EU/PIC都要求对于每个container 进行取样.  如果申请豁免，需参考几个consideration.  而且根据我们之前遇到的挑战，取样如何具有代表性也需要进行评估.

另外，混样检测是否具有代表性需要依据风险评估.

1-每一个包装做鉴别是EU GMP 附录8，其豁免不需做鉴别的条件做了具体的限制，包括从中间商采购的原辅料不能豁免每一保证做鉴别，对于豁免每件做鉴别，建议基于风险评估决策，另外EU GMP规定辅料供应商应进行GMP适用性风险评估（ Excipients and excipient suppliers should be controlled appropriately based on the results of a formalised quality risk assessment in accordance with the European Commission ‘Guidelines on the formalised risk assessment for ascertaining the appropriate Good Manufacturing Practice for excipients of medicinal products for human use.应当基于按照欧洲委员会指南“确认人用药品辅料符合相应GMP要求的正式风险评估指南”进行的正式质量风险评估的结果，对辅料和辅料供应商进行适当控制。），该规定与是否能豁免每件鉴别息息相关，若评估不充分，则会被挑战豁免合理性。

附录8 原辅包装材料的取样

Starting materials

2. The identity of a complete batch of starting materials can normally only be ensured if individual samples are taken from all the containers and an identity test performed on each sample. It is permissible to sample only a proportion of the containers where a validated procedure has been established to ensure that no single container of starting material has been incorrectly labelled.

3. This validation should take account of at least the following aspects:

• the nature and status of the manufacturer and of the supplier and their understanding of the GMP requirements of the Pharmaceutical industry;
• the Quality Assurance system of the manufacturer of the starting material;
• the manufacturing conditions under which the starting material is produced and controlled;
• the nature of the starting material and the medicinal products in which it will be used.

Under such a system, it is possible that a validated procedure exempting identity testing of each incoming container of starting material could be accepted for:

• starting materials coming from a single product manufacturer or plant;
• starting materials coming directly from a manufacturer or in the manufacturer's sealed container where there is a history of reliability and regular audits of the manufacturer's Quality Assurance system are conducted by the purchaser (the manufacturer of the medicinal product) or by an officially accredited body.

It is improbable that a procedure could be satisfactorily validated for:

• starting materials supplied by intermediaries such as brokers where the source of manufacture is unknown or not audited;
• starting materials for use in parenteral products.
• 2．只有对每一个包装容器中的样品都进行鉴别试验后，才能确认整批物料的鉴别正确无误。只有通过验证建立了规程，能确保原辅材料的每一个包装的贴签不可能出现差错时，才允许对批的一部分容器进行取样。

• 3．验证应当至少考虑到以下几个方面：
  —生产商和供应商的身份和种类，以及他们对制药企业GMP要求的了解程度；
  —原辅材料生产商的质量保证体系；
  —原辅材料的生产和质量控制条件；
  —原辅材料的性质以及采用这些原辅材料的药品的性质。

  在以下条件下，才可能采用经验证而不要求对批的每一个容器抽样进行鉴别的规程：
  —当原辅材料只来自某一个生产商或车间时；
  —购货单位对供货商的质量保证系统定期进行审计，或由官方认可的第三方进行审计，供货商有可靠的历史，当原辅料直接来自这些生产商，或由他们以密封容器供货。

  下述情况，不考虑采用“经验证的规程”：
  —原辅材料是由中间商如经纪人供货，生产源头不详或未经审计；
  —用于生产注射类药品的原辅材料。

需要注意的是，以下情况必须进行逐件鉴别，尤其是第二条，是无法论述和评估的，根据多次经验，PIC/S成员国及欧盟审计是不接受论述和评估的。

It is improbable that a procedure could be satisfactorily validated for: 

 starting materials supplied by intermediaries such as brokers where the source of manufacture is unknown or not audited; 

起始原料来源于中间商（例如，代理商）供货，但生产来源不详或未经审计

 starting materials for use in parenteral products.

用作注射剂生产的起始物料。

1. 不需要，虽然在附录8里的确是写“只有对每一个包装容器中的样品都进行鉴别试验后，才能确认整批物料的鉴别正确无误。”但是在下面也有特别的“在以下条件下，才可能采用经验证而不要求对批的每一个容器抽样进行鉴别的规程”，总结就是对供应商的管理足够，认可供应商的资质，可以不用对每件做取样鉴别。当然，鉴别也不代表着一定要取样。很早就在推荐用近红外鉴别不必取样。

2. 混样并没有明确的禁令说不可以，但是其中风险就是混样后可能会掩盖某一份不合格品。在FDA - 药品cGMP问答有你的这个问题的回答：“某检验项目能够灵敏可以发现单个不合格的容器存在，那么将各容器内获得的等份样混合后，所得混合样做纯度分析是可以接受的。”