欧洲QP协会问答： 放行决定

欧洲QP协会问答： 放行决定  

2014-11-10 09:28:08|  分类： 欧盟知识

Release Decisions 放行决定

Q: An API is contaminated with very small amounts of glass (<0.02%). The API is micronized and then pressed to tablets (oral). Giving the fact that glass has a very low toxicology; would you release the batch of the final product? 假如一批原料药被非常少量的玻璃（<0.02%）污染了，而该原料药经过微粉，又压成了片剂（口服）。如果该玻璃毒性很低，你是否能放行该批制剂？

A: No. There is an excellent quote in the European Pharmacopoeia, Chapter 1. “General Notices, Tests and Assays”: “... It is not presumed, for example, that an impurity that is not detectable by means of the prescribed tests is tolerated if common sense and good pharmaceutical practice require that it be absent.” Good Manufacturing Practice and Good Pharmaceutical Practice require glass particles to be absent in APIs that will be used to manufacture oral solid preparations without any filtration step that would remove the particles! If during its production the API has undergone a last purification step by re-crystallisation after filtration using charcoal or a filter aid, this step should be repeated with the contaminated API (reprocessing) to remove the contaminant.

答：不能。在欧洲药典第1章“凡例 检测和含量”里有一个很好的说法可以引用“……不能假定，例如，一种杂质采用所描述的方法不能检出，

GMP和GPP要求用于生产口服固体制剂的原料药中不能有玻璃颗粒，不可以采用任何过滤的方法来去除这些颗粒物！如果在生产过程中，原料药在使用活性碳或助滤剂进行过滤后进行重结晶的方式进行精制，则应重复该步骤来去除被污染的原料药（返工）中的污染物。

Q: A sterility test failed most likely because of a contamination during testing: is a re-test justified? 无菌测试不合格，非常可能是因为在测试中有被污染，那么是否可以进行复测？

A: A retest of a positive sterility test must be very carefully justified based on a root cause investigation giving evidence that there has been a contamination in the laboratory during preparation or testing. It is not appropriate and acceptable to re-test based on mere suspicion. Reasons to invalidate a positive result would be e.g.

对无菌阳性进行测试要非常慎重，复测应基于对根本原因的调查中发现了证据，证明化验室在准备或测试期间发生了污染。仅仅是因为怀疑而进行复测是不恰当的，不能被接受。宣告一个阳性结果无效的理由可以是，例如

• Microbiological monitoring of the sterility testing facility shows evidence for a failure like detection of the contaminant(s) in the testing environment. This has to be proven by genetic identity of both isolates!
• 无菌测试间的微生物监控结果显示不合格，例如在检测环境测出污染。必须要由两个隔离物的基因鉴别才可以证明。
• Microbial growth is found in the negative controls
• 在阴性控制中发现微生物滋生
• After identifying the microorganisms isolated from the test, the growth of this species can be clearly linked to failures with respect to the material and/or the technique used when conducting the sterility test procedure - e.g. contaminated media or non sterile sterility testing units
• 在鉴别了测试中的微生物分离物后，该样本的生产可以清楚地与无菌测试中所用的物料和/或技术缺陷相连----例如，被培养基或无菌测试单元污染
  

Q: A product (sterile eye drops) meets all specifications. However during production some microbiological monitoring results were not OK. Can I certify the batch? 一种产品（无菌眼滴剂）符合所有质量标准，但是在生产期间，微生物监控结果不合格。我是否可以放行该批次？

A: Microbiological monitoring data are not describing the microbiological status of the batch itself. Monitoring data are considered to give information about the controlled environment. A level excursion in micro monitoring may be an indicator that there are deviations from the usual process, but they do not automatically indicate a microbiological problem of the batch. Following a positive outcome of a risk assessment of the non conforming monitoring results (type of contamination, level of contamination, place of the monitoring, other monitoring data, trending) it might well be possible to certify the batch.

答：微生物监测数据并不表示该批产品的微生物状态。监测数据并不能提供控制环境的信息。微生物监测在一定程度上的偏离可能表示与常规工艺有偏差，但并不一定就表示该批产品有微生物问题。在对不符合性监控结果进行风险评估的阳性结果出来后（污染类型、污染水平、监控地点、其它监控数据、趋势分析），还是非常有可能可以放行该批次产品的。

Q: What should happen if OOS investigations are inconclusive? 如果OOS调查没有结论，要怎么办？

A: The certifying Qualified Person should fully consider all of the information prior to making any decisions as to the final disposition of the batch. Any decision to release a batch where OOS results have not been invalidated should come only after a full investigation has shown that the OOS result does not reflect the quality of the batch. In making such a decision quality assurance and the Qualified Person should always err on the side of caution. (source: MHRA Q&A)

答：QP应在做出任何决定前，全面考虑所有的信息，以对批产品做出最终的处理决定。所有OOS结果的批放行决定并不反映批产品的质量。在做出放行决定时，QA和QP都要保持谨慎的态度（来源：MHRA 问答）
来源：http://zhuyujiao1972.blog.163.com/blog/static/98694727201410109288259/

好资料，感谢分享

微生物分布没有正态分布特征，因此，出现阳性结果，必须谨慎评估放行与否。