The understanding, control, and removal of nonoligonucleotide process-related impurities (PRI) are of key importance for the manufacturing of therapeutic oligonucleotides as their presence in the final product is both a quality and safety concern. Regulatory agencies require manufacturers to demonstrate that PRI are under control or adequately purged during the manufacturing process. Purging depends on the physicochemical properties of the impurities and the unit operations of the manufacturing process but should be independent of oligonucleotide size or type. The purging power of unit operations relevant to oligonucleotide manufacturing (synthesis, cleavage and deprotection, chromatography, ultrafiltration/diafiltration) was measured using representative solvents and other small molecules typical for oligonucleotide synthesis. The results show that each unit operation has significant purging capability (synthesis >1000; cleavage and deprotection >100 (reactivity, when applicable); chromatography >1000; ultrafiltration/diafiltration >10) and that large overall purge factors can be obtained (≥1 × 10⁷). Experimentally determined purge values are aligned with theoretical purge values; thus, the use of purge arguments in oligonucleotide control strategies is a sound scientific approach. Guidance on reasonable purge values for oligonucleotide unit operations is presented. Additionally, the data demonstrate that solvents and reagents typically used in oligonucleotide synthesis are robustly cleared by the process and should not require testing in the final product.

中文翻译：

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确定用于寡核苷酸控制策略的清除因子

非寡核苷酸工艺相关杂质 (PRI) 的了解、控制和去除对于治疗性寡核苷酸的制造至关重要，因为它们在最终产品中的存在既是质量问题又是安全问题。监管机构要求制造商证明 PRI 在制造过程中受到控制或充分净化。清除取决于杂质的物理化学性质和制造过程的单元操作，但应与寡核苷酸大小或类型无关。使用代表性溶剂和其他典型的寡核苷酸合成小分子测量与寡核苷酸制造相关的单元操作（合成、切割和脱保护、色谱、超滤/渗滤）的净化能力。⁷）。实验确定的净化值与理论净化值一致；因此，在寡核苷酸控制策略中使用清除参数是一种合理的科学方法。给出了关于寡核苷酸单元操作的合理清除值的指导。此外，数据表明，寡核苷酸合成中通常使用的溶剂和试剂已被该过程彻底清除，不需要在最终产品中进行测试。