{"id":20502,"date":"2018-07-27T01:00:00","date_gmt":"2018-08-08T01:19:18","guid":{"rendered":"http:\/\/www.05921.net\/index.php\/2018\/08\/08\/chmp%e8%a6%81%e6%b1%82%e5%90%ab%e7%bc%ac%e6%b2%99%e5%9d%a6%e8%8d%af%e5%93%81mah%ef%bc%88%e7%9a%84api%e7%94%9f%e4%ba%a7%e5%95%86%ef%bc%89%e5%9b%9e%e7%ad%94%e7%9a%84%e9%97%ae%e9%a2%98\/"},"modified":"2018-08-08T09:19:20","modified_gmt":"2018-08-08T01:19:20","slug":"chmp%e8%a6%81%e6%b1%82%e5%90%ab%e7%bc%ac%e6%b2%99%e5%9d%a6%e8%8d%af%e5%93%81mah%ef%bc%88%e7%9a%84api%e7%94%9f%e4%ba%a7%e5%95%86%ef%bc%89%e5%9b%9e%e7%ad%94%e7%9a%84%e9%97%ae%e9%a2%98","status":"publish","type":"post","link":"https:\/\/www.05921.net\/index.php\/20502\/","title":{"rendered":"CHMP\u8981\u6c42\u542b\u7f2c\u6c99\u5766\u836f\u54c1MAH\uff08\u7684API\u751f\u4ea7\u5546\uff09\u56de\u7b54\u7684\u95ee\u9898"},"content":{"rendered":"
\n

\u7ffb\u8bd1 JULIA   \u6765\u6e90\uff1aJulia\u6cd5\u89c4\u7ffb\u8bd1 <\/span><\/h2>\n

CHMP\u8981\u6c42\u542b\u7f2c\u6c99\u5766\u836f\u54c1MAH\u56de\u7b54\u7684\u95ee\u9898 <\/span><\/strong><\/h2>\n

16 July 2018<\/span><\/p>\n

EMA\/CHMP\/467845\/2018<\/span><\/p>\n

CHMP List of questions<\/span><\/p>\n

To be addressed by the marketing authorisation holders for valsartan-containing medicinal products<\/span><\/p>\n

CHMP<\/span>\u8981\u6c42\u542b\u7f2c\u6c99\u5766\u836f\u54c1<\/span>MAH<\/span>\u56de\u7b54\u7684\u95ee\u9898<\/span><\/span><\/p>\n

 <\/span><\/p>\n

Referral under Article 31 of Directive 2001\/83\/EC<\/span><\/p>\n

\u4f9d\u6307\u4ee4<\/span>2001\/83\/EC<\/span>\u7b2c<\/span>31<\/span>\u6761\u8f6c<\/span>EMA<\/span>\u5904\u7f6e\u4e8b\u9879<\/span><\/span><\/p>\n

Procedure number: EMEA\/H\/A-31\/1471<\/span><\/p>\n

\u7a0b\u5e8f\u7f16\u53f7\uff1a<\/span>EMEA\/H\/A-31\/1471<\/span><\/span><\/p>\n


<\/span><\/p>\n

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<\/span><\/p>\n

Active substance: valsartan<\/span><\/p>\n

\u6d3b\u6027\u7269\u8d28\uff1a\u7f2c\u6c99\u5766<\/span><\/p>\n


<\/p>\n

1.  Background <\/span>\u80cc\u666f<\/span><\/strong><\/span><\/p>\n

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.<\/span><\/p>\n

\u7f2c\u6c99\u5766\u662f\u5728<\/span>EU<\/span>\u5185\u6279\u51c6\u7684\u8840\u7ba1\u7d27\u5f20\u7d20\u53d7\u4f53\u62ee\u6297\u5242\uff0c\u7528\u4f5c\u5355\u5242\u6216\u4e0e\u5176\u5b83\u6d3b\u6027\u7269\u8d28\u4e00\u8d77\u7528\u4f5c\u590d\u5408\u5242\uff0c\u6cbb\u7597\u9ad8\u8840\u538b\u3001\u8fd1\u671f\u5fc3\u810f\u75c5\u53d1\u53ca\u5fc3\u529b\u8870\u7aed\uff0c\u8be5\u836f\u54c1\u5728\u56fd\u5bb6\u836f\u76d1\u548c\u96c6\u4e2d\u5ba1\u8bc4\u5747\u6709\u6279\u51c6\u3002<\/span><\/span><\/p>\n

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.<\/span><\/p>\n

EU<\/span>\u836f\u76d1\u6536\u5230\u901a\u77e5\uff0c\u4e00\u4e2a<\/span>API<\/span>\u751f\u4ea7\u5546\uff08\u6d59\u6c5f\u534e\u6d77\u836f\u4e1a\uff0c\u4e2d\u56fd\uff09\u5728\u5176\u5ddd\u5357\u5de5\u5382\u751f\u4ea7\u7684\u7f2c\u6c99\u5766<\/span>API<\/span>\u4e2d\u68c0\u51fa\u4e4b\u524d\u672a\u68c0\u51fa\u6742\u8d28\uff0c<\/span>N-<\/span>\u4e8c\u7532\u57fa\u4e9a\u785d\u80fa\uff08<\/span>NDMA<\/span>\uff09\u3002\u6d59\u6c5f\u534e\u6d77\u662f\u4e3a<\/span>EU<\/span>\u6279\u51c6\u7684\u836f\u54c1\u4f9b\u5e94\u7f2c\u6c99\u5766\u7684<\/span>API<\/span>\u751f\u4ea7\u5546\u4e4b\u4e00\u3002<\/span><\/span><\/p>\n

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).<\/span><\/p>\n

NDMA<\/span>\u662f\u4e00\u79cd\u52a8\u7269\u57fa\u56e0\u6bd2\u6027\u548c\u81f4\u764c\u7269\u8d28\uff0c<\/span>IARC<\/span>\u5c06\u5176\u5f52\u7c7b\u4e3a\u53ef\u80fd\u7684\u4eba\u7c7b\u81f4\u764c\u7269\u8d28\uff08<\/span>WHO<\/span>\u56fd\u9645\u764c\u75c7\u7814\u7a76\u673a\u6784\uff09\u3002<\/span><\/span><\/p>\n

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.<\/span><\/p>\n

\u751f\u4ea7\u5546\u5bf9<\/span>NDMA<\/span>\u51fa\u73b0\u7684\u6839\u672c\u539f\u56e0\u521d\u6b65\u8c03\u67e5\u62a5\u544a\u663e\u793a<\/span>NDMA<\/span>\u662f\u5728\u7f2c\u6c99\u5766<\/span>API<\/span>\u751f\u4ea7\u5de5\u827a\u7684\u7279\u5b9a\u6b65\u9aa4\u5f62\u6210\u7684\uff0c<\/span>NDMA<\/span>\u7684\u6c34\u5e73\u53ef\u80fd\u53d6\u51b3\u4e8e\u6240\u7528\u7684\u53cd\u5e94\u6761\u4ef6\u3002<\/span><\/span><\/p>\n

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.<\/span><\/p>\n

\u4f9d\u636e\u6b64\u751f\u4ea7\u5546\u5bf9<\/span>API<\/span>\u6279\u6b21\u5c0f\u91cf\u968f\u673a\u62bd\u6837\u68c0\u6d4b\uff0c<\/span>NDMA<\/span>\u68c0\u51fa\u6c34\u5e73\u5728<\/span>3.4ppm<\/span>\u81f3<\/span>120ppm<\/span>\u4e4b\u95f4\uff0c\u5e73\u5747\u4e3a<\/span>66.5ppm<\/span>\u3002\u4f9d\u636e<\/span>ICM M7<\/span>\u539f\u5219\uff0c\u8003\u8651\u5230<\/span>NDMA<\/span>\u5c5e\u4e8e<\/span>N-<\/span>\u4e9a\u80fa\u7c7b\u5316\u5408\u7269\uff0c\u6b64\u6c34\u5e73\u4ee4\u4eba\u62c5\u5fe7\u3002<\/span><\/span><\/p>\n

The EC requestedon 5 July 2018 the initiation of a Referral under Article 31 of Directive2001\/83\/EC.<\/span><\/p>\n

EC<\/span>\u8981\u6c42\u5728<\/span>2018<\/span>\u5e74<\/span>7<\/span>\u6708<\/span>5<\/span>\u65e5\u4f9d\u636e\u6307\u4ee4<\/span>2001\/83\/EC<\/span>\u7b2c<\/span>31<\/span>\u6761\u542f\u52a8\u8f6c<\/span>EMA<\/span>\u5904\u7f6e\u7a0b\u5e8f\u3002<\/span><\/span><\/p>\n

2.   Questions <\/span>\u95ee\u9898<\/span><\/strong><\/span><\/p>\n

The marketingauthorisation holders (MAHs) of valsartan-containing medicinal products arerequested to address the following questions:<\/span><\/p>\n

\u73b0\u5728\u8981\u6c42\u542b\u7f2c\u6c99\u5766\u836f\u54c1\u7684\u4e0a\u5e02\u8bb8\u53ef\u6301\u6709\u4eba\uff08<\/span>MAH<\/span>\uff09\u56de\u7b54\u4ee5\u4e0b\u95ee\u9898\uff1a<\/span><\/span><\/p>\n

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.<\/span><\/p>\n

NDMA<\/span>\u53ef\u80fd\u4f1a\u5728\u56db\u5511\u73af\u5f62\u6210\u8fc7\u7a0b\u4e2d\u901a\u8fc7\u4e8c\u7532\u80fa\uff08\u53ef\u80fd\u4f1a\u4ee5\u6742\u8d28\u5f62\u5f0f\u51fa\u73b0\u5728<\/span>DMF<\/span>\u6eb6\u5242\u4e2d\u6216\u7531\u5176\u964d\u89e3\u800c\u6210\uff09\u4e0e\u4e9a\u785d\u9178\u94a0\u5728\u9178\u6027\u6761\u4ef6\u4e0b\uff08\u5f62\u6210\u4e9a\u785d\u9178\uff09\u53cd\u5e94\u751f\u6210\u3002\u4e0e\u5176\u5b83\u6eb6\u5242\u6216\u5728\u5176\u5b83\u6709\u5176\u5b83\u80fa\u7c7b\u5b58\u5728\u65f6\u5728\u7279\u5b9a\u53cd\u5e94\u6761\u4ef6\u4e0b\u751f\u6210\u5176\u5b83<\/span>N-<\/span>\u4e9a\u785d\u80fa\u7c7b\u7684\u60c5\u51b5\u4ea6\u4e0d\u53ef\u6392\u9664\u3002<\/span><\/span><\/p>\n

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.<\/span><\/p>\n

\u8bf7\u8bf4\u660e\u4f60\u4eec\u76ee\u524d\u662f\u5426\u6709\u4f7f\u7528\uff08\u6216\u4e4b\u524d\u66fe\u4f7f\u7528\u7684\uff09\u4efb\u4f55<\/span>API<\/span>\u4f9b\u5e94\u5546\uff08\u6d59\u6c5f\u534e\u6d77\u6216\u5176\u5b83\uff09\uff0c\u4ed6\u4eec\u4f7f\u7528\u4e86\u53ef\u80fd\u4f1a\u5bfc\u81f4\uff0c\u6216\u5df2\u7ecf\u5bfc\u81f4\uff0c<\/span>NDMA<\/span>\u6216\u5176\u5b83\u4efb\u4f55\u53ef\u80fd\u7684<\/span>N-<\/span>\u4e9a\u785d\u80fa\u6742\u8d28\u7684\u7f2c\u6c99\u5766\u751f\u4ea7\u5de5\u827a\u6b65\u9aa4\u3002<\/span><\/span><\/p>\n

2.         If the answer to Q1 is yes, you arerequested to provide details on:<\/span><\/p>\n

\u5982\u679c\u5bf9\u7b2c\u4e00\u4e2a\u95ee\u9898\u7684\u56de\u7b54\u662f\u80af\u5b9a\u7684\uff0c\u8bf7\u63d0\u4ea4\u4ee5\u4e0b\u8be6\u7ec6\u4fe1\u606f\uff1a<\/span><\/p>\n

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;<\/span><\/p>\n

\u4f7f\u7528\u8fd9\u4e9b\u4f9b\u5e94\u5546\u7684\u65f6\u6bb5\uff0c\u4ee5\u53ca\u5176\u5bf9\u653e\u884c\u81f3\u6b27\u6d32\u5e02\u573a\u7684\u6700\u7ec8\u836f\u54c1\u6279\u6b21\u7684\u5f71\u54cd\uff0c\u5305\u62ec\u9500\u552e\u6570\u636e\u4ee5\u53ca<\/span>EU\/EEA<\/span>\u6210\u5458\u56fd\u5185\u66b4\u9732\u4e8e\u542b<\/span>NDMA<\/span>\u6742\u8d28\u7684\u836f\u54c1\u7684\u60a3\u8005\u6570\u636e\uff1b<\/span><\/span><\/p>\n

b)         data in the annexed table on the use inclinical practice including information on indication, dose, and duration oftreatment;<\/span><\/p>\n

\u9644\u8868\u4e2d\u7528\u4e8e\u4e34\u5e8a\u8bd5\u9a8c\u7684\u6570\u636e\uff0c\u5305\u62ec\u9002\u7528\u75c7\u4fe1\u606f\u3001\u5242\u91cf\u548c\u6cbb\u7597\u65f6\u957f\uff1b<\/span><\/p>\n

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;<\/span><\/p>\n

\u5728\u4f60\u4eec\u7684\u5236\u5242\u4e2d<\/span>NDMA<\/span>\u51fa\u73b0\u7684\u6c34\u5e73\u5982\u4f55\u3002\u5982\u679c\u5236\u5242\u6279\u6b21\u7ecf\u8fc7\u68c0\u6d4b\uff0c\u8bf7\u63d0\u4ea4\u6240\u7528\u7684\u5206\u6790\u65b9\u6cd5\u8be6\u7ec6\u4fe1\u606f\uff0c\u5305\u62ec\u5176\u9a8c\u8bc1\uff1b<\/span><\/span><\/p>\n

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;<\/span><\/p>\n

\u5982\u679c\u5c1a\u672a\u8fdb\u884c\u68c0\u6d4b\uff0c\u4f60\u4eec\u7684\u8ba1\u5212\uff0c\u5305\u62ec\u68c0\u6d4b\u53d6\u6837\u7b56\u7565\u3001\u76f8\u5173\u5206\u6790\u65b9\u6cd5\u5f00\u53d1\u548c\u9a8c\u8bc1\u8ba1\u5212\uff1b<\/span><\/p>\n

e)         a calculation of NDMA acceptable dailyintake levels considering the framework described in ICH M7 as applicable tothe class of nitrosamines.<\/span><\/p>\n

\u8003\u8651<\/span>ICH M7<\/span>\u4e2d\u9002\u7528\u4e8e\u4e9a\u80fa\u7c7b\u7684\u6240\u8ff0\u6846\u67b6\uff0c\u8ba1\u7b97<\/span>NDMA<\/span>\u65e5\u53ef\u63a5\u53d7\u6444\u5165\u6c34\u5e73\u7684\u8ba1\u7b97\u60c5\u51b5\uff1b<\/span><\/span><\/p>\n

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.<\/span><\/p>\n

\u5173\u4e8e\u4e0a\u8ff0\u5185\u5bb9\u7684\u6240\u6709\u62df\u5b9a<\/span>CAPA<\/span>\uff0c\u786e\u4fdd\u5236\u5242\u4e2d\u4e0d\u542b\u6709\u8d85\u51fa\u65e5\u53ef\u63a5\u53d7\u6444\u5165\u91cf\u3002\u8bf7\u8bf4\u660e\u53ef\u80fd\u505a\u51fa\u7684\u5bf9\u4e2d\u63a7\u3001\u5236\u5242\u8d28\u91cf\u6807\u51c6\u548c\u6709\u5173\u5206\u6790\u65b9\u6cd5\u53ca\u5176\u9a8c\u8bc1\u7684\u53ef\u9884\u89c1\u53d8\u66f4\u3002<\/span><\/span><\/p>\n


<\/span><\/p>\n

<\/span>Annex \u9644\u5f55<\/span><\/span><\/p>\n\n\n\n\n
\n

INN<\/span><\/strong><\/span><\/p>\n<\/td>\n

\n

Product<\/span><\/strong> na<\/span><\/span><\/strong>me<\/span><\/strong><\/span><\/p>\n<\/td>\n

\n

Indicat<\/span><\/strong><\/span>ions<\/span><\/strong><\/span><\/p>\n<\/td>\n

\n

Pharmaceuticalforms andstrengths<\/span><\/p>\n<\/td>\n

\n

Doses  (asapproved and usedin clinicalpractice)<\/span><\/p>\n<\/td>\n

\n

Treatment duration (asapproved  and used inclinicalpractice)<\/span><\/p>\n<\/td>\n<\/tr>\n

\n

\u901a\u7528\u540d<\/span><\/p>\n<\/td>\n

\n

\u54c1\u540d<\/span><\/p>\n<\/td>\n

\n

\u9002\u5e94\u75c7<\/span><\/p>\n<\/td>\n

\n

\u5242\u578b\u89c4\u683c<\/span><\/p>\n<\/td>\n

\n

\u5242\u91cf\uff08\u6279\u51c6\u53ca\u4e34\u5e8a\u4f7f\u7528\uff09<\/span><\/p>\n<\/td>\n

\n

\u6cbb\u7597\u65f6\u957f\uff08\u6279\u51c6\u53ca\u4e34\u5e8a\u4f7f\u7528\uff09<\/span><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n


<\/p>\n

CHMP\u8981\u6c42\u542b\u7f2c\u6c99\u5766\u836f\u54c1\u7684API\u751f\u4ea7\u5546\u56de\u7b54\u7684\u95ee\u9898 <\/strong><\/span><\/h2>\n

16 July 2018<\/span><\/p>\n

EMA\/CHMP\/466974\/2018<\/span><\/p>\n

CHMP List ofquestions<\/span><\/p>\n

To be addressed bythe API manufacturers for valsartan-containing medicinal products<\/span><\/p>\n

CHMP<\/span>\u8981\u6c42\u542b\u7f2c\u6c99\u5766\u836f\u54c1\u7684<\/span>API<\/span>\u751f\u4ea7\u5546\u56de\u7b54\u7684\u95ee\u9898<\/span><\/span><\/p>\n

Referral under Article 31 of Directive2001\/83\/EC<\/span><\/p>\n

\u4f9d\u6307\u4ee4<\/span>2001\/83\/EC<\/span>\u7b2c<\/span>31<\/span>\u6761\u8f6c<\/span>EMA<\/span>\u5904\u7f6e\u4e8b\u9879<\/span><\/span><\/p>\n

Procedure number: EMEA\/H\/A-31\/1471<\/span><\/p>\n

\u7a0b\u5e8f\u7f16\u53f7\uff1a<\/span>EMEA\/H\/A-31\/1471<\/span><\/span><\/p>\n

Active substance: valsartan<\/span><\/p>\n

\u6d3b\u6027\u7269\u8d28\uff1a\u7f2c\u6c99\u5766<\/span><\/p>\n

1.<\/span><\/strong>Background<\/span><\/strong>\u80cc\u666f<\/span><\/strong><\/span><\/span><\/p>\n

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.<\/span><\/p>\n

\u7f2c\u6c99\u5766\u662f\u5728<\/span>EU<\/span>\u5185\u6279\u51c6\u7684\u8840\u7ba1\u7d27\u5f20\u7d20\u53d7\u4f53\u62ee\u6297\u5242\uff0c\u7528\u4f5c\u5355\u5242\u6216\u4e0e\u5176\u5b83\u6d3b\u6027\u7269\u8d28\u4e00\u8d77\u7528\u4f5c\u590d\u5408\u5242\uff0c\u6cbb\u7597\u9ad8\u8840\u538b\u3001\u8fd1\u671f\u5fc3\u810f\u75c5\u53d1\u53ca\u5fc3\u529b\u8870\u7aed\uff0c\u8be5\u836f\u54c1\u5728\u56fd\u5bb6\u836f\u76d1\u548c\u96c6\u4e2d\u5ba1\u8bc4\u5747\u6709\u6279\u51c6\u3002<\/span><\/span><\/p>\n

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.<\/span><\/p>\n

EU<\/span>\u836f\u76d1\u6536\u5230\u901a\u77e5\uff0c\u4e00\u4e2a<\/span>API<\/span>\u751f\u4ea7\u5546\uff08\u6d59\u6c5f\u534e\u6d77\u836f\u4e1a\uff0c\u4e2d\u56fd\uff09\u5728\u5176\u5ddd\u5357\u5de5\u5382\u751f\u4ea7\u7684\u7f2c\u6c99\u5766<\/span>API<\/span>\u4e2d\u68c0\u51fa\u4e4b\u524d\u672a\u68c0\u51fa\u6742\u8d28\uff0c<\/span>N-<\/span>\u4e8c\u7532\u57fa\u4e9a\u785d\u80fa\uff08<\/span>NDMA<\/span>\uff09\u3002\u6d59\u6c5f\u534e\u6d77\u662f\u4e3a<\/span>EU<\/span>\u6279\u51c6\u7684\u836f\u54c1\u4f9b\u5e94\u7f2c\u6c99\u5766\u7684<\/span>API<\/span>\u751f\u4ea7\u5546\u4e4b\u4e00\u3002<\/span><\/span><\/p>\n

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).<\/span><\/p>\n

NDMA<\/span>\u662f\u4e00\u79cd\u52a8\u7269\u57fa\u56e0\u6bd2\u6027\u548c\u81f4\u764c\u7269\u8d28\uff0c<\/span>IARC<\/span>\u5c06\u5176\u5f52\u7c7b\u4e3a\u53ef\u80fd\u7684\u4eba\u7c7b\u81f4\u764c\u7269\u8d28\uff08<\/span>WHO<\/span>\u56fd\u9645\u764c\u75c7\u7814\u7a76\u673a\u6784\uff09\u3002<\/span><\/span><\/p>\n

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.<\/span><\/p>\n

\u751f\u4ea7\u5546\u5bf9<\/span>NDMA<\/span>\u51fa\u73b0\u7684\u6839\u672c\u539f\u56e0\u521d\u6b65\u8c03\u67e5\u62a5\u544a\u663e\u793a<\/span>NDMA<\/span>\u662f\u5728\u7f2c\u6c99\u5766<\/span>API<\/span>\u751f\u4ea7\u5de5\u827a\u7684\u7279\u5b9a\u6b65\u9aa4\u5f62\u6210\u7684\uff0c<\/span>NDMA<\/span>\u7684\u6c34\u5e73\u53ef\u80fd\u53d6\u51b3\u4e8e\u6240\u7528\u7684\u53cd\u5e94\u6761\u4ef6\u3002<\/span><\/span><\/p>\n

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.<\/span><\/p>\n

\u4f9d\u636e\u6b64\u751f\u4ea7\u5546\u5bf9<\/span>API<\/span>\u6279\u6b21\u5c0f\u91cf\u968f\u673a\u62bd\u6837\u68c0\u6d4b\uff0c<\/span>NDMA<\/span>\u68c0\u51fa\u6c34\u5e73\u5728<\/span>3.4ppm<\/span>\u81f3<\/span>120ppm<\/span>\u4e4b\u95f4\uff0c\u5e73\u5747\u4e3a<\/span>66.5ppm<\/span>\u3002\u4f9d\u636e<\/span>ICM M7<\/span>\u539f\u5219\uff0c\u8003\u8651\u5230<\/span>NDMA<\/span>\u5c5e\u4e8e<\/span>N-<\/span>\u4e9a\u80fa\u7c7b\u5316\u5408\u7269\uff0c\u6b64\u6c34\u5e73\u4ee4\u4eba\u62c5\u5fe7\u3002<\/span><\/span><\/p>\n

The EC requested on 5 July 2018 the initiation of a Referral under Article 31 of Directive 2001\/83\/EC.<\/span><\/p>\n

EC<\/span>\u8981\u6c42\u5728<\/span>2018<\/span>\u5e74<\/span>7<\/span>\u6708<\/span>5<\/span>\u65e5\u4f9d\u636e\u6307\u4ee4<\/span>2001\/83\/EC<\/span>\u7b2c<\/span>31<\/span>\u6761\u542f\u52a8\u8f6c<\/span>EMA<\/span>\u5904\u7f6e\u7a0b\u5e8f\u3002<\/span><\/span><\/p>\n

2. Questions <\/span><\/strong>\u95ee\u9898<\/span><\/strong><\/span><\/span><\/p>\n

The valsartan API manufactuers are requested to address the following questions:<\/span><\/p>\n

\u73b0\u5728\u8981\u6c42\u7f2c\u6c99\u5766\u7684<\/span>API<\/span>\u751f\u4ea7\u5546\u56de\u7b54\u4ee5\u4e0b\u95ee\u9898\uff1a<\/span><\/span><\/p>\n

To all API manufacturers with confirmed presence of NDMA in the API:<\/span><\/strong><\/span><\/p>\n

\u6240\u6709\u5df2\u786e\u8ba4\u5728<\/span>API<\/span>\u4e2d\u6709\u51fa\u73b0<\/span>NDMA<\/span>\u7684<\/span>API<\/span>\u751f\u4ea7\u5546\uff1a<\/span><\/strong><\/span><\/p>\n

Please provide summaries and any updates since the last response to EMA on the below points:<\/span><\/p>\n

\u8bf7\u5411<\/span>EMA<\/span>\u63d0\u4ea4\u5173\u4e8e\u4ee5\u4e0b\u51e0\u4e2a\u95ee\u9898\u81ea\u4e0a\u6b21\u56de\u590d\u4e4b\u540e\u7684\u603b\u7ed3\u548c\u66f4\u65b0\uff1a<\/span><\/span><\/p>\n

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.<\/span><\/p>\n

\u751f\u4ea7\u5546\u9700\u8981\u63d0\u4ea4\u4e3a<\/span>EU\/EEA<\/span>\u6279\u51c6\u7684\u5177\u6709\u542b<\/span>NDMA<\/span>\u98ce\u9669\u7684\u836f\u54c1\u6240\u751f\u4ea7\u7684<\/span>API<\/span>\u6279\u6b21\u4e2d<\/span>NDMA<\/span>\u542b\u91cf\u7684\u4fe1\u606f\uff08\u4f8b\u5982\uff0c\u5728\u751f\u4ea7\u53d8\u66f4\u540e\uff09\u3002\u6b64\u5916\uff0c\u4ea6\u5e94\u63d0\u4ea4\u5173\u4e8e\u68c0\u6d4b\u8ba1\u5212\u7684\u8fdb\u5c55\u4fe1\u606f\u548c\u6240\u6709\u4e34\u65f6\u7ed3\u679c\u60c5\u51b5\u3002<\/span><\/span><\/p>\n

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.<\/span><\/p>\n

\u8bf7\u8bf4\u660e\u6240\u6d4b\u6279\u6b21\u4e2d\u6c61\u67d3\u7684\u6ce2\u52a8\u60c5\u51b5\uff0c\u4f8b\u5982\uff0c\u4ece\u53ef\u80fd\u5f71\u54cd<\/span>NDMA<\/span>\u5f62\u6210\u7684\u5de5\u827a\u53c2\u6570\u89d2\u5ea6\u6765\u770b\uff0c\u6216\u8005\u662f\u7531\u4e8e\u6240\u7528\u8f66\u95f4\u4e0d\u540c\u53ef\u80fd\u5bfc\u81f4\u8bbe\u5907\u5dee\u5f02\u3002<\/span><\/span><\/p>\n

3. Please provide details on <\/span>\u8bf7\u63d0\u4ea4\u4ee5\u4e0b\u8be6\u7ec6\u4fe1\u606f<\/span><\/span><\/p>\n

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.<\/span><\/p>\n

\u5728<\/span>API<\/span>\u7f2c\u6c99\u5766\u4e2d\u68c0\u51fa<\/span>NDMA<\/span>\u7684\u5b9a\u91cf\u5206\u6790\u65b9\u6cd5\u3001\u68c0\u51fa\u9650\u3001\u5b9a\u91cf\u9650\u53ca\u8be5\u65b9\u6cd5\u7684\u9a8c\u8bc1\u72b6\u6001\u8bf4\u660e\u3002<\/span><\/span><\/p>\n

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.<\/span><\/p>\n

\u6240\u6709\u4e3a\u786e\u4fdd\u751f\u4ea7\u5de5\u827a\u4e0d\u751f\u6210<\/span>NDMA<\/span>\u6216\u63a7\u5236<\/span>NDMA<\/span>\u6c34\u5e73\u5728\u53ef\u63a5\u53d7\u7684\u65e5\u6444\u5165\u6c34\u5e73\u4ee5\u4e0b\u7684<\/span>CAPA<\/span>\u3002\u8bf7\u8bf4\u660e\u6240\u6709\u53ef\u80fd\u7684\u5bf9\u751f\u4ea7\u5de5\u827a\u3001\u4e2d\u63a7\u3001<\/span>API<\/span>\u8d28\u91cf\u6807\u51c6\u548c\u76f8\u5173\u5206\u6790\u65b9\u6cd5\u53ca\u5176\u9a8c\u8bc1\u7684\u53ef\u9884\u89c1\u53d8\u66f4\u3002<\/span><\/span><\/p>\n

To all other API manufacturers:<\/span><\/strong><\/span><\/p>\n

\u6240\u6709\u5176\u5b83<\/span><\/strong>API<\/span><\/strong>\u751f\u4ea7\u5546\uff1a<\/span><\/strong><\/span><\/p>\n

1.    <\/span>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.<\/span>
<\/span><\/span><\/p>\n

NDMA<\/span>\u53ef\u80fd\u4f1a\u5728\u56db\u5511\u73af\u5f62\u6210\u8fc7\u7a0b\u4e2d\u901a\u8fc7\u4e8c\u7532\u80fa\uff08\u53ef\u80fd\u4f1a\u4ee5\u6742\u8d28\u5f62\u5f0f\u51fa\u73b0\u5728<\/span>DMF<\/span>\u6eb6\u5242\u4e2d\u6216\u7531\u5176\u964d\u89e3\u800c\u6210\uff09\u4e0e\u4e9a\u785d\u9178\u94a0\u5728\u9178\u6027\u6761\u4ef6\u4e0b\uff08\u5f62\u6210\u4e9a\u785d\u9178\uff09\u53cd\u5e94\u751f\u6210\u3002\u4e0e\u5176\u5b83\u6eb6\u5242\u6216\u5728\u5176\u5b83\u6709\u5176\u5b83\u80fa\u7c7b\u5b58\u5728\u65f6\u5728\u7279\u5b9a\u53cd\u5e94\u6761\u4ef6\u4e0b\u751f\u6210\u5176\u5b83<\/span>N-<\/span>\u4e9a\u785d\u80fa\u7c7b\u7684\u60c5\u51b5\u4ea6\u4e0d\u53ef\u6392\u9664\u3002<\/span><\/span><\/p>\n

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.<\/span><\/p>\n

\u8bf7\u8bf4\u660e\u4f60\u4eec\u76ee\u524d\u662f\u5426\u6709\u4f7f\u7528\uff08\u6216\u4e4b\u524d\u66fe\u4f7f\u7528\u7684\uff09\u4efb\u4f55\u53ef\u80fd\u4f1a\u5bfc\u81f4\uff0c\u6216\u5df2\u7ecf\u5bfc\u81f4\uff0c<\/span>NDMA<\/span>\u6216\u5176\u5b83\u4efb\u4f55\u53ef\u80fd\u7684<\/span>N-<\/span>\u4e9a\u785d\u80fa\u6742\u8d28\u7684\u7f2c\u6c99\u5766\u751f\u4ea7\u5de5\u827a\u6b65\u9aa4\u3002<\/span><\/span><\/p>\n

2.    <\/span>If the answer to Q1 is yes, you are requested to provide details on:<\/span>
<\/span><\/span><\/p>\n

\u5982\u679c\u5bf9\u7b2c\u4e00\u4e2a\u95ee\u9898\u7684\u56de\u7b54\u662f\u80af\u5b9a\u7684\uff0c\u8bf7\u63d0\u4ea4\u4ee5\u4e0b\u8be6\u7ec6\u4fe1\u606f\uff1a<\/span><\/p>\n

a)    <\/span>when was this process introduced for the manufacture of valsartan (or for how long it has been used, if in the past);<\/span>
<\/span><\/span><\/p>\n

\u4f55\u65f6\u5f15\u5165\u6b64\u5de5\u827a\u7528\u4e8e\u7f2c\u6c99\u5766\u751f\u4ea7\uff08\u6216\u5982\u679c\u5728\u8fc7\u53bb\u5c31\u5df2\u4f7f\u7528\uff0c\u4f7f\u7528\u4e86\u591a\u957f\u65f6\u95f4\uff09\uff1b<\/span><\/p>\n

b)   <\/span>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;<\/span>
<\/span><\/span><\/p>\n

\u5728\u6d3b\u6027\u7269\u8d28\u6279\u6b21\u4e2d<\/span>NDMA<\/span>\u7684\u6c34\u5e73\u5982\u4f55\u3002\u8bf7\u63d0\u4ea4\u7528\u4e8e\u9274\u522b\u548c\u5b9a\u91cf<\/span>NDMA<\/span>\u7684\u5206\u6790\u65b9\u6cd5\u7684\u5168\u90e8\u7ec6\u8282\uff0c\u5305\u62ec\u65b9\u6cd5\u9a8c\u8bc1\uff1b<\/span><\/span><\/p>\n

c)    <\/span>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;<\/span>
<\/span><\/span><\/p>\n

\u5982\u679c\u5c1a\u672a\u786e\u5b9a\u5176\u6c34\u5e73\uff0c\u4f60\u4eec\u5728\u68c0\u6d4b\u53d6\u6837\u7b56\u7565\u3001\u76f8\u5173\u5206\u6790\u65b9\u6cd5\u5f00\u53d1\u548c\u9a8c\u8bc1\u65b9\u9762\u7684\u8ba1\u5212\u5982\u4f55\uff1b<\/span><\/p>\n

d)   <\/span>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;<\/span>
<\/span><\/span><\/p>\n

\u5bf9\u5f53\u524d\u7684\uff08\u6216\u8fc7\u53bb\u7684\uff09\u751f\u4ea7\u5de5\u827a\u91c7\u53d6\u7684\u51cf\u5c11\u3001\u6d88\u9664\u6216\u907f\u514d\u6210\u54c1<\/span>API<\/span>\u5de5\u827a\u4e2d\u6216\u6210\u54c1\u4e2d<\/span>NDMA<\/span>\u5f62\u6210\u7684\u6240\u6709\u98ce\u9669\u964d\u4f4e\u6b65\u9aa4\uff1b<\/span><\/span><\/p>\n

e)    <\/span>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.<\/span>
<\/span><\/span><\/p>\n

\u4e3a\u786e\u4fdd\u751f\u4ea7\u5de5\u827a\u4e0d\u751f\u6210<\/span>NDMA<\/span>\u6216\u4f7f\u5f97<\/span>NDMA<\/span>\u6c34\u5e73\u5728\u53ef\u63a5\u53d7\u65e5\u6444\u5165\u91cf\u6c34\u5e73\u4ee5\u4e0b\u800c\u62df\u5b9a\u7684<\/span>CAPA<\/span>\u3002\u8bf7\u8bf4\u660e\u5bf9\u6240\u6709\u53ef\u80fd\u7684\u5bf9\u751f\u4ea7\u5de5\u827a\u3001\u4e2d\u63a7\u3001<\/span>API<\/span>\u8d28\u91cf\u6807\u51c6\u548c\u76f8\u5173\u5206\u6790\u65b9\u6cd5\u53ca\u5176\u9a8c\u8bc1\u7684\u53ef\u9884\u89c1\u53d8\u66f4\u3002<\/span><\/span><\/p>\n

\"CHMP\u8981\u6c42\u542b\u7f2c\u6c99\u5766\u836f\u54c1MAH\uff08\u7684API\u751f\u4ea7\u5546\uff09\u56de\u7b54\u7684\u95ee\u9898\"<\/p>\n

\n

\u59cb\u53d1\u4e8e\u5fae\u4fe1\u516c\u4f17\u53f7\uff1a \u84b2\u516c\u82f1 <\/p>\n<\/blockquote>\n<\/div>\n","protected":false},"excerpt":{"rendered":"

\u7ffb\u8bd1 JULIA   \u6765\u6e90\uff1aJulia\u6cd5\u89c4\u7ffb\u8bd1  CHMP\u8981\u6c42\u542b\u7f2c\u6c99\u5766 […]<\/p>\n","protected":false},"author":1,"featured_media":20503,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":[],"categories":[2],"tags":[],"_links":{"self":[{"href":"https:\/\/www.05921.net\/index.php\/wp-json\/wp\/v2\/posts\/20502"}],"collection":[{"href":"https:\/\/www.05921.net\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.05921.net\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.05921.net\/index.php\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.05921.net\/index.php\/wp-json\/wp\/v2\/comments?post=20502"}],"version-history":[{"count":1,"href":"https:\/\/www.05921.net\/index.php\/wp-json\/wp\/v2\/posts\/20502\/revisions"}],"predecessor-version":[{"id":20508,"href":"https:\/\/www.05921.net\/index.php\/wp-json\/wp\/v2\/posts\/20502\/revisions\/20508"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.05921.net\/index.php\/wp-json\/wp\/v2\/media\/20503"}],"wp:attachment":[{"href":"https:\/\/www.05921.net\/index.php\/wp-json\/wp\/v2\/media?parent=20502"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.05921.net\/index.php\/wp-json\/wp\/v2\/categories?post=20502"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.05921.net\/index.php\/wp-json\/wp\/v2\/tags?post=20502"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}