integrations with other CMC development activities, as well as downstream clearance potentials. The clearance data from 28 mAbs successfully addressed safety concerns but did not fully reveal the process clearance potentials. Therefore, we carried out studies with 13 commonly seen LMW PRIs in a typical downstream process for mAbs. Generally, Protein A chromatography and cation exchange chromatography operating in bind-and-elute mode showed excellent clearances with greater than 1,000- and 100-fold clearance, respectively. The diafiltration step had better clearance (greater than 100-fold) for the positively and neutrally charged LMW PRIs than for the negatively charged or hydrophobic PRIs. We propose that a typical mAb downstream process provides an overall clearance of 5,000-fold. Additionally, the determined sieving coefficients will facilitate diafiltration process development. This report helps establish effective safety risk management and downstream process design with robust clearance for LMW PRIs.

中文翻译：

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单克隆抗体治疗中低分子量工艺相关杂质的安全风险管理：利用清除潜力的分类、风险评估、测试策略和工艺开发

来自生产过程的过程相关杂质 (PRI) 应在最终药物产品中降至最低。ICH Q3A 提供了 PRI 的监管路线图，但不包括含有生物 PRI（例如宿主细胞蛋白和 DNA）和低分子量 (LMW) PRI（例如发酵培养基成分和下游化学试剂）的单克隆抗体 (mAb) 等生物药物. 前 PRI 的风险通常通过例行测试来解决，以满足监管期望，而类似的例行测试策略对于 LMW PRI 来说是不现实的和不必要的，因此经常使用风险评估指导的测试策略。在本报告中，我们讨论了安全风险管理策略，包括分类、风险评估、测试策略及其与其他 CMC 开发活动的集成，以及下游的清除潜力。来自 28 个 mAb 的清除数据成功解决了安全问题，但并未完全揭示过程清除潜力。因此，我们在 mAb 的典型下游工艺中对 13 种常见的 LMW PRI 进行了研究。通常，以结合和洗脱模式操作的蛋白 A 色谱和阳离子交换色谱显示出优异的清除率，分别大于 1,000 倍和 100 倍。渗滤步骤对带正电荷和中性电荷的 LMW PRI 的清除率比带负电荷或疏水 PRI 的清除率更高（大于 100 倍）。我们建议典型的 mAb 下游工艺可提供 5,000 倍的总体清除率。此外，确定的筛分系数将有助于渗滤工艺的开发。