【参考文献或指南】

1、EQDM：CERTIFICATION POLICY DOCUMENT

Content of the dossier for chemical purity and microbiological quality

For semi-synthetic drug substances (where starting material is obtained from fermentation or by extraction from botanical material), the fermented or extracted starting material should be well characterised, and in addition to typical impurity discussion (as mentioned above) the possibility of fermentation specific impurities (e.g. DNA, proteins etc.) from the fermentation process to the final substance should be discussed and similarly, carry-over of herbal related impurities such as pesticides, fumigants, heavy metals, aflatoxins etc. should be discussed, and, where applicable, demonstrated absent. The EMA Q&A on Starting materials of herbal origin and the Ph.Eur monograph on Herbal Drugs (1433) should be consulted as needed.

2、EMA：CERTIFICATION POLICY DOCUMENT
Content of the dossier for chemical purity and microbiological quality

For semi-synthetic drug substance (where starting material is obtained from fermentation or by extraction from botanical material), the fermented or extracted starting material should be well characterised, and in addition to typical impurity discussion (as mentioned above) the possibility of fermentation specific impurities (e.g. DNA, proteins etc.) from the fermentation process to the final substance should be discussed and similarly, carry-over of herbal related impurities such as pesticides, fumigants, elemental impurities, aflatoxins etc. should be discussed, and, where applicable, demonstrated absent. The EMA Q&A on Starting materials of herbal origin and the Eur. monograph on Herbal Drugs (1433) should be consulted as needed.

3、EP1468 Products of fermentation

对发酵产品的研发和生产提供一般要求。

1）培养基或进气的生物负载水平应降低至一定的低水平，以保证如果发生微生物污染，不会对产品质量、纯度和安全性造成负面影响。

2）在发酵期间加入相关成分，如营养剂、前体和基质的操作应为无菌操作。

3）后处理，发酵结束后，产生的微生物被灭活或清除，后期用于降低菌种培养基产生的残留至可接受水平，保证获得品质一致的产品。

4）可以采用不同的提纯工艺，如活性炭处理，超滤，溶剂萃取。必须证明所选用的这些工艺可以最大程度降低或移除以下杂质：微生物、培养基和前体中的残留；预期之外的基质和前体转化产品。

4、M4Q The CTD-Quality

3.2.S.2.3 Control of materials
Information demonstrating that materials (including biologically sourced materials (e.g., media components, monoclonal antibodies, enzymes)) meet standards appropriate for their intended use (including the clearance or control of adventitious agents) should be provided, as appropriate. For biologically sourced materials, this can include information on the source, manufacture, and characterization. (Provide details in Appendix 3.2.A.2 for both NCE and Biotech.)

5、其他参考：

1）Guideline on setting specifications for related impurities in antibiotics

2）国家药品审评中心电子刊物：如1.微生物来源药物制备工艺研究中质量控制要素探讨(二)-发酵工艺的过程控制以及发酵来源的化学药物的工艺研究等

【建议和思考】

1、无论是半合成还是全发酵产品，大分子析残留必然是杂质讨论需要考虑的一部分。

2、是否需要纳入过程控制或者定入质量标准，则取决于具体的产品和工艺（尤其是纯化工序）。

以上，希望对你有所帮助。

申报CEP的半发酵产品，首次提交论证了工艺过程对于蛋白，DNA和RNA的去除能力，仅仅从工艺的角度进行了论述，例如纳滤操作等，官方并不接受没有实际数据的论述。

实例：我们有一个半发酵半合成的产品在申报CEP证书，缺陷问题中就提到需要研究发酵过程中的蛋白残留和DNA残留，所以在潜在杂质残留的控制策略中，需要增加这方面的分析讨论。

回答：

这个要看你的产品开发和CMC控制的策略，如果你开发的工艺中已经有有效的工艺对相应的杂质进行去除，如酸碱裂解、层析超滤等，那可以不需要检测大分子的杂质。之前公司有一个全发酵的原料，经过种子培养、发酵、提取和纯化，到后期更多的考虑的是有机溶剂的残留，希望对你有所参考！