#意见征集#

8月15日,欧洲药品管理局(EMA)发布《Guideline on quality of herbal medicinal products/traditional herbal medicinal products》(草药产品/传统草药产品质量指南)草案,用于征求公众意见。

自2006年发布第一版征求意见稿,2006年10月1日正式启用,直至2011年发布第二版定稿。

此次所发文为第三版草案。涵盖人类和兽医用草药产品的一般质量方面,包括供人类使用的传统草药产品。它描述了草药产品的特殊问题以及含有化学成分确定的活性物质的药品之间的差异。

考虑到新修订的指南,问题和答案以及欧洲药典修订的一般专著“草药提取物”以及多年来应用该指南所获得的经验。通过改进措辞,结构和参考概述文件EMA / HMPC / 217631/2015中概述的最新相关准则,进一步澄清了质量数据要求。

Guideline on quality of herbal medicinal products/traditional herbal medicinal products

草药产品/传统草药产品质量指南

Table of contents 目录

5. Deion of the manufacturing process

5. 制造工艺说明

5.1. Active substance

5.1.有效成分

5.2. Herbal medicinal product

5.2.草药产品

6. Control of starting materials for the manufacture of the herbal medicinal product/traditional herbal medicinal product

6. 用于制造草药产品/传统草药产品的起始材料的控制

6.1. Control of herbal substances and of herbal preparations

6.1. 草药物质和草药制剂的控制

6.1.1. Control of herbal substances

6.1.1. 草药物质的控制

6.1.2. Control of herbal preparations

6.1.2.草药制剂的控制

6.2. Control of vitamins and minerals (if applicable)

6.2. 维生素和矿物质的控制(如适用)

6.3. Control of excipients

6.3. 辅料的控制

7. Control tests carried out at an intermediate stage of the manufacturing process of the herbal medicinal product

7. 在草药产品的制造过程的中间阶段进行对照试验

8. Control tests on the herbal medicinal product

8. 草药产品的对照试验

9. Stability tests

9.稳定性测试

9.1. General principles

9.1.总则

9.2. Stability of herbal substances/herbal preparations

9.2.草药/草药制剂的稳定性

9.3. Stability of herbal medicinal products

9.3. 草药产品的稳定性

Definitions

定义

References

参考

接上期内容: EMA发布 | 草药产品/传统草药产品质量指南

5

Deion of the manufacturing process 制造工艺说明

5.1. Active substance 有效成分

Appropriate information should be provided to adequately describe the manufacturing process of the active substance (herbal substance(s) and/or herbal preparation(s)). This should include details of the process together with the controls exercised and suitable validation data should be presented. The maximum holding time and storage conditions of bulk products should be stated and supported by appropriate validation data.

应提供适当的资料,以充分描述活性物质(草药物质和/或草药制剂)的制造过程。这应该包括流程的详细信息以及所执行的控制,并且应该提供适当的验证数据。散装产品的最大保存时间和存储条件应由适当的验证数据加以说明和支持。

5.2. Herbal medicinal product 草药产品

The manufacturing process, within the meaning of this section, is the preparation of the HMP from herbal substance(s) and/or herbal preparation(s). In the case of THMPs, the manufacturing process, within the meaning of this section, is the preparation of the HMP from herbal substance(s) and/or herbal preparations and may include the addition of vitamins and/or minerals.

应提供适当的信息以充分描述本节所指的生产过程,即从草药物质和/或草药制剂中制备HMP的过程。在THMPs的情况下,本节所指的制造过程是由草药物质和/或草药制剂制备HMP,可能包括添加维生素和/或矿物质。

The deion should include details of the process together with the controls exercised. The maximum holding time and storage conditions of bulk products should be stated and supported by appropriate validation data. This section should be in accordance with the ‘Guideline on manufacture of the finished dosage form’ (EMA/CHMP/QWP/245074/2015 and EMEA/CVMP/126/95).

描述应该包括流程的详细信息以及所执行的控制。散装产品的最大保存时间和存储条件应由适当的验证数据加以说明和支持。本节应符合《成品剂型制造指南》(EMA/CHMP/QWP/245074/2015和EMEA/CVMP/126/95)。

Information on development pharmaceutics and process validation should also be provided in accordance with the ‘Note for guidance on development pharmaceutics’ (CPMP/QWP/155/96), the ‘ICH Guideline Q8 (R2) on pharmaceutical development’ (EMA/CHMP/ICH/167068/2004), the ‘Note for guidance: development pharmaceutics for veterinary medicinal products’ (EMEA/CVMP/315/98) and ‘Guideline on process validation for finished products - information and data to be provided in regulatory submissions’ (EMA/CHMP/CVMP/QWP/BWP/70278/2012 as revised).

开发制剂和工艺验证的信息也应按照《开发制剂指南说明》(CPMP/QWP/155/96)、《药物开发ICH指南Q8 (R2)》(EMA/CHMP/ICH/167068/2004)、《指南说明:兽药制剂开发》(EMEA/CVMP/315/98)和《成品工艺验证指南-监管意见书中提供的信息和数据》(EMA/CHMP/CVMP/QWP/BWP/70278/2012修订版)。

6

Control of starting materials for the manufacture of the herbal medicinal product/traditional herbal medicinal product

用于制造草药产品/传统草药产品的起始材料的控制

6.1. Control of herbal substances and of herbal preparations 草药物质和草药制剂的控制

This section should be in accordance with the ‘Guideline on specifications: Test procedures and acceptance criteria for herbal substances, herbal preparations and herbal medicinal products/traditional herbal medicinal products’ (EMA/CPMP/QWP/2820/00 and EMA/CVMP/815/00 as revised).

本节应按照《规范指南:草药物质、草药制剂和草药产品/传统草药产品的测试程序和验收标准》(EMA/CPMP/QWP/2820/00和EMA/CVMP/815/00修订版)。

6.1.1. Control of herbal substances 草药物质的控制

A comprehensive specification for each herbal substance must be submitted.

必须提交一份关于每一种草药物质的全面规范。

In the case of fatty or essential oils used as active substances of HMPs, a specification for the herbal substance is required unless justified (for details see: ‘Reflection paper on quality of essential oils as active substances in herbal medicinal products/traditional herbal medicinal products’ (EMA/HMPC/84789/2013). If fresh material is used and/or the oil production is linked to the collecting or harvesting processes, it is often difficult to establish a full analytical characterisation of the herbal substance. At least the identity of the herbal substance should be guaranteed, but other tests can be transferred to the essential oil (with reference to the Ph. Eur. monograph ‘Herbal Drugs’).

在脂肪或精油用作HMP活性物质的的情况下,除非有正当理由,否则需要草药物质的规格(详情见:'关于精油质量作为草药产品/传统草药产品中活性物质的解析 '(EMA / HMPC / 84789/2013)。如果使用了新鲜的材料,并且和/或油类产品收集或收获过程有关,通常很难建立草药物质的全面分析特征。至少草药物质的身份应该得到保证,但是其他的测试可以转移到精油(参考Ph. Eur专著“草药”)。

For each herbal substance, the binomial scientific name of the plant (genus, species, variety and author), chemotype (where applicable) and plant part have to be stated (Annex I of Directives 2001/83/EC or 2001/82/EC).

对于每一种草物质,必须说明该植物(属、种、品种和作者)、化学类型(如适用)和植物部分的二项科学名称(指令2001/83/EC或2001/82/EC附件一)。

Detailed information on the site of cultivation/collection, the time of harvesting and stage of growth, treatment during growth with pesticides etc., and drying and storage conditions should be included. It should be confirmed that an adequate quality assurance system for the collection and/or cultivation, harvest and primary processing according to the ‘Guideline on good agricultural and collection practice for starting materials of herbal origin’ (GACP) (EMEA/HMPC/246816/05) is verified to be in place. A written GACP declaration for the herbal substance should be provided by the manufacturer of the active substance or the HMP, as appropriate.

应包括养植/采集地点、收获时间和生长阶段、使用农药生长过程中的处理等详细信息,以及干燥和储存条件。应确认,根据“良好的农业和植物源性原料采集实践指南”(GACP) (EMEA/HMPC/246816/05),为采集和/或栽培、收获和初级加工建立了足够的质量保证体系。草药物质的GACP书面声明应由活性物质的生产商或HMP(视情况而定)提供。

If a monograph for a herbal substance exists in the European Pharmacopoeia (Ph.Eur.) or another Pharmacopoeia referred to in Annex I of Directives 2001/83/EC or 2001/82/EC, the herbal substance must be in accordance with this monograph.

如果欧洲药典(Ph.Eur.)或指令2001/83/EC或2001/82/EC附件一所述的另一药典中存在草药物质专著,该草药物质必须符合本专著。

If no monograph for the herbal substance is given in a Pharmacopoeia referred to in Annex I of Directives 2001/83/EC or 2001/82/EC, a comprehensive specification for the herbal substance must be developed which should be set out in the same way as the monographs on herbal drugs in the Ph. Eur. The comprehensive specification should be established on the basis of recent scientific data and in general give particulars of the characteristics, identification tests, assay and purity tests.

如果没有在指令2001/83 / EC或2001/82 / EC附件1中提到的药典中给出草药物质的专论,则必须制定草药物质的综合规范,该规范应以相同的方式列出。作为Ph.Eur的草药的专著。应在最近的科学数据的基础上建立综合规范,并总体上给出特征,鉴定试验,化验和纯度测试的细节。

Chromatographic fingerprinting should be used based on appropriate chromatographic methods. With regard to assay, the content of constituent(s) with known therapeutic activity or where constituents with known therapeutic activity are not known, marker substances, are required. The choice of markers should be justified (see EMA ‘Reflection paper on markers used for quantitative and qualitative analysis of herbal medicinal products and traditional herbal medicinal products’ (EMA/HMPC/253629/2007)). In exceptional cases it may be acceptable to replace the assay by other tests (e.g. bitterness value, swelling index), based on appropriate limits.

应根据合适的色谱方法使用色谱指纹图谱。对于分析,需要已知治疗活性的成分或不知道已知治疗活性的成分的标记物质的含量。标记的选择应该是合理的“见中药材和中草药产品定量定性分析标记的”(EMA/HMPC/253629/2007))。在特殊情况下,可以根据适当的限度,用其他测试(如苦味值、膨胀系数)代替化验。

As a general rule, herbal substances must be tested, unless otherwise justified, for microbiological quality, mycotoxins (aflatoxins, ochratoxin A), residues of pesticides and fumigation agents, heavy metals and likely contaminants (including heavy metals not mentioned in the monograph ’Herbal drugs’ of the Ph. Eur. and contaminants present in the specific environment), foreign matter and adulterants, etc. If details on the collection site are limited, the potential for residues of pesticides and other contaminants should be fully addressed and where necessary appropriate screening techniques applied. The potential for pyrrolizidine alkaloid (PA) contamination, due, for example, to co- harvested/collected PA-containing plants, should be fully addressed. The need to control other potentially toxic contaminants from extraneous sources or specific conditions of processing (e.g. polycyclic aromatic hydrocarbons (PAHs) contamination) should also be considered. Unless otherwise fully justified, suitable validated methods should be used to control potential contaminants and the acceptance criteria should be justified. Radioactive contamination should be tested for if there are reasons for concern

作为一般规则,除非另有说明,否则必须测试草药物质的微生物水平,霉菌毒素(黄曲霉毒素,赭曲霉毒素A),杀虫剂和熏蒸剂残留物,重金属和可能的污染物(包括Ph. Eur.专著‘草药’中没有提到的重金属和特定环境中存在的污染物)异物和掺杂物等。如果收集地点的细节有限,则应充分解决农药和其他污染物残留的可能性,并在必要时采用适当的筛选技术。应完全解决由于例如共同收获/收集的含PA植物而引起的吡咯里西啶生物碱(PA)污染的可能性。还应考虑控制来自外来源或特定加工条件(例如多环芳烃(PAH)污染)的其他潜在有毒污染物的需要。除非另有充分理由,否则应使用适当的经验证的方法来控制潜在的污染物,并且验收标准是合理的。如果有理由担心,应测试放射性污染。

The use of ethylene oxide is prohibited for the decontamination of herbal substances4.

禁止使用环氧乙烷来为草药物质灭菌。

Consideration on approaches to possible microbial decontamination of herbal substances and herbal preparations is given in the ‘Reflection paper on microbiological aspects of herbal medicinal products and traditional herbal medicinal products’ (EMA/HMPC/95714/2013).

关于草药物质和草药制剂可能的微生物净化方法的考虑在“关于草药产品和传统草药产品的微生物学方面的反思文件”(EMA / HMPC / 95714/2013)中给出。

Deions of the analytical procedures must be submitted, together with the limits applied. Analytical procedures not given in a Pharmacopoeia should be validated in accordance with the ‘Note for guidance on validation of analytical procedures: Text and methodology’ (CPMP/ICH/381/95), unless otherwise justified.

必须提交分析程序的说明以及适用的限制。 除非另有说明,否则药典中未给出的分析程序应根据“分析程序验证指南说明:文本和方法”(CPMP / ICH / 381/95)进行验证

Reference materials of the herbal substances must be available for use in comparative tests e.g. macro- and microscopic examination, chromatography etc.

草药物质的参考材料必须可用于比较试验,例如宏观和微观检查,色谱等

6.1.2. Control of herbal preparations 草药制剂的控制

If the HMP contains a herbal preparation as active substance, rather than merely the herbal substance itself, the comprehensive specification for the herbal substance must be followed by information on the herbal preparation. A comprehensive specification from the manufacturer/marketing authorization holder for each herbal preparation must be submitted.

如果HMP含有草药制剂作为活性物质,而不仅仅是草药物质本身,草药物质的综合规格必须遵循草药制剂的信息。必须提交制造商/销售授权持有人对每种草药制剂的全面规范。

If a monograph for the herbal preparation exists in the Ph. Eur. or another Pharmacopoeia referred to in Annex I of Directives 2001/83/EC or 2001/82/EC, the herbal preparation would generally be in accordance with this monograph, taking into account the provisions of Ph. Eur. 5.23 (Monograph on Herbal Drug Extracts (Information Chapter)).

如果草药制剂专论存在于欧洲药典中。或者指令2001/83 / EC或2001/82 / EC附件I中提到的另一种药典,草药制剂通常与本专论一致,同时考虑到Ph. Eur.5.23(草药提取物专著(信息章节))的规定。

Where the herbal preparation is the subject of a European Pharmacopoeia monograph, the EDQM Certification procedure PA/PH/CEP (02) 6 1R (for Certificates of Suitability: CEPs) can be used to demonstrate compliance with the relevant Ph. Eur. monograph.

如果草药制剂是欧洲药典专著的主题,则EDQM认证程序PA / PH / CEP(02)6 1R(适用性证书:CEPs)可用于证明符合相关的Ph.Eur。

If no monograph for the herbal preparation is given in a Pharmacopoeia referred to in Annex I of Directives 2001/83/EC or 2001/82/EC, a comprehensive specification for the herbal preparation must be developed also taking into account the provisions of Ph. Eur. 5.23 (Monograph on Herbal Drug Extracts (Information Chapter)).” This comprehensive specification should be established on the basis of recent scientific data and should, in general, give particulars of the characteristics, identification tests, assay and purity tests. Chromatographic fingerprinting should be used based on appropriate chromatographic methods.

如果在指令2001/83/EC或2001/82/EC附件一提到的药典中没有关于草药制剂的专著,也必须考虑到Ph. Eur. 5.23(草药提取物专著(信息章))的规定,制定草药制剂的全面规范。“这项全面的规范应以最近的科学数据为基础,一般应详细说明特性、鉴定试验、化验和纯度试验。应根据合适的色谱方法使用色谱指纹图谱。

Tests on microbiological quality have to be included. If deemed necessary by analysis of the herbal substance being the starting material for the manufacture of the herbal preparation, tests on mycotoxins (aflatoxins, ochratoxin A), residues of pesticides and fumigation agents, toxic metals, and likely contaminants (including heavy metals not mentioned in the monograph ’Herbal drugs’ of the Ph. Eur. and contaminants present in the specific environment), adulterants and solvents should be performed. The potential for pyrrolizidine alkaloid (PA) and polycyclic aromatic hydrocarbon (PAH) contamination should be fully addressed and controls applied, as needed, using suitable validated methods. Radioactivity should be tested for if there are reasons for concern.

必须包括微生物质量的测试。如果认为有必要通过分析作为制备草药制剂的起始原料的草药物质,检测霉菌毒素(黄曲霉毒素,赭曲霉毒素A),杀虫剂和熏蒸剂残留物,有毒金属和可能的污染物(包括在Ph. Eur.的专著“草药”未提及的重金属和特定环境中存在的污染物中)应该进行掺杂物和溶剂处理。 应充分解决吡咯里西啶生物碱(PA)和多环芳烃(PAH)污染的可能性,并根据需要使用适当的验证方法进行控制。如果有理由担心,应测试放射性。

A quantitative determination (assay) of constituent(s) with known therapeutic activity or of marker(s) is also required.

还需要对已知治疗活性的成分或标记物进行定量测定。

For Standardised herbal preparations, the content of constituent(s) with known therapeutic activity must be indicated with the lowest possible tolerance (with both upper and lower limits, e.g. x%±y%)For Quantified herbal preparations, the content of active marker(s) has to be given as a defined range.

对于标准化草药制剂,具有已知治疗活性的成分含量必须以尽可能低的耐受性(具有上限和下限,例如x%±y%)表示。对于定量草药制剂,活性标记物的含量必须作为规定的范围给出。

For‘Other’ herbal preparations, for control purposes, one or more constituents are used as analytical markers and determined quantitatively within the acceptance criteria.

对于“其他”草药制剂,出于控制目的,将一种或多种成分用作分析标记并在验收标准内定量测定。

In general, acceptance limits for the content of a proposed marker should be specified and justified on the basis of the validated analytical range and historical data, if available (see ‘Reflection paper on markers used for quantitative and qualitative analysis of herbal medicinal products and traditional herbal medicinal products (EMEA/HMPC/253629/07)). In exceptional cases it may be acceptable to replace the assay by other tests (e.g. bitterness value, swelling index), based on appropriate limits.

一般来说,建议的标记内容的接受限度应根据经过验证的分析范围和历史数据加以规定和证明(见“草药产品和传统草药产品定量和定性分析标记的反思报告”(EMEA/HMPC/253629/07))。在特殊情况下,可以根据适当的限度,用其他测试(如苦味值、膨胀指数)代替化验。

Deion of the analytical procedures with details of reference standards must be submitted, together with the limits applied. Analytical procedures not given in a Pharmacopoeia should be validated in accordance with the ‘Note for guidance on validation of analytical procedures: Text and methodology’ (CPMP/ICH/381/95), unless otherwise justified.

分析程序的说明和参考标准的细节必须连同适用的限度一起提交。除非另有理由,药典中未提供的分析程序应按照《分析程序验证指南指南:文本和方法》(CPMP/ICH/381/95)进行验证。

6.2. Control of vitamins and minerals (if applicable) 维生素和矿物质的控制(如适用)

Vitamin(s) and mineral(s), which could be ancillary substances in THMPs for human use, should fulfil the requirements of all relevant legislation and guidelines.

维生素和矿物质可能是人体使用THMPs所需的辅助物质,应符合所有相关法规和指南的要求。

6.3. Control of excipients 辅料的控制

Excipients, including those added during the manufacture of the herbal preparations, should be described according to the ‘Guideline on excipients in the dossier for application for marketing authorisation of medicinal products’ (EMEA/CHMP/QWP/396951/2006), or the ‘Note for guidance on excipients in the dossier for application for marketing authorisation of veterinary medicinal products’ (EMEA/CVMP/004/98).

辅料,包括在草药制剂生产过程中添加的辅料,应根据“申请药品上市许可的档案中辅料指南”(EMEA / CHMP / QWP / 396951/2006)或'' 关于申请兽药产品上市许可的档案中辅料的指导说明(EMEA / CVMP / 004/98)。

For solvents used in the manufacture of herbal preparations the ‘Reflection paper on the use of recovered/recycled solvents in the manufacture of herbal preparations for use in herbal medicinal products/traditional herbal medicinal products’ (EMA/HMPC/453258/2013) should be considered.

对于制造草药制剂所用的溶剂,应考虑使用回收/回收溶剂生产草药制剂/传统草药制剂(EMA/HMPC/453258/2013)。

For novel excipients, the dossier requirements for active substances apply (refer to Directive 2001/83/EC for human medicinal products and Directive 2001/82/EC for veterinary medicinal products).

对于新型辅料,适用活性物质的档案要求(参见人类医药产品指令2001/83 / EC和兽药产品指令2001/82 / EC)。

7

Control tests carried out at an intermediate stage of the manufacturing process of the herbal medicinal product

在草药产品的制造过程的中间阶段进行对照试验

Details of all control tests, with details of test procedures and limits applied at any intermediate stages of the manufacturing processes and/or at stage of the bulk, are required especially if these tests cannot be performed on the HMP.

所有控制测试的详细信息,以及在制造过程的任何中间阶段和/或批量阶段应用的测试程序和限制的细节都是必需的,特别是如果这些测试不能在HMP上进行的话。

8

Control tests on the herbal medicinal product

草药产品的对照试验

This section should be in accordance with the ‘Guideline on specifications and control tests on the finished product’ (Eudralex 3AQ 11A), the ‘Guideline on specifications: test procedures and acceptance criteria for herbal substances, herbal preparations and herbal medicinal products/traditional herbal medicinal products’ (EMA/CPMP/QWP/2820/00 and EMA/CVMP/815/00 as revised) and the analytical procedures should be validated according to the ‘Note for guidance on validation of analytical procedures: Text and methodology’ (CPMP/ICH/381/95).

本部分应符合“成品规格和控制试验指南”(Eudralex 3AQ 11A),“规格指南:草药物质,草药制剂和草药产品/传统草药的试验程序和验收标准” 医药产品(EMA / CPMP / QWP / 2820/00和EMA / CVMP / 815/00修订版)和分析程序应根据“分析程序验证指南说明:文本和方法”进行验证(CPMP/ ICH/ 381/95)。

The control tests on the finished product5 should allow the qualitative and quantitative determination of the active substance(s) as well as the determination of characteristic properties of the dosage form and the entire finished product including packaging characteristics. Chromatographic fingerprinting should be used, based on appropriate chromatographic methods. A specification should be provided including tests for all relevant parameters.

对成品的对照试验应该允许定性和定量测定活性物质以及确定剂型和整个成品的特征性质,包括包装特性。应根据适当的色谱方法使用色谱指纹图谱。应提供包括所有相关参数的测试的规范。

In the case of HMPs containing as active substances herbal substance(s)/herbal preparation(s) with constituents of known therapeutic activity, these constituents should be specified and quantitatively determined. In general, the limits acceptable for the content of constituents with known therapeutic activity in the finished product at the time of release is the declared value ± 5%.

如果HMPs以活性物质的形式存在,那么含有已知治疗活性成分的草药物质/草药制剂,这些成分应该被指定并定量测定。一般来说,接受选民的内容范围与已知的治疗活动完成产品发布的时候是申报价值±5%。

In the case of HMPs containing as active substances herbal substance(s)/herbal preparation(s) where the constituents with known therapeutic activity are not known, active or analytical markers should be specified and quantitatively determined. In general, the limits acceptable for the quantity of the genuine herbal preparation in the finished product at the time of release is the declared value±5%; if fully justified, a widening to maximum ± 10% of the declared value could be acceptable.

在含有作为活性物质的HMPs的情况下,其中具有已知治疗活性的成分未知的草药物质/草药制剂,应指定和定量确定活性或分析标记物。一般而言,成品在释放时的真正草药制剂的数量可接受的限度是声明值±5%; 如果完全合理,可以接受扩大到声明值的±10%的最大值。

In exceptional cases it may be acceptable to replace the assay by other tests (e.g. bitterness value, swelling index), based on appropriate limits.

在特殊情况下,可以接受基于适当限制的其他测试(例如苦味值,膨胀指数)替换测定。

If a HMP/THMP contains a combination of several herbal substances and/or preparations as active substances, and if it is not possible to perform a quantitative determination of each active substance, the determination may be carried out jointly for several active substances. The need for this approach should be justified, see ‘Guideline on quality of combination herbal medicinal products/traditional herbal medicinal products’ (EMEA/HMPC/CHMP/CVMP/214869/2006).

如果HMP / THMP含有几种草药物质和/或制剂作为活性物质的组合,并且如果不能对每种活性物质进行定量测定,则可以对几种活性物质联合进行测定。这种方法的必要性应该是合理的,参见“组合草药产品/传统草药产品质量指南”(EMEA / HMPC / CHMP / CVMP / 214869/2006)。

For THMPs for human use containing vitamins and/or minerals, the vitamins and/or minerals should also be specified qualitatively and quantitatively determined.

对于含有维生素和/或矿物质的人用THMP,还应定性和定量地确定维生素和/或矿物质。

The criteria given by the Ph. Eur. to ensure the microbiological quality should be applied unless justified. The frequency of testing for microbial contamination should be justified according to the ‘Note for guidance on specifications: Test procedures and acceptance criteria for new drug substances and new drug products: Chemical substances’ (CPMP/ICH/367/96) and ‘Note for guidance on specifications: Test procedures and acceptance criteria for new veterinary drug substances and new medicinal products: Chemical substances’ (EMEA/CVMP/VICH/10/04).

除非有正当理由,否则Ph. Eur.为确保微生物质量而给出的标准应适用。微生物污染的频率的测试应该是合理的,以《指导规范:测试程序和验收标准为新药物物质和新药产品:化学物质》(CPMP /我/ 367/96)和《指导规范:测试程序和验收标准为新兽药物质和新医药产品:化学物质》(EMEA / CVMP / VICH / 10/04)。《分析程序验证指南说明:文本和方法》(CPMP/ICH/381/95)等为依据对程序进行验证。

9

Stability tests 稳定性测试

9.1. General principles 总则

This section should be in accordance with the‘Note for guidance on stability testing of new active substances and products’(CPMP/ICH/2736/99 as revised) and‘Guideline on stability testing of new veterinary drug substances and medicinal products’(CVMP/VICH/899/99 as revised), the‘Guideline on stability testing of existing active substances and related finished products’(CPMP/QWP/122/02 and EMEA/CVMP/846/99 as revised), the‘Note for guidance on in-use stability testing of human medicinal products’ (CPMP/QWP/2934/99), the‘Note for guidance on in-use stability testing of veterinary medicinal products (excluding immunological veterinary medicinal products)’(EMEA/CVMP/424/01) and Questions & answers on quality of herbal medicinal products/traditional herbal medicinal products (EMA/HMPC/41500/2010 as revised).

本节应符合“关于新活性物质和产品稳定性测试指南的说明”(CPMP/ICH/2736/99,修订本)和“关于新活性物质和产品稳定性测试的指南”。“兽药物质和医药产品”(CVMP/VICH/899/99,修订本),“现有活性物质及相关成品稳定性测试指南”(CPMP/QWP/122/02和经修订的EMEA/CVMP/846/99),“人体药用产品在用稳定性测试指南”(CPMP/QWP/2934/99),“兽药产品在用稳定性测试指南(不包括免疫兽药)”(EMEA/CVMP/424/01)及中草药/中草药产品质量问答(EMA/HMPC/41500/2010,修订本)。

The herbal substance/herbal preparation in its entirety is regarded as the “active substance”. For this reason, the basis for determining the stability of the herbal substance/herbal preparation and products thereof needs to be considered.

该草物质/草药制剂的整体被视为“活性物质”。因此,需要考虑确定草药物质/草药制剂及其产品稳定性的依据。

In cases where constituent(s) with known therapeutic activity are known and shown to be responsible for the overall effects of the herbal substance/herbal preparation, e.g. hydroxyanthracene derivatives, then stability testing of these constituents and their potential degradants will suffice.

如果已知具有治疗活性的成分对草药物质/草药制剂(如羟氰菊酯衍生物)的整体效果负责,那么对这些成分及其潜在降解物的稳定性测试就足够了。

However, in cases where the herbal substance/herbal preparation does not have constituent(s) with known therapeutic activity simply determining the stability of active marker(s) or analytical marker(s), will not suffice and a series of stability-indicating tests (eg. TLC, HPLC) will be needed. The stability of the herbal substance/herbal preparation as a multi-component system, should, as far as possible, also be demonstrated, e.g. by means of appropriate fingerprint chromatograms. It should also be demonstrated that their proportional content remains comparable to the initial chromatographic fingerprint.

然而,如果草药物质/草药制剂没有已知治疗活性的成分,仅仅确定活性标记物或分析标记物的稳定性是不够的,还需要进行一系列的稳定性指示测试(例如:TLC, HPLC)。草药物质/草药制剂作为一个多组分系统的稳定性也应尽可能地得到证明,例如通过适当的指纹图谱。还应证明它们的比例含量与最初的色谱指纹图谱相当。

Similarly, if more than one group of constituents is generally accepted to contribute to the therapeutic activity (quantified herbal substances/preparations) and/or if more than one group of constituents is of known relevance regarding quality, the chromatographic fingerprints should cover all relevant constituent groups.

同样地,如果普遍接受一组以上的成分对治疗活性有贡献(定量的草药物质/制剂)和/或如果一组以上的成分对质量有已知的相关性,色谱指纹图谱应该覆盖所有相关的成分组。

Unless extensive degradation is expected during the first three months, it is considered acceptable to start the stability studies with a herbal substance/herbal preparation/HMP up to three months after the manufacturing date.

除非预期在前三个月发生大量的降解,否则在制造日期后三个月开始使用草药物质/草药制剂/HMP进行稳定性研究是可以接受的。

The testing frequency is set out in the ‘Guideline on stability testing of existing active substances and related finished products’ (CPMP/QWP/122/02 as revised).

测试频率载于《现有活性物质及相关成品稳定性测试指引》(CPMP/QWP/122/02修订版)。

9.2. Stability of herbal substances/herbal preparations 草药/草药制剂的稳定性

Testing at the accelerated storage condition or at the intermediate storage condition may be omitted for herbal substances/herbal preparations, if justified by the applicant and if the storage conditions below 25°C are clearly labelled.

对于草药物质/草药制剂,如果申请人证明合理,并且如果低于25°C的储存条件有明确标签,则可以省略在加速储存条件下或在中间储存条件下的测试。

Stress testing is usually considered unnecessary for herbal substances/herbal preparations except when, according to the toxicological assessment, toxic degradation products could appear.

对于草药物质/草药制剂,压力测试通常被认为是不必要的,除非根据毒理学评估,可能出现毒性降解产物。

Herbal substances which are used as starting materials in the manufacturing process for a herbal preparation shall comply with their specification immediately before use (e.g. before extraction).

在草药制剂的制备过程中用作起始原料的草药物质应在使用前立即符合其规格(例如在提取前)。

Regarding the parameter content, specific characteristics of different types of herbal substances/herbal preparations should be taken into account.

关于参数含量,应考虑不同类型的草药物质/草药制剂的具体特征。

Herbal substances/herbal preparations with constituents of known therapeutic activity:

具有已知治疗活性成分的草药物质/草药制剂:

The stability of the constituents with known therapeutic activity should be demonstrated, e.g. by means of appropriate fingerprint chromatograms of these constituents and an assay.

应证明具有已知治疗活性的成分的稳定性,例如,通过这些成分的适当指纹色谱图和测定法。

For stability studies of herbal substances/herbal preparations with constituents of known therapeutic activity, the results obtained for the content of these constituents must be compliant with the release acceptance criterion.

对于具有已知治疗活性成分的草药物质/草药制剂的稳定性研究,获得的这些成分含量的结果必须符合释放接受标准。

Herbal substances/herbal preparations for which constituents with known therapeutic activity are not known:

未知具有已知治疗活性的成分的草药物质/草药制剂:

The stability of active marker(s) or analytical marker(s) should be demonstrated, e.g. by means of appropriate fingerprint chromatograms of these constituents and an assay.

应证明活性标记物或分析标记物的稳定性,例如,通过这些成分的适当指纹色谱图和测定法。

Active markers 活性标记

In the retest/shelf-life specification, a variation in active markers content of ± 5% from the initial value is acceptable. If fully justified, a widening to ± 10% from the initial content could be acceptable if it is ensured that also at the end of re-test/shelf-life the content is within the defined range.

在重新测试/保质期规范中,活性标记物含量与初始值的±5%的变化是可接受的。 如果完全合理,如果确保在重新测试/保质期结束时内容在规定范围内,则可以接受从初始含量扩大到±10%。

Analytical markers分析标记

In the retest/shelf-life specification, a variation in analytical markers of ± 5% of the initial batch- specific value is acceptable. If justified, a widening to ± 10% from the initial batch-specific content could be acceptable. All analytical markers should remain within the release acceptance criteria, unless otherwise justified.

在重新测试/保质期规范中,分析标记的变化在初始批次特定值的±5%之内是可接受的。如果合理,可以接受从最初的批次特定内容扩大到±10%。除非另有说明,否则所有分析标记应保持在放行验收标准内。

9.3. Stability of herbal medicinal products 草药产品的稳定性

Regarding the parameter content, specific characteristics of different types of herbal substances/herbal preparations used as active substances in HMP should be taken into account:

关于参数含量,应考虑在HMP中用作活性物质的不同类型草药物质/草药制剂的具体特征:

HMP containing, as active substances, herbal substances/herbal preparations with constituents of known therapeutic activity:

含有已知治疗活性成分的草药物质/草药制剂作为活性物质的HMP:

In the case of a HMP containing a herbal substance and/or a herbal preparation with constituent(s) of known therapeutic activity, the variation in content during the proposed shelf-life should not exceed ± 5% of the declared assay value; in exceptional cases a widening to a maximum ± 10% of the declared content value may be acceptable with sufficient justification.

在含有草药物质和/或含有已知治疗活性成分的草药制剂的HMP的情况下,在建议的保质期内含量的变化不应超过声明的测定值的±5%;在特殊情况下,如果有足够的理由,可以接受扩大到声明含量值的±10%的最大值。

HMP containing, as active substances, herbal substances/herbal preparations for which constituents with known therapeutic activity are not known:

HMP作为活性物质,含有已知的治疗活性成分的未知的草药物质/草药制剂:

Active markers 活性标记

During the proposed shelf-life the content of the active substance (calculated using one active marker) should remain within ± 5% of the initial value; if justified a widening to ± 10% from the initial value could be acceptable. All active markers should remain within ± 10% of the initial value and within the acceptance criteria ranges, unless otherwise justified.

在拟议的保质期活性物质的内容(使用一个活动标记计算)应保持在±5%的初始值;如果合理,扩大初始值的±10%也可以接受。除非有合理依据,所有活性标记应该保持在±10%的初始值和验收标准范围内。

Analytical markers 分析标记

During the proposed shelf-life a variation of the batch-specific content of the analytical marker of ± 5% from the initial value is acceptable; a widening to ± 10% from the initial batch-specific content could be acceptable if justified.

在建议的保质期内,分析标记的批次特定含量与初始值相差±5%是可以接受的; 如果合理,可以接受从最初的批次特定含量扩大到±10%。

For active or analytical markers, it is agreed that in some cases wider limits may be necessary, but the range should not be widened in general. Wider ranges can be accepted with adequate justifications. Different ranges for different markers in one active substance or one herbal medicinal product can be accepted.

对于活性或分析标记,一致认为在某些情况下可能需要更宽的限制,但一般不应扩大范围。若有充分的理由,可接受更宽的范围。可以接受一种活性物质或一种草药产品中不同标记物的不同范围。

If a HMP contains combinations of several herbal substances and/or herbal preparations, and if it is not possible to determine the stability of each active substance, the stability of the HMP should be determined by appropriate fingerprint chromatograms, appropriate overall methods of assay and physical and sensory tests or other appropriate tests. The appropriateness of the tests shall be justified by the applicant in accordance to the ‘Guideline on quality of combination herbal medicinal products/traditional herbal medicinal products’ (EMEA/HMPC/CHMP/CVMP/214869/06).

如果HMP包含若干草药物质和/或草药制剂的组合,如果它是不可能确定每个活性物质的稳定性,HMP的稳定性应由适当的指纹色谱图,适当的总体分析和物理方法和感官测试或其他适当的测试。申请人应按照“中草药产品/传统中草药产品质量指南”(EMEA/HMPC/CHMP/CVMP/214869/06)的规定证明测试的适宜性。

In the case of THMPs for human use containing vitamins and/or minerals, the stability of the vitamins and/or minerals should also be demonstrated.

在含有维生素和/或矿物质的人用THMP的情况下,还应证明维生素和/或矿物质的稳定性。

Definitions 定义

Acceptance criteria: Numerical limits, ranges, or other suitable measures for acceptance of the results of analytical procedures.

验收标准:数值限制,范围或其他适用于接受分析程序结果的措施。

Chromatographic fingerprinting: Application of chromatographic techniques to create a characteristic chromatographic pattern of phytochemical constituents which represents the multicomponent system typical of the herbal substance/herbal preparation/HMP.

色谱指纹图谱:应用色谱技术创建植物化学成分的特征色谱图,代表草药物质/草药制剂/ HMP的典型多组分系统。

Constituents with known therapeutic activity: are chemically defined substances or groups of substances, which are generally accepted to contribute substantially to the therapeutic activity of a herbal substance, a herbal preparation or a HMP.

具有已知治疗活性的成分:是化学上确定的物质或物质组,其通常被认为对草药物质,草药制剂或HMP的治疗活性有实质性贡献。

Drug extract ratio (DER): The ratio between the quantity of herbal drug (herbal substance) used in the manufacture of an extract and the quantity of extract obtained. The number (given as the actual range) written before the colon is the relative quantity of the herbal drug; the number written after the colon is the relative quantity of the extract obtained. Two DER can be distinguished:

药物提取物比率(DER):在提取物的制造中使用的草药(草药物质)的量与所获得的提取物的量之间的比率。冒号前写的数字(以实际范围给出)是草药的相对数量; 冒号后写的数字是获得的提取物的相对量。可以区分两个DER:

Genuine (native) drug extract ratio (DERgenuine): is the ratio between the quantity of herbal drug (herbal substance) used in the manufacture of an extract and the quantity of genuine (native) extract obtained.

真正的(天然)药物提取物比率(DERgenuine):是在制备提取物中使用的草药(草药物质)的量与获得的真正(天然)提取物的量之间的比率。

Total drug extract ratio (DERtotal): is the ratio between the quantity of herbal drug (herbal substance) used in the manufacture of an extract and the quantity of whole extract (with excipients) obtained.

总药物提取物比率(DERtotal):是在制备提取物中使用的草药(草药物质)的量与获得的总提取物(与赋形剂)的量之间的比率。

Extraction solvents: are solvents, which are used for the extraction process.

萃取溶剂:是用于萃取过程的溶剂。

Genuine herbal preparation: refers to the preparation without excipients, even if for technological reasons the genuine herbal preparation is not available. However, for soft and liquid herbal preparations the genuine herbal preparation may contain variable amounts of (extraction) solvent.

天然草药制剂:指不含辅料的制剂,即使由于技术原因,也没有天然的草药制剂。然而,对于软质和液体草药制剂,天然的草药制剂可含有可变量的(提取)溶剂。

Herbal drugs: The term herbal drug, used in European Pharmacopoeia, is synonymous with the term herbal substance used in European Community legislation on herbal medicinal products.

草药:欧洲药典中使用的草药这一术语与欧洲共同体草药产品立法中使用的草药物质同义。

Herbal medicinal products (HMPs): Any medicinal product, exclusively containing as active substances one or more herbal substances or one or more herbal preparations, or one or more such herbal substances in combination with one or more such herbal preparations.

草药产品(HMPs):任何草药产品,只含有一种或多种草药制剂或一种或多种草药制剂作为活性物质,或与一种或多种草药制剂联合使用的一种或多种草药制剂。

Herbal preparations: are obtained by subjecting herbal substances to treatments such as extraction, distillation, expression, fractionation, purification, concentration or fermentation. These include comminuted or powdered herbal substances, tinctures, extracts, essential oils, expressed juices and processed exudates.

草药制剂:通过对草药物质进行提取、蒸馏、表达、分离、纯化、浓缩或发酵等处理而得。这些物质包括粉碎或粉末状的草药物质、酊剂、提取物、精油、果汁和加工过的分离物。

Herbal substances: The term herbal substance is synonymous with the term herbal drug used in European Pharmacopoeia, All mainly whole, fragmented or cut plants, plant parts, algae, fungi, lichen in an unprocessed, usually dried form but sometimes fresh. Certain exudates that have not been subjected to a specific treatment are also considered to be herbal substances. Herbal substances are precisely defined by the plant part used and the botanical name according to the binomial system (genus, species, variety and author).

草药物质:草药物质是欧洲药典中使用的草药药物的同义词,主要是未经加工、整株的、破碎的或切割的植物、植物部分、藻类、真菌、地衣,通常是干燥的,但有时是新鲜的。某些未经过特定处理的分泌物也被认为是草药物质。根据双命名法(属、种、品种和作者),用植物部分和植物学名称来精确定义草药物质。

Herbal teas: consist exclusively of one or more herbal substance(s) intended for oral aqueous preparations by means of decoction, infusion or maceration. The preparation is prepared immediately before use. Herbal teas are usually supplied in bulk form or in sachets.

草药茶:由一种或多种草药组成,通过汤剂、浸泡或浸渍的方式用于口服水制剂。使用前应立即准备好。草药茶通常以散装或袋装形式供应。

Markers: are chemically defined constituents or groups of constituents of a herbal substance, a herbal preparation or a herbal medicinal product which are of interest for control purposes independent of whether they have any therapeutic activity. Markers serve to calculate the quantity of herbal substance(s) or herbal preparation(s) in the HMP if the marker has been quantitatively determined in the herbal substance or herbal preparation.

标记物:是一种草药物质、一种草药制剂或一种草药药物的化学定义成分或成分组,其控制目的与是否具有治疗活性无关。如果标记在草药物质或草药制剂中被定量测定,则标记用于计算HMP草药物质或草药制剂的数量。

There are two categories of markers:

有两类标记物

Active markers: are constituents or groups of constituents which are generally accepted to contribute to the therapeutic activity.

活性标记物:是被普遍接受的对治疗活性有贡献的成分或成分组。

Analytical markers: are constituents or groups of constituents that serve for analytical purposes, irrespective of any pharmacological or therapeutic activity, which they may be reported to possess.

分析标记物:是用于分析目的成分或组分,而不论其可能具有何种药理或治疗活性。

Native herbal preparation: synonymous with Genuine herbal preparation

天然草药制剂:真正草药制剂的同义词

Quantification: means adjusting the herbal preparation to a defined range of constituents exclusively achieved by blending different batches of herbal substances and/or herbal preparations (e.g. quantified extracts).

定量:指通过混合不同批次的草药物质和/或草药制剂(例如定量提取液),将草药制剂调整到特定的成分范围内。

Solvent: An inorganic or an organic liquid used for the preparation of solutions or suspensions in the manufacture of a herbal preparation or the manufacture of a herbal medicinal product.

溶剂:一种无机或有机液体,用于制备草药制剂或草药产品中溶液或悬浮液。

Specification: A list of tests, references to analytical procedures, and appropriate acceptance criteria, which are numerical limits, ranges, or other criteria for the tests described. It establishes the set of criteria to which a herbal preparation/herbal substance or HMP should conform to be considered acceptable for its intended use. "Conformance to specification" means that the herbal preparation/herbal substance and/or HMP, when tested according to the listed analytical procedures, will meet the listed acceptance criteria. Specifications are legally binding quality standards that are proposed and justified by the manufacturer/marketing authorization holder and approved by regulatory authorities.

规范:测试列表,参考分析程序,以及适当的验收标准,即所述试验的数值限制、范围或其他标准。它建立了草药制剂/草药物质或HMP应符合的一套标准,可视为其预定用途可以接受。“符合规格”是指草药制剂/草药物质和/或HMP,当根据列出的分析程序进行测试时,将符合列出的验收标准。规格是由制造商/营销授权持有人提出并经监管机构批准的具有法律约束力的质量标准。

Standardisation: means adjusting the herbal substance/herbal preparation to a defined content of a constituent or a group of constituents with known therapeutic activity respectively either by adding excipients or by blending batches of the herbal substance and/or herbal preparation (e.g. standardised extracts).

标准化:指通过添加辅料或将各批次的草药物质和/或草药制剂(例如标准化提取物)混合,将草药物质/草药制剂调整为具有已知治疗活性的成分或一组成分的规定含量。

Traditional herbal medicinal products (THMPs): Medicinal products for human use that fulfil the conditions laid down in article 16a (1) of Directive 2001/83/EC.

传统草药产品(THMPs):符合指令2001/83/EC第16a(1)条规定条件的人类使用的药物。

Types of herbal substances/herbal preparations:

草药物质/草药制剂的种类:

Standardised herbal substances/herbal preparations are adjusted to a defined content of one or more constituents with known therapeutic activity. This is achieved by adjustment of the herbal substance/herbal preparation with inert excipients or by blending batches of the herbal substance/herbal preparation.

标准化的草药物质/草药制剂根据已知的治疗活性对一个或多个成分的确定含量进行调整。这是通过调整草药物质/草药制剂与惰性赋形剂或混合批次的草药物质/草药制剂来实现的。

Quantified herbal substances/herbal preparations are adjusted to one or more active markers, the content of which is controlled within a limited, specified range. Adjustments are made by blending batches of the herbal substance/herbal preparation.

定量的草药物质/草药制剂被调整为一个或多个活性标记,其含量被控制在一个有限的,指定的范围内。通过混合不同批次的草药物质/草药制剂进行调整。

‘Other’ herbal substances/herbal preparations are not adjusted to a particular content of

constituents. For control purposes, one or more constituents are used as analytical markers.

“其他”草药物质/草药制剂不调整特定成分的含量。为了控制目的,一个或多个成分被用作分析标记。

References 参考

李佳雯整理 素材来自EMA官网

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