EMA更新其网站问答

julia朱玉姣

http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/q_and_a/q_and_a_detail_000071.jsp&mid=WC0b01ac058002c2af

Q. What is the basis for the calculation of thresholds to set limits for impurities in the finished product specification? H March 2015

制剂标准中计算杂质阈值设定限度的基础是什么？

Mono-component products 单方制剂

For medicinal products containing only one active substance, the calculated thresholds should be based on the highest maximum daily dose of the respective active substance in authorised medicinal products and the limits in the specification set accordingly. The threshold for impurities should be the same for all strengths. The applicant is responsible to consider the maximum daily dose (MDD) that is approved for a given active substance in those Member States where the medicinal product is to be licensed.

对于只含有一种活性物质的制剂，应根据批准的上市制剂中所含的对应的活性物质的最大日剂量计算阈值，然后相应地设定质量标准中的限度。所有剂量中杂质阈值应相同。申报人有责任考虑颁发给其药品上市许可的成员国里指定活性物质所批准的最大日剂量（MDD）。

Fixed Dose Combination products (FDC) 固定配方复方制剂（FDC）

For medicinal products containing more than one active substance, the calculated threshold should be based on the maximum daily dose (MDD) described in the SPC of the FDC(s) under evaluation. The FDC(s) are indeed developed in a specific ratio of active substances composing the medicinal product and therefore considering the MDD of an active substance in mono-component medicinal products would not be appropriate.

对于含有多于一种活性物质的制剂，阈值计算应根据所评估的FDC的SPC中描述的最大日剂量（MDD）。由于FDC的开发中所用的活性物质在制剂中以特定比例配比，因此考虑单方制剂中的活性物质MDD是不恰当的。

If an unidentified impurity cannot be assigned to one of the active substances in the FDC it has to be compared to the signals of all active substances in order to verify whether the respective ICH identification threshold is exceeded or not. If exceeded, the impurity should be identified and assigned to the signal of the respective active substance. If not exceeded, the specification limit should be set with reference to the active substance that would ensure the lowest amount/exposure to the patient.

如果发现有一种未鉴别的杂质无法将其归属于FDC中的任一种活性物质，则必须将其与所有活性物质的信号进行比较，以确认是否超出相应的ICH鉴别阈值。如果超出，则该杂质应进行鉴定，并将其信号归属于相应的活性物质。如果没有超出，则应设定相对于活性物质的质量标准限度，保证患者暴露的最低量。

http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/q_and_a/q_and_a_detail_000027.jsp&mid=WC0b01ac05800296ca

Q. Should metal detectors be used routinely in manufacturing processes for certain dosage forms e.g. tablet compression and encapsulation processes? H+V February 2015

在特定的剂型生产工艺中，例如片剂压片和胶囊填充过程，是否需要常规地使用金属探测器？

Metal could originate from raw materials as well as from equipment in manufacturing processes where metal parts could generate fragments due to the conditions of operation or damage to the equipment.

金属可能会来自原料，也可能来自生产工艺所用的设备，在这些设备中金属部件会由于操作条件或设备损坏而产生碎屑。

It is recommended that metal detection is used for processes prone to this.

建议此类工艺中使用金属探测器。

In order to avoid routine use of metal detectors the company must demonstrate that it has identified and managed the risks such that the use of metal detectors for that particular process is not needed.

如果不想常规地使用金属检测器，则公司必须证明已识别并管理不需要在特定工艺使用金属探测器所带来的风险。

Q. Is it possible to ask for a voluntary inspection of an active substance manufacturer? H+V February 2015

原料药生产商是否可以自愿申请要求官方检查？

First, the responsibility for only using active substances that have been manufactured in accordance with GMPs is placed on the holders of a manufacturing authorisation (MA). An inspection of the active substance manufacturer by an EEA authority does not liberate a MA holder from this responsibility.

首先，保证只使用在GMP状态下生产的原料药的责任是赋予上市许可持有人的。由EEA药监局对原料药进行检查不并解除MA持有人的责任。

Article 111 (1f) of [url=http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CONSLEG:2001L0083:20091005:ENDF]Directive 2001/83/EC [/url]and Article 80(1) of Directive 2001/82/EC , have provision for the competent authority of the Member State concerned to carry out inspections of starting material manufacturers at the specific request of the manufacturer. The request for the inspection should be made to the EEA competent authority where the site is located or, in case of sites located in third countries, to a competent authority where the starting material is used in the manufacture of medicinal products. If this is not the case, any EEA authority can be approached.

在指令 2001/83/EC第111（1f）条和指令 2001/82/EC第80（1）条中，有关于成员国药监在生产商申请时对起始物料生产商进行检查的条款规定。检查申请应向工厂所在地的EEA药监局提交，如果工厂在第三国，则应向使用该起始物料的制剂生产商所在地药监局提交。如果都不是，则可以向任何EEA药监局提交。

There is no guarantee that such a request will be fulfilled since competent authorities primarily use risk-based principles to plan starting material inspections. Thus, when a starting material manufacturer applies for a voluntary inspection, this does not constitute an obligation for the competent authority to trigger an inspection.

药监局不会保证针对这样的申请实施检查，因为药监局使用的是基于风险的原则来制订起始物料检查计划。因此，当一个起始物料生产商申请自愿检查时，并不形成药监局的义务来实施检查。

Q. What is the frequency for the routine re-inspection of an active substance manufacturer? H+V February 2015

原料药生产商常规再检查频次是怎样的？

Article 111 (1b) of Directive 2001/83/EC requires that Member States have a system of supervision including inspections at an appropriate frequency based on risk, at the premises of the manufacturers, importers, or distributors of active substances located on its territory.

指令2001/83/EC第111（1b）条要求成员国建立一个体系来监管包括基于风险根据适当的频次对其领土内原料药生产商、进口商或分销商进行检查，

In line with the document “Model for Risk Based Planning for Inspections of Pharmaceutical Manufacturers” available in the Compilation of Union Procedures, sterile and biological active substances are considered a relatively higher risk. Consequently, competent authorities may decide to submit these substances to a higher or a set inspection frequency.

根据欧盟符合性程序“基于风险的药品生产商检查计划模式”，无菌和生物原料药被认为是风险相对较高。因而，药监局可以决定对这些物质进行高频次或固定频次的检查。

cgc717

谢谢分享！

一沙一叶

金属检测器的要求还是比较高的  

曹小芬爱疯叮

围观学习。。。