求助：清洁验证限度的计算

JL052

冷血无情 发表于 2017-9-21 09:47
然而并木有啊 我们说了 借鉴的先进企业的数据 但是原件 他们也木有 原件（含数据支持）都在“总部”

看来检查官的接受标准 并没有文件中的那么高~~
那个附件“毒理学专家的评估报告”应该是 以后的一个方向

sunshineqa

beiwei5du 发表于 2017-9-21 09:46
其实这个法规最主要是针对于高活性的共线风险评估，首先你需要依据EMA共线的指南Q&A的那个标准确定是否是hi ...

检查现场时是这样解释的，根据LD50，产品活性成分是低毒的，而且活性成分所占制剂的百分比很小，但检查员最后还是建议再看看EMA法规

beiwei5du

Q4. Can calculation of HBELs be based on clinical data only (e.g. to establish the HBEL on 1/1000th of the minimum therapeutic dose)?
A: Many existing commercial products and new products for which clinical safety profiles are wellestablished and that do not belong to the highly hazardous category (see response to Q2) have a favourable therapeutic index (also referred to as the therapeutic window or safety window). This means that unwanted or adverse health effects (that may have been identified as toxic effects in animal studies at high doses) may occur - if at all - at dose levels orders of magnitude above the therapeutic dose range and the pharmacological activity would therefore be the most sensitive/critical effect. In this situation, therapeutic dose information could be used as the ‘Point of Departure’ for calculation of an HBEL (e.g. the PDE). Under these circumstances, HBEL based on the 1/1000th minimum therapeutic dose approach would be considered as sufficiently conservative and could be utilised for risk assessment and cleaning purposes.

22.03.2017

MHRA's Interpretation of Cross Contamination & PDEs

The British inspectorate MHRA has recently published an interpretation that goes into detail on the use of health based exposure limits and explains the cases where EMA's new concept can be applied. One essential element of that concept is EMA's Q&A Paper describing when a product should be classified as highly active.

After the revisions of Chapters 3 and 5 of the EU GMP Guide in 2015, more attention has been given to the topic cross contamination.  At the same time, a guideline of the EMA was published introducing the concept of PDE values. Those health based exposure limits should be used to assess whether a product can be produced in a dedicated or in a multipurpose facitility. The background for that was the request of the pharmaceutical industry to be able to decide itself on a risk-based approach whether a product can be produced in a multipurpose facitility, or not. Previously, there was a rather inconclusive list requiring a dedicated facility e.g. for special products, special cytototix products or hormones. Because the 1/1,000 dose criterion used so far isn't really scientific and therefore not very suitable for a risk-based approach, the EMA introduced the PDE concept. This has led to some discussion as the calculation without toxicological/pharmocaological data and knowledge is not so clear-cut.

Now, the MHRA states that the full use of  EMA's guide for the calculation of the PDE values is only necessary for so-called "highly hazardous" products. To answer the question whether a product is highly hazardous or not, one can refer to the new Q&A document of the EMA. Nevertheless, one should keep in mind that the assessment of hazard by means of EMA's paper, scientific data are also required which would also enable the calculation of the PDE limits.

However, Health Based Exposure Limits (HBELs) should be determined for all products. If a product is classified as not "highly hazardous", the 1/1,000 dose criterion can still be used. Now the question remains why the MHRA has published its interpretation before the final adoption of EMA's Q&A  document. Generally, the cleaning limits calculated by means of the 1/1,000 dose criterion are more conservative than when using the PDE value as a basis.

EMA's Q&A document is currently at the draft stage. Comments can be submitted until the end of April to the EMA.

Faclilitating the understanding of the procedure of the development of the new values which should be used for the cleaning validation, for example, is the goal of an industrial guidance document - provided at the ECA Training Course Cross Contamination from 5-6 April in Heidelberg. There you will also train the calculation of ADE/PDE values in a workshop.

beiwei5du

sunshineqa 发表于 2017-9-21 09:55
检查现场时是这样解释的，根据LD50，产品活性成分是低毒的，而且活性成分所占制剂的百分比很小，但检查员 ...

你们使用LD50来进行high hazardous药品确认解释就是有问题的。LD50并不能用来基于计算HBEL。
Q2. What products/active substances are considered to be highly hazardous?
A: Highly hazardous products are those that can cause serious adverse effects at low doses and that therefore would benefit from a full toxicological assessment in order to derive a safe HBEL. Highly hazardous products are identified based on their inherent toxicological and pharmacological characteristics and include the groups below (this list is not an exhaustive list and if evidence is available indicating that the product may cause adverse effects at low doses by other mechanisms it should be considered as highly hazardous). Manufacturers should consider, via a safety assessment against the guidance below, if products/active substances should be considered highly hazardous. Evidence indicating a product or active substance falls within any of the categories below should result in a product being considered highly hazardous. If in doubt, manufacturers should consider the product potentially highly hazardous and apply the EMA guide (EMA/CHMP/CVMP/SWP/169430/2012) in full to derive a safe HBEL. 1. Genotoxic (specifically mutagenic) compounds that are known to be, or highly likely to be, carcinogenic to humans. Compounds of this group are easily identifiable, since genotoxicity would be related to the pharmacology, e.g. as DNA alkylating cytostatics, and their use is usually restricted to oncology indications with respective warning statements in the Summary of Product Characteristics. 2. Compounds that can produce reproductive and/or developmental effects at low dosages, for example where evidence exists of such effects being caused by a clinical dose of <10 mg/day (veterinary dose equivalent 0.2 mg/kg/day) or dosages in animal studies of ≤1 mg/kg/day. 3. Compounds that can produce serious target organ toxicity or other significant adverse effects at low doses, for example where evidence exists of such effects being caused by a clinical dose of <10 mg/day (veterinary dose equivalent 0.2 mg/kg/day) or dosages in animal studies of ≤1 mg/kg/day. 4. Compounds with a high pharmacological potency i.e. recommended daily dose of <1 mg (veterinary dose equivalent 0.02 mg/kg). 5. Compounds with a high sensitising potential.

sunshineqa

beiwei5du 发表于 2017-9-21 10:01
Q4. Can calculation of HBELs be based on clinical data only (e.g. to establish the HBEL on 1/1000th  ...

谢谢，我再学习一下

beiwei5du

sunshineqa 发表于 2017-9-21 10:11
谢谢，我再学习一下

这个EMA Q&A还是在draft阶段，可以关注其是否后期会有修订

sunshineqa

beiwei5du 发表于 2017-9-21 10:15
这个EMA Q&A还是在draft阶段，可以关注其是否后期会有修订

嗯呐

冷血无情

JL052 发表于 2017-9-21 09:51
看来检查官的接受标准 并没有文件中的那么高~~
那个附件“毒理学专家的评估报告”应该是 以后的一个方向

是的 毕竟 欧盟也不全是全球十强
或许是趋势 但不能一口噎死

椒陵小小兵

北重楼 发表于 2017-9-21 08:29

能把这份详细额PPT发给我么，学习下，谢谢

八月莫莫

北重楼 发表于 2017-9-21 08:29

关键是各因子的取值根据，这个是难点。