{"id":36575,"date":"2018-09-07T01:00:00","date_gmt":"2018-09-17T06:04:53","guid":{"rendered":"http:\/\/www.05921.net\/index.php\/2018\/09\/17\/%e6%b8%85%e6%b4%81%e9%aa%8c%e8%af%81%ef%bc%9a%e5%93%aa%e4%ba%9b%e4%ba%a7%e5%93%81%e9%9c%80%e8%a6%81%e8%ae%a1%e7%ae%97pde%ef%bc%9f\/"},"modified":"2018-09-17T14:04:55","modified_gmt":"2018-09-17T06:04:55","slug":"%e6%b8%85%e6%b4%81%e9%aa%8c%e8%af%81%ef%bc%9a%e5%93%aa%e4%ba%9b%e4%ba%a7%e5%93%81%e9%9c%80%e8%a6%81%e8%ae%a1%e7%ae%97pde%ef%bc%9f","status":"publish","type":"post","link":"https:\/\/www.05921.net\/index.php\/36575\/","title":{"rendered":"\u6e05\u6d01\u9a8c\u8bc1\uff1a\u54ea\u4e9b\u4ea7\u54c1\u9700\u8981\u8ba1\u7b97PDE\uff1f"},"content":{"rendered":"
\n
<\/mpcps><\/section>\n

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\"\u6e05\u6d01\u9a8c\u8bc1\uff1a\u54ea\u4e9b\u4ea7\u54c1\u9700\u8981\u8ba1\u7b97PDE\uff1f\"
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\u5916\u8d44\u5927\u578b\u5236\u836f\u516c\u53f8\u6280\u672f\u3001\u7814\u53d1\u3001\u8d28\u91cf\u603b\u76d1\uff0c\u9a8c\u8bc1\u7ba1\u7406\u8d44\u6df1\u4e13\u5bb6\uff0c\u591a\u5bb6\u5236\u836f\u516c\u53f8\u987e\u95ee\uff0c\u836f\u5b66\u7855\u58eb\u3002\u56fd\u5bb6\u5de5\u827a\u6838\u5bf9\u672a\u96e8\u7ef8\u7f2a\u4e4b\u9645\uff0c\u6210\u529f\u89e3\u51b3\u4e86\u591a\u5bb6\u5728\u4ea7\u4ea7\u54c1\u5904\u65b9\u3001\u5de5\u827a\u95ee\u9898\u3002\u5904\u65b9\u5de5\u827a\u7684\u4e8c\u6b21\u5f00\u53d1\uff0c\u514d\u8d39\u54a8\u8be2\uff0c\u5168\u7a0b\u4fdd\u5bc6\u3002\u90ae\u7bb1\uff1a1193686015@qq.com\u3002<\/span><\/span><\/p>\n<\/section>\n<\/section>\n<\/section>\n<\/section>\n<\/section>\n<\/section>\n<\/section>\n


<\/p>\n

MHRA\u5728\u5176\u535a\u5ba2\u4e2d\u63d0\u5230PDE\u503c\u8ba1\u7b97\u6307\u5357\u53ea\u662f\u5bf9\u4e8e\u201c\u9ad8\u6709\u5bb3\u201d\u7269\u8d28\u624d\u662f\u6709\u5fc5\u8981\u7684\uff1a<\/p>\n


<\/p>\n

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

\u73b0\u5728MHRA\u8bf4\u5168\u9762\u5e94\u7528EMA\u5173\u4e8ePDE\u503c\u8ba1\u7b97\u6307\u5357\u53ea\u662f\u5bf9\u4e8e\u201c\u9ad8\u6709\u5bb3\u201d\u7269\u8d28\u624d\u662f\u6709\u5fc5\u8981\u7684<\/span>\u3002\u4e3a\u4e86\u89e3\u7b54\u4e00\u4e2a\u4ea7\u54c1\u662f\u5426\u9ad8\u6709\u5bb3\u6027\uff0c\u5927\u5bb6\u53ef\u4ee5\u53c2\u7167\u65b0\u7684EMA\u95ee\u7b54\u6587\u4ef6\u3002\u4e0d\u8bba\u5982\u4f55\uff0c\u5927\u5bb6\u8981\u8c28\u8bb0\uff0c\u6839\u636eEMA\u6587\u4e2d\u65b9\u6cd5\u8fdb\u884c\u7684\u5371\u5bb3\u5206\u6790\u4e5f\u9700\u8981\u79d1\u5b66\u6570\u636e<\/span>\uff0c\u7528\u8fd9\u4e9b\u6570\u636e\u4e5f\u53ef\u4ee5\u8ba1\u7b97PDE\u9650\u5ea6\u3002<\/span><\/p>\n


<\/p>\n

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. <\/p>\n

\u4f46\u662f\uff0c\u5e94\u8be5\u8ba1\u7b97\u6240\u6709\u4ea7\u54c1\u7684\u57fa\u4e8e\u5065\u5eb7\u7684\u66b4\u9732\u9650\uff08HBEL\uff09\u3002\u5982\u679c\u6709\u4e00\u4e2a\u4ea7\u54c1\u88ab\u5206\u7c7b\u4e3a\u975e\u201c\u9ad8\u5371\u5bb3\u201d\u4ea7\u54c1\uff0c\u5219\u4ecd\u53ef\u4ee5\u4f7f\u75281\/1000\u5242\u91cf\u6807\u51c6<\/span>\u3002<\/span><\/p>\n


<\/p>\n


<\/p>\n

\u90a3\u4e48\u4ec0\u4e48\u6837\u7684\u4ea7\u54c1\u88ab\u8ba4\u5b9a\u4e3a\u9ad8\u6709\u5bb3\u4ea7\u54c1\u5462\uff0cEMA\u5728\u4e00\u4efd\u95ee\u7b54\u4e2d\u7ed9\u51fa\u4e86\u7b54\u6848\uff1a<\/p>\n


<\/p>\n

\n

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.
\u9ad8\u6709\u5bb3\u7269\u8d28\u662f\u6307\u4f4e\u5242\u91cf\u5373\u53ef\u80fd\u5bfc\u81f4\u4e25\u91cd\u4e0d\u826f\u53cd\u5e94<\/span>\uff0c\u56e0\u800c\u9700\u8981\u8fdb\u884c\u5168\u9762\u6bd2\u6027\u8bc4\u4f30\u4ee5\u5236\u8ba2\u5b89\u5168\u7684HBEL\u7684\u7269\u8d28\u3002
<\/span>
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).
\u9ad8\u6709\u5bb3\u7269\u8d28\u5e94\u6839\u636e\u5176\u5185\u5728\u6bd2\u6027\u548c\u836f\u5b66\u7279\u6027\u8fdb\u884c\u8bc6\u522b\uff0c\u5e76\u5206\u4e3a\u4ee5\u4e0b\u51e0\u7c7b\uff08\u6b64\u6e05\u5355\u5e76\u4e0d\u5305\u542b\u6240\u6709\u60c5\u51b5\uff0c\u5982\u679c\u6709\u8bc1\u636e\u663e\u793a\u8be5\u4ea7\u54c1\u53ef\u80fd\u56e0\u5176\u5b83\u673a\u5236\u7531\u4f4e\u5242\u91cf\u5373\u5bfc\u81f4\u4e0d\u826f\u53cd\u5e94\uff0c\u5219\u4e5f\u5e94\u4f5c\u4e3a\u9ad8\u6709\u5bb3\u7269\u8d28\u8003\u8651\uff09\u3002
<\/span>
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.
\u5982\u679c\u836f\u54c1\/\u6d3b\u6027\u7269\u8d28\u5e94\u4f5c\u4e3a\u9ad8\u6709\u5bb3\u7269\u8d28\uff0c\u5219\u751f\u4ea7\u5546\u5e94\u6839\u636e\u4ee5\u4e0b\u6307\u5357\u8fdb\u884c\u5b89\u5168\u8bc4\u4f30\u3002\u663e\u793a\u4e00\u79cd\u836f\u54c1\u6216\u6d3b\u6027\u7269\u8d28\u5c5e\u4e8e\u4ee5\u4e0b\u67d0\u4e2a\u7c7b\u522b\u7684\u8bc1\u636e\u5e94\u80fd\u8bc1\u660e\u4e00\u79cd\u836f\u54c1\u4f5c\u4e3a\u9ad8\u6709\u5bb3\u7269\u8d28\u6765\u8003\u8651\u3002\u5982\u679c\u6709\u7591\u95ee\uff0c\u5219\u751f\u4ea7\u5546\u5e94\u5c06\u8be5\u7269\u8d28\u4f5c\u4e3a\u6f5c\u5728\u9ad8\u6709\u5bb3\u7269\u8d28\u8003\u8651\uff0c\u5e76\u5168\u9762\u5e94\u7528EMA\u6307\u5357\uff08EMA\/CHMP\/CVMP\/SWP\/169430\/2012\uff09\u6765\u5efa\u7acb\u5b89\u5168HBEL\u3002
<\/span>
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.
\u57fa\u56e0\u6bd2\u6027<\/span>\uff08\u5c24\u5176\u662f\u57fa\u56e0\u8bf1\u53d8\uff09\u5316\u5408\u7269\u4e00\u822c\u662f\uff0c\u6216\u8005\u975e\u5e38\u53ef\u80fd\u662f\uff0c\u5bf9\u4eba\u7c7b\u81f4\u764c\u7684\u3002\u6b64\u7c7b\u5316\u5408\u7269\u4e00\u822c\u6613\u4e8e\u8bc6\u522b\uff0c\u56e0\u4e3a\u57fa\u56e0\u6bd2\u6027\u4e00\u822c\u4e0e\u836f\u5b66\u76f8\u5173\uff0c\u4f8b\u5982\uff0c\u662fDNA\u70f7\u57fa\u5316\u7ec6\u80de\u6291\u5236\u5242\uff0c\u5b83\u4eec\u7684\u4f7f\u7528\u4e00\u822c\u5c40\u9650\u4e8e\u80bf\u7624\u75c7\u72b6\uff0c\u5728\u4ea7\u54c1\u7279\u6027\u6458\u8981\u4e0a\u6709\u76f8\u5173\u7684\u8b66\u793a\u58f0\u660e\u3002<\/span>

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 \u22641 mg\/kg\/day.
\u4f4e\u5242\u91cf\u5373\u53ef\u4ee5\u4ea7\u751f\u751f\u6b96\u53cd\u5e94\u548c\/\u6216\u53d1\u80b2\u53cd\u5e94\u7684\u5316\u5408\u7269<\/span>\uff0c\u4f8b\u5982\uff0c\u6709\u8bc1\u636e\u8bc1\u660e\u6b64\u7c7b\u53cd\u5e94\u662f\u7531\u4e34\u5e8a\u5242\u91cf<10mg\/\u5929<\/span>\uff08\u517d\u836f\u5242\u91cf\u7b49\u4e8e0.2mg\/kg\/\u5929<\/span>\uff09\u6216\u517d\u7528\u7814\u7a76\u22641 mg\/kg\/\u5929<\/span>\u5242\u91cf\u5f15\u53d1\u3002<\/span>

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 \u22641 mg\/kg\/day.
\u4f4e\u5242\u91cf\u5373\u53ef\u80fd\u4f1a\u5bfc\u81f4\u76ee\u6807\u5668\u5b98\u4e25\u91cd\u6bd2\u6027<\/span>\uff0c\u6216\u5176\u5b83\u91cd\u5927\u4e0d\u826f\u53cd\u5e94\u7684\u5316\u5408\u7269\uff0c\u4f8b\u5982\uff0c\u6709\u8bc1\u636e\u8bc1\u660e\u6b64\u7c7b\u53cd\u5e94\u662f\u7531\u4e34\u5e8a\u5242\u91cf<10mg\/\u5929<\/span>\uff08\u517d\u836f\u5242\u91cf\u7b49\u4e8e0.2mg\/kg\/\u5929<\/span>\uff09\u6216\u517d\u7528\u7814\u7a76\u22641 mg\/kg\/\u5929<\/span>\u5242\u91cf\u5f15\u53d1\u3002<\/span>

4.      Compounds with a high pharmacological potency i.e. recommended daily dose of <1 mg (veterinary dose equivalent 0.02 mg\/kg).
\u5177\u6709\u9ad8\u836f\u6548\u7684\u5316\u5408\u7269<\/span>\uff0c\u5373\uff0c\u5efa\u8bae\u65e5\u5242\u91cf<1 mg<\/span> (\u517d\u836f\u5242\u91cf\u7b49\u4e8e0.02 mg\/kg<\/span>)\u3002<\/span>

5.      Compounds with a high sensitising potential.
\u5177\u6709\u9ad8\u81f4\u654f<\/span>\u53ef\u80fd\u6027\u7684\u5316\u5408\u7269\u3002<\/span><\/p>\n


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

PDE\u7531\u5bf9\u5927\u591a\u6570\u76f8\u5173\u52a8\u7269\u7814\u7a76\u5f97\u5230\u7684\u4e0d\u80fd\u89c2\u5bdf\u5230\u53cd\u5e94\u7684\u91cf(NOEL)\uff0c\u6216\u80fd\u89c2\u5bdf\u5230\u53cd\u5e94\u7684\u6700\u4f4e\u91cf (LOEL)\uff0c\u6309\u4e0b\u5f0f\u63a8\u5bfc\u800c\u5f97:<\/p>\n


<\/p>\n

\"\u6e05\u6d01\u9a8c\u8bc1\uff1a\u54ea\u4e9b\u4ea7\u54c1\u9700\u8981\u8ba1\u7b97PDE\uff1f\"<\/p>\n

PDE\u9996\u5148\u7531NOEL\u8ba1\u7b97\uff0c\u5982\u679c\u65e0NOEL\u503c\uff0c\u53ef\u7528LOEL\u3002\u6b64\u5904\u6240\u7528\u7684\u7528\u4e8e\u4eba\u4f53\u7684\u4fee\u6b63\u7cfb\u6570\u4e0e\u73af\u5883\u5065\u5eb7\u6807\u51c6 (\u73af\u5883\u5065\u5eb7\u6807\u51c6170\uff0cWHO\uff0c\u65e5\u5185\u74e6\uff0c1994) \u6240\u7528\u7684 \u201c\u672a\u5b9a\u7cfb\u6570\u201d\u3001\u201c\u836f\u5178\u8bba\u575b\u201d \u6240\u7528\u7684 \u201c\u6821\u6b63\u7cfb\u6570\u201d \u53ca \u201c\u5b89\u5168\u7cfb\u6570\u201d \u76f8\u4f3c, \u65e0\u8bba\u4f55\u79cd\u7ed9\u836f\u9014\u5f84\u5747\u5047\u5b9a100%\u7684\u5168\u8eab\u63a5\u89e6\u6765\u8ba1\u7b97\u3002<\/p>\n

\u4ee5\u4e0b\u662f\u4fee\u6b63\u7cfb\u6570:<\/p>\n

F1 \u4e3a\u8003\u8651\u79cd\u7c7b\u4e4b\u95f4\u5dee\u5f02\u7684\u7cfb\u6570<\/p>\n

F1= 5 \u4ece\u5927\u9f20\u5242\u91cf\u63a8\u65ad\u4eba\u7528\u5242\u91cf\u7684\u7cfb\u6570<\/p>\n

F1 =12 \u4ece\u5c0f\u9f20\u5242\u91cf\u63a8\u65ad\u4eba\u7528\u5242\u91cf\u7684\u7cfb\u6570<\/p>\n

F1=2 \u4ece\u72d7\u5242\u91cf\u63a8\u65ad\u4eba\u7528\u5242\u91cf\u7684\u7cfb\u6570<\/p>\n

F1 =2.5 \u4ece\u5154\u5242\u91cf\u63a8\u65ad\u4eba\u7528\u5242\u91cf\u7684\u7cfb\u6570<\/p>\n

F1=3 \u4ece\u7334\u5b50\u5242\u91cf\u690e\u65ad\u4eba\u7528\u5242\u91cf\u7684\u7cfb\u6570<\/p>\n

F1=10 \u4ece\u5176\u4ed6\u52a8\u7269\u5242\u91cf\u63a8\u65ad\u4eba\u7528\u5242\u91cf\u7684\u7cfb\u6570<\/p>\n

F1 \u8003\u8651\u76f8\u5bf9\u4f53\u8868\u9762\u79ef\uff0c\u6709\u5173\u52a8\u7269\u79cd\u7c7b\u4e0e\u4eba\u7684\u4f53\u91cd\u6bd4<\/p>\n


<\/p>\n

\"\u6e05\u6d01\u9a8c\u8bc1\uff1a\u54ea\u4e9b\u4ea7\u54c1\u9700\u8981\u8ba1\u7b97PDE\uff1f\"<\/p>\n

\u5176\u4e2dM=\u4f53\u91cd\uff0c\u5e38\u6570k\u4e3a10\uff0c\u65b9\u7a0b\u4e2d\u6240\u7528\u7684\u4f53\u91cf\u89c1\u8868A3.1\u3002<\/p>\n

F2=10\uff0c\u8bf4\u660e\u4e2a\u4f53\u95f4\u7684\u53d8\u5f02<\/p>\n

\u5bf9\u6709\u673a\u6eb6\u5242F2\u7cfb\u6570\u4e00\u822c\u4e3a 10, \u672c\u6307\u5bfc\u539f\u5219\u4e00\u5f8b\u752810\u3002<\/p>\n

F3\u4e3a\u77ed\u671f\u63a5\u89e6\u6025\u6027\u6bd2\u6027\u7814\u7a76\u7684\u53ef\u53d8\u7cfb\u6570<\/p>\n

F3=1\u7814\u7a76\u65f6\u95f4\u81f3\u5c11\u4e3a\u52a8\u7269\u5bff\u547d\u4e00\u534a (\u556e\u9f7f\u52a8\u7269\u3001\u51541\u5e74, \u732b\u3001\u72d7\u3001\u73347\u5e74)\u3002<\/p>\n

F3=1\u5668\u5b98\u5f62\u6210\u7684\u6574\u4e2a\u8fc7\u7a0b\u7684\u751f\u6b96\u7814\u7a76\u3002<\/p>\n

F3=2 \u5bf9\u556e\u9f7f\u52a8\u72696\u4e2a\u6708\u7814\u7a76\u6216\u975e\u556e\u9f7f\u52a8\u72693.5\u5e74\u7684\u7814\u7a76\u3002<\/p>\n

F3=5 \u5bf9\u556e\u9f7f\u52a8\u72693\u4e2a\u6708\u7814\u7a76\u6216\u975e\u556e\u9f7f\u52a8\u72692\u5e74\u7684\u7814\u7a76\u3002<\/p>\n

F3=10\u66f4\u77ed\u65f6\u95f4\u7684\u7814\u7a76\u3002<\/p>\n

\u5728\u6240\u6709\u60c5\u51b5\u4e0b\uff0c\u5bf9\u7814\u7a76\u65f6\u95f4\u4ecb\u4e8e\u4e0a\u8ff0\u65f6\u95f4\u70b9\u4e4b\u95ee\u7684\u7814\u7a76\uff0c\u5e94\u7528\u8f83\u5927\u7684\u7cfb\u6570\uff0c\u5982\u5bf9\u556e\u9f7f\u7c7b\u52a8\u72699\u4e2a\u6708\u6bd2\u6027\u7814\u7a76\uff0c\u5176\u7cfb\u6570\u75282\u3002<\/p>\n

F4\u4e3a\u7528\u4e8e\u4ea7\u751f\u4e25\u91cd\u6bd2\u6027\u60c5\u51b5\u7684\u7cfb\u6570, \u5982:\u975e\u9057\u4f20\u81f4\u764c\u6bd2\u6027, \u795e\u7ecf\u6bd2\u6027\u6216\u81f4\u7578\u6027\uff0c\u7814\u7a76\u751f\u6b96\u6bd2\u6027\u65f6\uff0c \u7528\u4ee5\u4e0b\u7cfb\u6570:<\/p>\n

F4=1 \u4e0e\u6bcd\u4f53\u6bd2\u6027\u6709\u5173\u7684\u80ce\u513f\u6bd2\u6027<\/p>\n

F4=1 \u65e0\u6bcd\u4f53\u6bd2\u6027\u7684\u80ce\u513f\u6bd2\u6027<\/p>\n

F4=5 \u53d7\u6bcd\u4f53\u6bd2\u6027\u5f71\u54cd\u7684\u81f4\u7578\u53cd\u5e94<\/p>\n

F4=10 \u65e0\u6bcd\u4f53\u6bd2\u6027\u5f71\u54cd\u7684\u81f4\u7578\u53cd\u5e94<\/p>\n

F5=\u4e00\u4e2a\u53ef\u53d8\u7cfb\u6570, \u5728\u6ca1\u6709\u5efa\u7acb\u4e0d\u80fd\u89c2\u5bdf\u5230\u53cd\u5e94\u7684\u91cf(NOEL) \u65f6\u5e94\u7528\u3002<\/p>\n

\u5f53\u53ea\u6709\u80fd\u89c2\u5bdf\u5230\u53cd\u5e94\u7684\u6700\u4f4e\u91cf (LOEL) \u65f6\uff0c\u6839\u636e\u6bd2\u6027\u7684\u4e25\u91cd\u6027\uff0c\u7cfb\u6570\u53ef\u8fbe\u523010\u3002<\/p>\n

\u201c\u4f53\u91cd\u8c03\u6574” \u5047\u5b9a\u4e00\u4e2a\u4efb\u610f\u7684\u6210\u4eba\u4f53\u91cd\uff08\u4e0d\u8bba\u6027\u522b)\u4e3a50kg\uff0c\u76f8\u5bf9\u4e8e\u5e38\u7528\u4e8e\u8fd9\u7c7b\u8ba1\u7b97\u7684\u6807\u51c6\u4f53\u91cd\u4e3a60kg\u621670kg\u7684\u4eba, \u8fd9\u4e00\u76f8\u5bf9\u4f4e\u7684\u91cd\u91cf\u63d0\u4f9b\u4e86\u4e00\u4e2a\u9644\u52a0\u7684\u5b89\u5168\u56e0\u7d20\uff0c\u5e94\u8be5\u6307\u51fa\u6709\u4e9b\u6210\u5e74\u75c5\u4eba\u4f53\u91cd\u5c0f\u4e8e50kg\uff0c\u5bf9\u8fd9\u4e9b\u75c5\u4eba\uff0c\u5e94\u8003\u8651\u7528\u5df2\u5efa\u7acb\u7684\u7528\u4e8e\u6d4b\u5b9aPDE\u7684\u5b89\u5168\u7cfb\u6570\u8fdb\u884c\u8c03\u8282\u3002 \u5982\u679c\u513f\u7ae5\u7528\u836f\u7684\u5904\u65b9\u4e2d\u542b\u6709\u6eb6\u5242\uff0c\u7528\u8f83\u8f7b\u7684\u4f53\u91cd\u8fdb\u884c\u8c03\u8282\u662f\u5408\u9002\u7684\u3002<\/p>\n

\u4e3e\u4f8b\u8bf4\u660e\u65b9\u7a0b\u7684\u5e94\u7528, \u5c0f\u9f20\u4e2d\u4e59\u8148\u6bd2\u6027\u7814\u7a76\u603b\u7ed3Pharmeuropa. Vol.9.No.1\u589e\u8865\u672c\uff0c1997\u5e74 4\u6708\u7b2cS24\u9875\u3002NOEL\u4e3a50.7mg\u00b7kg\u02c91\u00b7d\u02c91\uff0c\u4e59\u8148\u7684PDE\u5982\u4e0b\u8ba1\u7b97:<\/p>\n


<\/p>\n

\"\u6e05\u6d01\u9a8c\u8bc1\uff1a\u54ea\u4e9b\u4ea7\u54c1\u9700\u8981\u8ba1\u7b97PDE\uff1f\"<\/p>\n

\u672c\u4f8b\u4e2d<\/p>\n

F1=12 \u8bf4\u660e\u4ece\u5c0f\u9f20\u5242\u91cf\u63a8\u690e\u65ad\u5230\u4eba\u7528\u5242\u91cd\u7684\u7cfb\u6570<\/p>\n

F2=10 \u8bf4\u660e\u4e0d\u540c\u4eba\u4f53\u7684\u5dee\u5f02<\/p>\n

F3=5 \u56e0\u4e3a\u7814\u7a76\u65f6\u95f4\u53ea\u670913\u5468<\/p>\n

F4=1 \u56e0\u4e3a\u672a\u53d1\u73b0\u4e25\u91cd\u7684\u6bd2\u6027<\/p>\n

F5=1 \u56e0\u4e3a\u5df2\u6d4b\u5f97\u4e0d\u80fd\u89c2\u5bdf\u5230\u53cd\u5e94\u7684\u91cf<\/p>\n


<\/p>\n

\"\u6e05\u6d01\u9a8c\u8bc1\uff1a\u54ea\u4e9b\u4ea7\u54c1\u9700\u8981\u8ba1\u7b97PDE\uff1f\"<\/p>\n

\u7406\u60f3\u6c14\u4f53\u65b9\u7a0bPV=nRT,\u7528\u4e8e\u5c06\u5438\u5165\u7814\u7a76\u7684\u6c14\u4f53\u6d53\u5ea6ppm\u8f6c\u6362\u4e3amg\/L\u6216mg\/m\u00b3\u3002\u4f8b\u5982\u4ee5\u5927\u9f20\u5438\u5165\u56db\u6c2f\u5316\u78b3 (\u5206\u5b50\u91cf153.84) \u7684\u751f\u6b96\u6bd2\u6027\u7814\u7a76\u4e3a\u4f8b, \u89c1Pharmeuropa\uff0cVol9\uff0cNo.1\uff0c\u589e\u8865\u672c\uff0c1997\u5e744\u6708\uff0cS9\u9875\u3002
<\/p>\n

\n

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\n

APIC GUIDANCE ON ASPECTS OF CLEANING VALIDATION IN ACTIVE PHARMACEUTICAL INGREDIENT PLANTS<\/span><\/span>, May 2014 \u548c <\/span>EMA Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities<\/span><\/span>, 20 November 2014 \u5747\u63d0\u5230\u4f7f\u7528ADE\uff08NOAEL\uff09\u3001NOEL\uff08LD50\uff09\u548cPDE\u8ba1\u7b97\u6bd2\u6027MACO\u3002
<\/p>\n


<\/p>\n

\u540e\u8005\u8fd8\u8981\u6c42\u201c\u5e94\u57fa\u4e8e\u5168\u9762\u7684\u6587\u732e\u68c0\u7d22\uff0c\u5305\u62ec\u624b\u518c\u3001\u4e13\u8457\u4ee5\u53ca\u7535\u5b50\u79d1\u5b66\u6570\u636e\u5e93\u7b49\u7684\u68c0\u7d22\u201d\uff0c\u7531\u4e13\u5bb6\u8bc4\u4f30\u786e\u5b9aPDE\u503c\u3002\u8bf7\u5728\u901a\u8fc7\u6b27\u76dfGMP<\/span><\/span>\u8ba4\u8bc1\u4f01\u4e1a\u4efb\u804c\u7684\u670b\u53cb\u6295\u7968\uff0c\u4f60\u516c\u53f8\u6709\u6bd2\u6027\u6216\u836f\u7406\u5b66\u4e13\u5bb6\u5417\uff1f

\u968f\u4fbf\u63d0\u4f9b\u51e0\u4e2a\u67e5\u8bf4\u660e\u4e66(PI)\u548cMSDS\u7684\u7f51\u5740\uff1a
Drugs@FDA<\/span><\/span>
http:\/\/www.drugbank.ca<\/span><\/span>
http:\/\/www.pfizer.com\/products<\/span><\/span>
Hospira Drugs<\/span><\/span>
AstraZeneca – MSDS<\/span><\/span>
Santa Cruz Biotech Datasheet<\/span><\/span>
http:\/\/www.lookchem.com<\/span><\/span>
\u5f53\u7136\u4e5f\u53ef\u4ee5\u7528\u836f\u54c1\u540d+MSDS\u76f4\u63a5\u5728cn.bing.com\u4e2d\u641c\u7d22\uff08google\u592a\u9ebb\u70e6\u4e86\uff09\u3002<\/p>\n

\n

\u901a  \u8fc7  PDE  \u8ba1  \u7b97  \u9650  \u5ea6<\/span><\/strong><\/span><\/p>\n


<\/p>\n

ICHQ3C<\/span>\u4e2d\u6536\u8f7d\u4e86<\/span>PDE<\/span>\u7684\u8ba1\u7b97\u65b9\u6cd5\uff1a<\/span><\/p>\n


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

PDE = NOEL x Mass Adjustment\/[F1 x F2 x F3 x F4 x F5]<\/span><\/p>\n


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

\u5176\u4e2d<\/span>PDE<\/span>\u4e3a\u5141\u8bb8\u65e5\u66b4\u9732\u91cf\uff0c\u5355\u4f4d\u4e3a<\/span>mg\/<\/span>\u5929\uff1b<\/span>NOEL<\/span>\u4e3a\u8be5\u6742\u8d28\u7684\u6700\u5927\u65e0\u4f5c\u7528\u7684\u5242\u91cf\uff0c\u5355\u4f4d\u4e3a<\/span>mg\/kg\/<\/span>\u5929\u3002<\/span><\/p>\n


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

Mass Adjustment<\/span>\u4e3a\u4f53\u91cd\u8c03\u6574\u7cfb\u6570\uff0c\u4e00\u822c\u53d6\u4e3a<\/span>50kg<\/span>\u3002<\/span>F1\u2026.. F5<\/span>\u4e3a\u5404\u79cd\u4fee\u6b63\u56e0\u5b50\uff0c\u5176\u542b\u4e49\u4e0e\u5e94\u53d6\u7684\u503c\u8bf7\u67e5\u9605<\/span>ICHQ3C<\/span>\u76f8\u5e94\u5185\u5bb9\uff0c\u4e0d\u518d\u7ec6\u8ff0\u3002<\/span><\/p>\n


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

\u901a\u8fc7\u4ee5\u4e0a\u516c\u5f0f\u5f97\u51fa<\/span>PDE<\/span>\u7684\u503c\u4e4b\u540e\uff0c\u7136\u540e\u9664\u4ee5\u836f\u54c1\u7684\u6700\u5927\u65e5\u5242\u91cf\uff0c\u5373\u5f97\u51fa\u8be5\u5316\u5b66\u8bd5\u5242\u7684\u9650\u5ea6\u3002<\/span><\/p>\n


<\/p>\n

\u4ece LD50 \u8ba1 \u7b97 NOEL<\/span><\/strong><\/span><\/p>\n


<\/p>\n

\u5f88\u591a\u65f6\u5019\u6211\u4eec\u67e5\u627e\u4e0d\u5230<\/span>NOEL<\/span>\u7684\u6570\u636e\uff0c\u6211\u4eec\u53ea\u80fd\u67e5\u5230<\/span>LD50<\/span>\uff08\u534a\u6570\u81f4\u6b7b\u91cf\uff09\u3002\u76ee\u524d\u6700\u6743\u5a01\u7684\u8ba1\u7b97\u65b9\u6cd5\u51fa\u81ea\u6b27\u76df\u539f\u6599\u836f\u59d4\u5458\u4f1a\u5728\u5176\u53d1\u5e03\u7684\u300a\u539f\u6599\u836f\u5de5\u5382\u4e2d\u6e05\u6d01\u9a8c\u8bc1\u6307\u5357\u300b\uff0c\u5176\u4e2d\u6536\u8f7d\u4e86\u7531<\/span>LD50<\/span>\u8ba1\u7b97<\/span>NOEL<\/span>\u7684\u516c\u5f0f\uff1a<\/span>NOEL=LD50\u00d770\/2000<\/span>\u3002\u4f46\u8fd9\u4e00\u516c\u5f0f\u5374\u4f1a\u8bef\u5bfc<\/span>PDE<\/span>\u7684\u8ba1\u7b97\uff0c\u56e0\u4e3a\u5f88\u591a\u4eba\u4f1a\u7528\u8fd9\u4e00\u516c\u5f0f\u8ba1\u7b97\u51fa\u6765\u7684<\/span>NOEL<\/span>\u76f4\u63a5\u4ee3\u5165\u4e0a\u6587\u7684\u516c\u5f0f\u8ba1\u7b97<\/span>PDE<\/span>\uff0c\u5374\u6ca1\u6709\u6ce8\u610f\u5230\u300a\u539f\u6599\u836f\u5de5\u5382\u4e2d\u6e05\u6d01\u9a8c\u8bc1\u6307\u5357\u300b\u4e00\u6587\u4e2d\u7684<\/span>NOEL <\/span><\/span>\u7684\u5355\u4f4d\u662f<\/span>mg\/<\/span>\u5929\uff0c\u800c\u4e0d\u662f\u4e0a\u6587\u516c\u5f0f\u4e2d\u7684<\/span>mg\/kg\/<\/span>\u5929\u3002\u539f\u56e0\u5c31\u662f\u516c\u5f0f\u4e2d\u7684<\/span>70<\/span>\u662f\u6b27\u6d32\u4eba\u7684\u8bc4\u4ef7\u4f53\u91cd\u3002\u6240\u4ee5\u5982\u679c\u9700\u8981\u7528<\/span>LD50<\/span>\u8ba1\u7b97<\/span>NOEL<\/span>\u7528\u4e8e\u8ba1\u7b97<\/span>PDE<\/span>\uff0c\u5219\u4e0d\u5e94\u8be5\u4e58\u4ee5<\/span>70<\/span>\uff0c\u516c\u5f0f\u5e94\u8be5\u662f<\/span>NOEL=LD50\/2000<\/span>\uff0c<\/span>2000<\/span>\u662f\u7ecf\u9a8c\u5e38\u6570\u3002<\/span><\/p>\n

\u8be5\u516c\u5f0f\u53ef\u53c2\u89c1\u6587\u732e<\/span>Layton D W<\/span>\uff0c<\/span>Mallon B J<\/span>\uff0c<\/span>RosenblattD H<\/span>\uff0c<\/span>et<\/span>\uff0e<\/span>Deriving allowable daily intakes for systemic toxicants lacking chronic toxicity data[J]<\/span>.<\/span>Reg02 To’xicol Pharm<\/span>\uff0c<\/span>1983<\/span>\uff0c<\/span>3(1)<\/span>\uff1a<\/span>224<\/span>\u3002<\/span>
<\/p>\n


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

\u7531 ppm \u8ba1 \u7b97 \u76f8 \u5e94 NOEL<\/span><\/strong><\/span><\/p>\n


<\/p>\n

\u6709\u4e9b\u65f6\u5019\u6211\u4eec\u67e5\u5230\u7684\u76f8\u5e94\u836f\u7406\u6bd2\u7406\u7814\u7a76\u6570\u636e\uff08\u7279\u522b\u662f\u67d0\u4e9b\u4f4e\u6cb8\u70b9\u6eb6\u5242\uff09\u662f\u7814\u7a76\u7a7a\u6c14\u4e2d\u7279\u5b9a\u542b\u91cf\u7684\u5438\u5165\u4ea7\u751f\u7684\u6548\u679c\uff0c\u5176\u5355\u4f4d\u5e38\u89c1\u7684\u662f<\/span>ppm<\/span>\u4e3a\u4f53\u79ef\u6bd4\uff0c\u5982\u4f55\u6362\u7b97\u6210<\/span>mg\/kg\/<\/span>\u5929\u7684\u5355\u4f4d\u5462\uff1f\u4ee5\u4e09\u4e59\u80fa\u4e3a\u4f8b\uff0c\u5176\u7814\u7a76\u6570\u636e\u4e3a\u5927\u9f20\u6bcf\u5468<\/span>5<\/span>\u5929\uff0c\u6bcf\u5929<\/span>6<\/span>\u5c0f\u65f6\uff0c\u6301\u7eed<\/span>28<\/span>\u5468\uff0c<\/span>NOEL<\/span>\u4e3a<\/span>247ppm<\/span>\u3002<\/span>247ppm=247\u00d7101.19\/24.45=1.02mg\/L<\/span>\uff0c\u5176\u4e2d<\/span>101.19<\/span>\u4e3a\u4e09\u4e59\u80fa\u7684\u5206\u5b50\u91cf\uff0c<\/span>24.45<\/span>\u4e3a<\/span>25<\/span>\u2103<\/span>\u6c14\u4f53\u6469\u5c14\u4f53\u79ef\u3002\u6bcf\u5929\u5e73\u5747\u5438\u5165\u91cf\u4e3a<\/span>1.02\u00d76\u00d75\/24\/7=0.183mg\/L<\/span>\u3002<\/span>NOEL<\/span>\uff08<\/span>mg\/kg\/<\/span>\u5929\uff09<\/span>=0.183\u00d7290\/0.425=124.9<\/span>\uff0c\u5176\u4e2d<\/span>290<\/span>\u4e3a\u5927\u9f20\u6bcf\u65e5\u5438\u5165\u7a7a\u6c14\u4f53\u79ef\uff0c<\/span>0.425<\/span>\u4e3a\u5927\u9f20\u5e73\u5747\u4f53\u91cd\u3002<\/span><\/p>\n


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

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\u5982 \u4f55 \u786e \u5b9a \u9650 \u5ea6<\/span><\/strong><\/span><\/p>\n


<\/p>\n

\u5316\u5b66\u8bd5\u5242\u7684\u9650\u5ea6\u5236\u5b9a\u5982\u4e0a\u6587\u6240\u8ff0\u5e94\u6839\u636e\u5b89\u5168\u6027\u548c\u8d28\u91cf\u53ef\u63a7\u6027\u4e24\u4e2a\u65b9\u9762\u7efc\u5408\u5236\u5b9a\uff0c\u67d0\u4e9b\u5316\u5b66\u8bd5\u5242\u7684\u5b89\u5168\u6027\u975e\u5e38\u597d\uff0c\u5982\u6c2f\u5316\u94a0\u3001\u6c28\u57fa\u9178\u4e4b\u7c7b\uff0c\u5176\u9650\u5ea6\u5c31\u9700\u8981\u6839\u636e\u8d28\u91cf\u53ef\u63a7\u6027\u7684\u8981\u6c42\u5236\u5b9a\u3002\u5982\u4e0a\u6587\u7684\u4e09\u4e59\u80fa\uff0c<\/span>PDE<\/span>\uff08\u8ba1\u7b97\u8fc7\u7a0b\u89c1\u4e0a\u6587<\/span>PDE<\/span>\u76f8\u5173\u5185\u5bb9\uff09\u4e3a<\/span>62.5mg\/<\/span>\u5929\uff0c\u5047\u8bbe\u836f\u7269\u6bcf\u65e5\u6700\u5927\u5242\u91cf\u4e3a<\/span>100mg<\/span>\uff0c\u6839\u636e<\/span>PDE<\/span>\u8ba1\u7b97\u4e09\u4e59\u80fa\u5728\u8be5\u836f\u7269\u4e2d\u7684\u9650\u5ea6\u53ef\u4e3a<\/span>62.5%<\/span>\u3002\u8fd9\u660e\u663e\u4e0d\u5408\u7406\uff0c\u8fd9\u65f6\u5e94\u6839\u636e\u5b9e\u9645\u5de5\u827a\u53ef\u80fd\u8fbe\u5230\u7684\u503c\u786e\u5b9a\u4e00\u4e2a\u5408\u7406\u7684\u9650\u5ea6\uff0c\u5373\u8d28\u91cf\u63a7\u5236\u53ef\u4ee5\u5b9e\u73b0\u7684\u9650\u5ea6\uff0c\u4f8b\u5982<\/span>0.1%<\/span>\u3002<\/span><\/p>\n


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