翻译 JULIA 来源：Julia法规翻译
CHMP要求含缬沙坦药品MAH回答的问题
16 July 2018
EMA/CHMP/467845/2018
CHMP List of questions
To be addressed by the marketing authorisation holders for valsartan-containing medicinal products
CHMP要求含缬沙坦药品MAH回答的问题
Referral under Article 31 of Directive 2001/83/EC
依指令2001/83/EC第31条转EMA处置事项
Procedure number: EMEA/H/A-31/1471
程序编号：EMEA/H/A-31/1471
Amlodipine-Valsartan Mylan EMEA/H/A-31/1471/C/4037/0004
Copalia EMEA/H/A-31/1471/C/774/0099
Copalia HCT EMEA/H/A-31/1471/C/1159/0069
Dafiro EMEA/H/A-31/1471/C/776/0101
Dafiro HCT EMEA/H/A-31/1471/C/1160/0070
Entresto EMEA/H/A-31/1471/C/4062/0021
Exforge EMEA/H/A-31/1471/C/716/0098
Exforge HCT EMEA/H/A-31/1471/C/1068/0068
Neparvis EMEA/H/A-31/1471/C/4343/0020
Active substance: valsartan
活性物质：缬沙坦
1. Background 背景
Valsartan is anangiotensin-II-receptor antagonist authorised in the EU as a single agent or incombination with other active substances and indicated for the treatment ofhypertension, recent heart attack and heart failure, both in nationally andcentrally authorised medicinal products.
缬沙坦是在EU内批准的血管紧张素受体拮抗剂，用作单剂或与其它活性物质一起用作复合剂，治疗高血压、近期心脏病发及心力衰竭，该药品在国家药监和集中审评均有批准。
The EU authoritieswere notified that an Active Pharmaceutical Ingredient (API) manufacturer(Zhejiang Huahai Pharmaceutical, China) has detected the presence of apreviously undetected impurity, N-nitrosodimethylamine (NDMA, also known asdimethylnitrosamine) in the valsartan API manufactured at its site in Chuannan.Zhejiang Huahai is one of the API manufacturers that are supplying valsartanfor medicinal products authorised in the EU.
EU药监收到通知，一个API生产商（浙江华海药业，中国）在其川南工厂生产的缬沙坦API中检出之前未检出杂质，N-二甲基亚硝胺（NDMA）。浙江华海是为EU批准的药品供应缬沙坦的API生产商之一。
NDMA is agenotoxic and carcinogen agent in animals and it is classified as a probablehuman carcinogen by IARC (International Agency for Research on Cancer, WHO).
NDMA是一种动物基因毒性和致癌物质，IARC将其归类为可能的人类致癌物质（WHO国际癌症研究机构）。
An initialinvestigation report on the root cause of the presence of NDMA by themanufacturer indicates that NDMA formed at a specific step in the valsartan APImanufacturing process, and the level of NDMA present may depend on the reactionconditions used.
生产商对NDMA出现的根本原因初步调查报告显示NDMA是在缬沙坦API生产工艺的特定步骤形成的，NDMA的水平可能取决于所用的反应条件。
According to testsof a small random selection of API batches performed by this manufacturer, thelevels of NDMA detected range between 3.4 ppm to 120 ppm, with an average of66.5 ppm. According to the principles of ICH-M7, these levels raise concerns,considering that NDMA belongs to the group of N-nitroso compounds.
依据此生产商对API批次小量随机抽样检测，NDMA检出水平在3.4ppm至120ppm之间，平均为66.5ppm。依据ICM M7原则，考虑到NDMA属于N-亚胺类化合物，此水平令人担忧。
The EC requestedon 5 July 2018 the initiation of a Referral under Article 31 of Directive2001/83/EC.
EC要求在2018年7月5日依据指令2001/83/EC第31条启动转EMA处置程序。
2. Questions 问题
The marketingauthorisation holders (MAHs) of valsartan-containing medicinal products arerequested to address the following questions:
现在要求含缬沙坦药品的上市许可持有人（MAH）回答以下问题：
1. NDMA appears to be generated during theformation of the tetrazole ring by reaction of dimethylamine (which may bepresent as an impurity or degradant in the solvent dimethylformamide (DMF) andsodium nitrite under acidic conditions (where nitrous acid is formed). It canalso not be excluded that other N-nitrosamines could be generated with othersolvents or under other specific reaction conditions where other amines arepresent.
NDMA可能会在四唑环形成过程中通过二甲胺（可能会以杂质形式出现在DMF溶剂中或由其降解而成）与亚硝酸钠在酸性条件下（形成亚硝酸）反应生成。与其它溶剂或在其它有其它胺类存在时在特定反应条件下生成其它N-亚硝胺类的情况亦不可排除。
Please state ifyou are currently using (or have previously used) any API supplier (ZhejiangHuahai or others) that have steps in the valsartan manufacturing process thatmay potentially lead, or have led, to the generation of NDMA or any otherpossible N-nitroso impurity.
请说明你们目前是否有使用（或之前曾使用的）任何API供应商（浙江华海或其它），他们使用了可能会导致，或已经导致，NDMA或其它任何可能的N-亚硝胺杂质的缬沙坦生产工艺步骤。
2. If the answer to Q1 is yes, you arerequested to provide details on:
如果对第一个问题的回答是肯定的，请提交以下详细信息：
a) the time period when this(ese)supplier(s) has(ve) been used and its impact on final product batches releasedto the European market, including figures on sales and patient exposure ofproduct containing NDMA impurity (potential or confirmed) in EU/EEA member states;
使用这些供应商的时段，以及其对放行至欧洲市场的最终药品批次的影响，包括销售数据以及EU/EEA成员国内暴露于含NDMA杂质的药品的患者数据；
b) data in the annexed table on the use inclinical practice including information on indication, dose, and duration oftreatment;
附表中用于临床试验的数据，包括适用症信息、剂量和治疗时长；
c) what NDMA levels are/were present inyour finished product(s). If finished product batches have been tested, providefull details of the analytical methods used, including their validation;
在你们的制剂中NDMA出现的水平如何。如果制剂批次经过检测，请提交所用的分析方法详细信息，包括其验证；
d) if levels have not been determined yet,what is your plan to do so in terms of test sampling strategy, development ofrelevant analytical method and validation;
如果尚未进行检测，你们的计划，包括检测取样策略、相关分析方法开发和验证计划；
e) a calculation of NDMA acceptable dailyintake levels considering the framework described in ICH M7 as applicable tothe class of nitrosamines.
考虑ICH M7中适用于亚胺类的所述框架，计算NDMA日可接受摄入水平的计算情况；
f) In relation to the above, any proposedcorrective and preventive actions to ensure that the finished product does notcontain levels above an acceptable daily intake. Please comment on potentialforeseen changes to in-process controls, specifications and related analyticalmethods for the finished product and their validation.
关于上述内容的所有拟定CAPA，确保制剂中不含有超出日可接受摄入量。请说明可能做出的对中控、制剂质量标准和有关分析方法及其验证的可预见变更。
Annex 附录
|
INN |
Product name |
Indications |
Pharmaceuticalforms andstrengths |
Doses (asapproved and usedin clinicalpractice) |
Treatment duration (asapproved and used inclinicalpractice) |
|
通用名 |
品名 |
适应症 |
剂型规格 |
剂量（批准及临床使用） |
治疗时长（批准及临床使用） |
CHMP要求含缬沙坦药品的API生产商回答的问题
16 July 2018
EMA/CHMP/466974/2018
CHMP List ofquestions
To be addressed bythe API manufacturers for valsartan-containing medicinal products
CHMP要求含缬沙坦药品的API生产商回答的问题
Referral under Article 31 of Directive2001/83/EC
依指令2001/83/EC第31条转EMA处置事项
Procedure number: EMEA/H/A-31/1471
程序编号：EMEA/H/A-31/1471
Active substance: valsartan
活性物质：缬沙坦
1.Background背景
Valsartan is an angiotensin-II-receptor antagonist authorised in the EU as a single agent or in combination with other active substances and indicated for the treatment of hypertension, recent heart attack and heart failure, both in nationally and centrally authorised medicinal products.
缬沙坦是在EU内批准的血管紧张素受体拮抗剂，用作单剂或与其它活性物质一起用作复合剂，治疗高血压、近期心脏病发及心力衰竭，该药品在国家药监和集中审评均有批准。
The EU authorities were notified that an Active Pharmaceutical Ingredient (API) manufacturer (Zhejiang Huahai Pharmaceutical, China) has detected the presence of a previously undetected impurity, N-nitrosodimethylamine (NDMA, also known as dimethylnitrosamine) in the valsartan API manufactured at its site in Chuannan. Zhejiang Huahai is one of the API manufacturers that are supplying valsartan for medicinal products authorised in the EU.
EU药监收到通知，一个API生产商（浙江华海药业，中国）在其川南工厂生产的缬沙坦API中检出之前未检出杂质，N-二甲基亚硝胺（NDMA）。浙江华海是为EU批准的药品供应缬沙坦的API生产商之一。
NDMA is a genotoxic and carcinogen agent inanimals and it is classified as a probable human carcinogen by IARC (International Agency for Research on Cancer, WHO).
NDMA是一种动物基因毒性和致癌物质，IARC将其归类为可能的人类致癌物质（WHO国际癌症研究机构）。
An initial investigation report on the rootcause of the presence of NDMA by the manufacturer indicates that NDMA formed ata specific step in the valsartan API manufacturing process, and the level of NDMA present may depend on the reaction conditions used.
生产商对NDMA出现的根本原因初步调查报告显示NDMA是在缬沙坦API生产工艺的特定步骤形成的，NDMA的水平可能取决于所用的反应条件。
According to tests of a small random selection of API batches performed by this manufacturer, the levels of NDMA detected range between 3.4 ppm to 120 ppm, with an average of 66.5 ppm. According to the principles of ICH-M7, these levels raise concerns, considering that NDMA belongs to the group of N-nitroso compounds.
依据此生产商对API批次小量随机抽样检测，NDMA检出水平在3.4ppm至120ppm之间，平均为66.5ppm。依据ICM M7原则，考虑到NDMA属于N-亚胺类化合物，此水平令人担忧。
The EC requested on 5 July 2018 the initiation of a Referral under Article 31 of Directive 2001/83/EC.
EC要求在2018年7月5日依据指令2001/83/EC第31条启动转EMA处置程序。
2. Questions 问题
The valsartan API manufactuers are requested to address the following questions:
现在要求缬沙坦的API生产商回答以下问题：
To all API manufacturers with confirmed presence of NDMA in the API:
所有已确认在API中有出现NDMA的API生产商：
Please provide summaries and any updates since the last response to EMA on the below points:
请向EMA提交关于以下几个问题自上次回复之后的总结和更新：
1.The manufacturer is requested to provide information on the NDMA content in API batches manufactured for medicinal products authorised in the EU/EEA that are at risk of containing NMDA (e.g. following manufacturing changes). In addition, information on the progress of the testing plan and any interim results should be provided.
生产商需要提交为EU/EEA批准的具有含NDMA风险的药品所生产的API批次中NDMA含量的信息（例如，在生产变更后）。此外，亦应提交关于检测计划的进展信息和所有临时结果情况。
2. Please comment on any variability of the contamination in batches tested, e.g. in view of any process parameters that may specifically impact on the formation of NDMA or potential difference in equipment when different workshops are used.
请说明所测批次中污染的波动情况，例如，从可能影响NDMA形成的工艺参数角度来看，或者是由于所用车间不同可能导致设备差异。
3. Please provide details on 请提交以下详细信息
a) the analytical quantification method for detecting NDMA in the API valsartan, the limit of detection, limit of quantification and comment on the validation status of this method.
在API缬沙坦中检出NDMA的定量分析方法、检出限、定量限及该方法的验证状态说明。
c) any proposed corrective and preventive actions to ensure that the manufacturing process does not generate NDMA or yields NDMA levels within the acceptably daily intake. Please comment on potential foreseen changes to manufacturing process, in-process controls, specifications and related analytical methods for the API and their validation.
所有为确保生产工艺不生成NDMA或控制NDMA水平在可接受的日摄入水平以下的CAPA。请说明所有可能的对生产工艺、中控、API质量标准和相关分析方法及其验证的可预见变更。
To all other API manufacturers:
所有其它API生产商：
1. NDMA appears to be generated during the formation of the tetrazole ring by reaction of dimethylamine (which may be present as an impurity or degradant in the solvent dimethylformamide (DMF)) and sodium nitrite under acidic conditions (where nitrous acid is formed). It can also not be excluded that other N-nitrosamines could be generated with other solvents or under other specificreaction conditions where other amines are present.
NDMA可能会在四唑环形成过程中通过二甲胺（可能会以杂质形式出现在DMF溶剂中或由其降解而成）与亚硝酸钠在酸性条件下（形成亚硝酸）反应生成。与其它溶剂或在其它有其它胺类存在时在特定反应条件下生成其它N-亚硝胺类的情况亦不可排除。
Please provide information if you currently are using (or have in the past used) any step in the valsartan manufacturing process that may potentially lead to the generation of NDMA or any other possible N-nitroso impurity.
请说明你们目前是否有使用（或之前曾使用的）任何可能会导致，或已经导致，NDMA或其它任何可能的N-亚硝胺杂质的缬沙坦生产工艺步骤。
2. If the answer to Q1 is yes, you are requested to provide details on:
如果对第一个问题的回答是肯定的，请提交以下详细信息：
a) when was this process introduced for the manufacture of valsartan (or for how long it has been used, if in the past);
何时引入此工艺用于缬沙坦生产（或如果在过去就已使用，使用了多长时间）；
b) what NDMA levels are in batches of active substance. Please, provide the full details of the analytical methods used to identify and quantify NDMA, including the method validation;
在活性物质批次中NDMA的水平如何。请提交用于鉴别和定量NDMA的分析方法的全部细节，包括方法验证；
c) if levels have not been determined yet, what is your plan to do so in terms of test sampling strategy, development of relevant analytical method and validation;
如果尚未确定其水平，你们在检测取样策略、相关分析方法开发和验证方面的计划如何；
d) any mitigation steps in the current (or past) manufacturing process to reduce,eliminate, or avoid formation of NDMA during the process or from the finished API;
对当前的（或过去的）生产工艺采取的减少、消除或避免成品API工艺中或成品中NDMA形成的所有风险降低步骤；
e) any proposed corrective and preventive actions to ensure that the manufacturing process does not generate NDMA or yields NDMA levels within the acceptably daily intake. Please, comment on potential foreseen changes to manufacturing process, in-process controls, specifications and related analytical methods for the API and their validation.
为确保生产工艺不生成NDMA或使得NDMA水平在可接受日摄入量水平以下而拟定的CAPA。请说明对所有可能的对生产工艺、中控、API质量标准和相关分析方法及其验证的可预见变更。
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