{"id":47271,"date":"2018-09-19T01:00:00","date_gmt":"2018-09-26T01:38:18","guid":{"rendered":"http:\/\/www.05921.net\/index.php\/2018\/09\/26\/fda%e8%ad%a6%e5%91%8a%e4%bf%a1%ef%bc%9a%e5%8a%a0%e6%8b%bf%e5%a4%a7lernapharm-loris-inc\/"},"modified":"2018-09-26T09:38:18","modified_gmt":"2018-09-26T01:38:18","slug":"fda%e8%ad%a6%e5%91%8a%e4%bf%a1%ef%bc%9a%e5%8a%a0%e6%8b%bf%e5%a4%a7lernapharm-loris-inc","status":"publish","type":"post","link":"https:\/\/www.05921.net\/index.php\/47271\/","title":{"rendered":"FDA\u8b66\u544a\u4fe1\uff1a\u52a0\u62ff\u5927Lernapharm (Loris) Inc."},"content":{"rendered":"
\n

\u7ffb\u8bd1\uff1a JULIA   \u6765\u6e90<\/span>\uff1a <\/span>Julia\u6cd5\u89c4\u7ffb\u8bd1<\/span><\/p>\n


<\/p>\n

Warning Letter <\/span><\/strong>320-18-73              September 04, 2018<\/span><\/span><\/p>\n

Mr. Razmik Margoosian<\/span><\/p>\n

President, Lernapharm (Loris) Inc.<\/span><\/p>\n

2323 Halpern St., Saint-Laurent, Montreal, Quebec, Canada H4S 1S3<\/span><\/p>\n

 <\/span><\/p>\n

Dear Mr. Razmik Margoosian:<\/span><\/p>\n

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Lernapharm(Loris) Inc. at 2323 Halpern St., Saint-Laurent, Montreal, from December 4 to12, 2017.<\/span><\/p>\n

\u7f8e\u56fd<\/span>FDA<\/span>\u4e8e<\/span>2017<\/span>\u5e74<\/span>12<\/span>\u6708<\/span>4-12<\/span>\u65e5\u68c0\u67e5\u4e86\u4f60\u4eec\u4f4d\u4e8e\u52a0\u62ff\u5927\u8499\u7279\u5229\u5c14\u7684<\/span>Lernapharm (Loris) Inc.<\/span>\u751f\u4ea7\u573a\u6240\u3002<\/span><\/span><\/p>\n

This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See 21 CFR, parts 210 and 211.<\/span><\/p>\n

 <\/span>\u672c\u8b66\u544a\u4fe1\u603b\u7ed3\u4e86\u5236\u5242\u751f\u4ea7\u4e25\u91cd\u8fdd\u53cd<\/span>CGMP<\/span>\u7684\u884c\u4e3a\u3002\u53c2\u89c1<\/span>21CFR<\/span>\u7b2c<\/span>210<\/span>\u548c<\/span>211<\/span>\u90e8\u5206<\/span>.<\/span><\/span><\/p>\n

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug products are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21U.S.C. 351(a)(2)(B).<\/span><\/p>\n

\u7531\u4e8e\u4f60\u4eec\u7684\u5236\u5242\u751f\u4ea7\u3001\u52a0\u5de5\u3001\u5305\u88c5\u6216\u4fdd\u5b58\u7684\u65b9\u6cd5\u3001\u573a\u6240\u6216\u63a7\u5236\u4e0d\u7b26\u5408<\/span>CGMP<\/span>\u8981\u6c42\uff0c\u4f60\u4eec\u7684\u5236\u5242\u6839\u636e<\/span>FDCA<\/span>\u7684<\/span>501(a)(2)(B)<\/span>\u4ee5\u53ca<\/span>21U.S.C. 351(a)(2)(B)<\/span>\u88ab\u8ba4\u4e3a\u662f\u63ba\u5047\u836f\u54c1\u3002<\/span><\/span><\/p>\n

We reviewed your December 22, 2017, response in detail and acknowledge receipt of your subsequent correspondence.<\/span><\/p>\n

\u6211\u4eec\u8be6\u7ec6\u5ba1\u6838\u4e86\u4f60\u4eec<\/span>2017<\/span>\u5e74<\/span>12<\/span>\u6708<\/span>22<\/span>\u7684\u56de\u590d\uff0c\u5e76\u4e14\u6b64\u544a\u77e5\u5df2\u6536\u5230\u540e\u7eed\u901a\u4fe1\u3002<\/span><\/span><\/p>\n

During our inspection, our investigator observed specific violations including, but not limited to, the following.<\/span><\/p>\n

\u68c0\u67e5\u671f\u95f4\uff0c\u6211\u4eec\u7684\u8c03\u67e5\u4eba\u5458\u53d1\u73b0\u7684\u5177\u4f53\u95ee\u9898\u5305\u62ec\u4f46\u4e0d\u4ec5\u9650\u4e8e\u4ee5\u4e0b\uff1a<\/span><\/p>\n

1.   Your firm failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes (21 CFR 211.113(b)).<\/span><\/strong> <\/span><\/strong><\/span><\/p>\n

\u4f60\u516c\u53f8\u672a\u5efa\u7acb\u5e76\u9075\u5b88\u9002\u5f53\u7684\u4e66\u9762\u7a0b\u5e8f\uff0c\u8bbe\u8ba1\u7528\u4ee5\u9632\u6b62\u7406\u5e94\u65e0\u83cc\u7684\u836f\u54c1\u7684\u5fae\u751f\u7269\u6c61\u67d3\uff0c\u5305\u62ec\u6240\u6709\u65e0\u83cc\u548c\u706d\u83cc\u5de5\u827a\u7684\u9a8c\u8bc1\uff08<\/span><\/strong>21 CFR 211.113(b)<\/span><\/strong>\uff09\u3002<\/span><\/strong><\/span><\/p>\n

You failed to adequately validateyour drug manufacturing process for your (b)(4)<\/strong> drug products that you claim achieves \u201c(b)(4)<\/strong> sterilization.\u201d These products are labeled as sterile and are intended for significant indications, including \u201c(b)(4)<\/strong>.\u201d<\/span><\/p>\n

\u4f60\u4eec\u672a\u80fd\u5145\u5206\u9a8c\u8bc1\u4f60\u4eec\u58f0\u79f0\u8fbe\u5230\u201c<\/span>XX<\/span>\u706d\u83cc\u201d\u7684<\/span>XX<\/span>\u836f\u54c1\u751f\u4ea7\u5de5\u827a\u3002\u8fd9\u4e9b\u836f\u54c1\u6807\u793a\u4e3a\u65e0\u83cc\uff0c\u5e76\u4f1a\u7528\u4e8e\u4e25\u91cd\u75c7\u72b6\uff0c\u5305\u62ec<\/span>XX<\/span>\u3002<\/span><\/span><\/p>\n

For example, you reprocessed multiple batches of (b)(4) <\/strong>drug products, which purport to be sterile, that did not meet process parameters or quality attributes. In one instance,you reprocessed (b)(4)<\/strong> Lot (b)(4)<\/strong> after five biological indicator(BI) strips were found with microbial growth.<\/span><\/p>\n

\u4f8b\u5982\uff0c\u4f60\u4eec\u8fd4\u5de5\u4e86\u591a\u6279\u7406\u5e94\u65e0\u83cc\u7684<\/span>XX<\/span>\u836f\u54c1\uff0c\u4f46\u5e76\u4e0d\u7b26\u5408\u5de5\u827a\u53c2\u6570\u548c\u8d28\u91cf\u5c5e\u6027\u3002\u5728\u53e6\u4e00\u4e2a\u6848\u4f8b\u4e2d\uff0c\u4f60\u4eec\u5728\u53d1\u73b0<\/span>5<\/span>\u4e2a\u751f\u7269\u6307\u793a\u5242\uff08<\/span>BI<\/span>\uff09\u6761\u6709\u957f\u83cc\u540e\u8fd4\u5de5\u4e86<\/span>XX<\/span>\u6279\u53f7<\/span>XX<\/span>\u3002<\/span><\/span><\/p>\n

Your (b)(4) <\/strong>process relies on the exposure of your (b)(4) <\/strong>drug products to (b)(4) <\/strong>of approximately (b)(4)<\/strong> for your (b)(4)<\/strong>, and per your process summary report, a minimum of (b)(4)<\/strong> within the product bins placed invarious other locations around the room.  <\/span><\/p>\n

 <\/span>\u4f60\u4eec\u7684<\/span>XX<\/span>\u5de5\u827a\u4f9d\u8d56\u4e8e\u4f60\u4eec\u7684<\/span>XX<\/span>\u836f\u54c1\u66b4\u9732\u4e8e<\/span>XX<\/span>\u7ea6<\/span>XX<\/span>\uff0c\u5e76\u4e14\u6839\u636e\u4f60\u4eec\u7684\u5de5\u827a\u6458\u8981\u62a5\u544a\uff0c\u5728\u4ea7\u54c1\u6876\u4e2d\u6700\u5c11\u6709<\/span>XX<\/span>\u653e\u5728\u623f\u95f4\u5185\u5176\u5b83\u4e0d\u540c\u5730\u70b9\u3002<\/span><\/span><\/p>\n

You failed to test the sterility of finished product batches produced by this process, and instead relied on use ofa biological indicator organism (b)(4)<\/strong>.<\/span><\/p>\n

 <\/span>\u4f60\u4eec\u672a\u80fd\u68c0\u6d4b\u6b64\u5de5\u827a\u751f\u4ea7\u7684\u5236\u5242\u6279\u6b21\u7684\u65e0\u83cc\u6027\uff0c\u76f8\u53cd\u53ea\u662f\u4f9d\u8d56\u4e8e\u4f7f\u7528\u751f\u7269\u6307\u793a\u5242\u6709\u673a\u7269<\/span>XX<\/span>\u3002<\/span><\/span><\/p>\n

Your response states that you do not perform finished product sterility testing because you maintain written records and validation procedures for your parametric release \u201csterilization program.\u201d<\/span><\/p>\n

\u4f60\u4eec\u56de\u590d\u58f0\u79f0\u4f60\u4eec\u5e76\u672a\u5bf9\u6210\u54c1\u8fdb\u884c\u65e0\u83cc\u68c0\u6d4b\uff0c\u56e0\u4e3a\u4f60\u4eec\u4fdd\u7559\u4e86\u4f60\u4eec\u53c2\u6570\u653e\u884c\u201c\u706d\u83cc\u7a0b\u5e8f\u201d\u7684\u4e66\u9762\u8bb0\u5f55\u548c\u9a8c\u8bc1\u7a0b\u5e8f\u3002<\/span><\/p>\n

Your response is inadequate. Your firm lacks an adequate sterilization method. You have not demonstrated an ongoing state of control and your products, which purport to be sterile, are produced using manufacturing methods that are inappropriate to support this claim.<\/span><\/p>\n

 <\/span>\u4f60\u4eec\u7684\u56de\u590d\u662f\u4e0d\u5145\u5206\u7684\u3002\u4f60\u4eec\u516c\u53f8\u7f3a\u4e4f\u8db3\u591f\u7684\u706d\u83cc\u65b9\u6cd5\u3002\u4f60\u4eec\u672a\u80fd\u8bc1\u660e\u6301\u7eed\u53d7\u63a7\u72b6\u6001\uff0c\u4ee5\u53ca\u4f60\u4eec\u91c7\u7528\u4e86\u4e0d\u80fd\u5145\u5206\u652f\u6301\u6b64\u58f0\u660e\u7684\u548c\u5e73\u65b9\u6cd5\u751f\u4ea7\u4f60\u4eec\u7684\u65e0\u83cc\u4ea7\u54c1\u3002<\/span><\/span><\/p>\n

In addition, parametric release is only appropriate for robust sterilization methods (e.g., steam sterilization).The robust sterilization method must also be augmented by a strong sterility assurance program, an extensive ongoing characterization of batch process control, and a vigilant quality system. See FDA\u2019s Compliance Policy Guide (CPG)(b)(4) <\/strong>entitled, (b)(4).<\/strong><\/span><\/p>\n

 <\/span>\u6b64\u5916\uff0c\u53c2\u6570\u653e\u884c\u53ea\u6709\u9002\u5408\u4e8e\u7a33\u5065\u7684\u706d\u83cc\u65b9\u6cd5\uff08\u4f8b\u5982\uff0c\u84b8\u6c7d\u706d\u83cc\uff09\u3002\u7a33\u5065\u7684\u706d\u83cc\u65b9\u6cd5\u8fd8\u5fc5\u987b\u901a\u8fc7\u5f3a\u6709\u529b\u7684\u4fdd\u8bc1\u7a0b\u5e8f\u3001\u6279\u5de5\u827a\u63a7\u5236\u7684\u6df1\u5165\u6301\u7eed\u7279\u6027\u9274\u5b9a\u4ee5\u53ca\u9ad8\u5ea6\u8b66\u6212\u7684\u8d28\u91cf\u4f53\u7cfb\u6765\u8bc1\u660e\u3002\u53c2\u89c1<\/span>FDA<\/span>\u5408\u89c4\u653f\u7b56\u6307\u5357\uff08<\/span>CPG<\/span>\uff09<\/span>XX<\/span>\u6807\u9898<\/span>XX<\/span>\u3002<\/span><\/span><\/p>\n

In response to this letter, describe corrections to your manufacturing operation that will establish a high level of sterility assurance. If you intend to implement a terminal sterilization process, provide a robust sterilization method and rigorous validation protocol that assures the new method achieves a sterility assurance level of 10-6 <\/sup>or more (e.g., provide (b)(4) <\/strong>and (b)(4) <\/strong>data for any (b)(4) <\/strong>sterilization method), and uses an appropriate resistant biological indicator that represents the worst-case resistance of microbes that could be found in your environment and product. Regarding the latter, include (b)(4)<\/strong> determinations for each biological indicator lot to demonstrate its resistance to the specific sterilization method proposed for use by your firm. <\/span><\/p>\n

\u5728\u56de\u590d\u6b64\u51fd\u65f6\uff0c\u8bf7\u63cf\u8ff0\u4f60\u4eec\u5efa\u7acb\u9ad8\u6c34\u5e73\u65e0\u83cc\u4fdd\u8bc1\u7684\u751f\u4ea7\u64cd\u4f5c\u7ea0\u6b63\u63aa\u65bd\u3002\u5982\u679c\u4f60\u4eec\u60f3\u8981\u5b9e\u65bd\u7ec8\u7aef\u706d\u83cc\u5de5\u827a\uff0c\u8bf7\u63d0\u4ea4\u4e00\u4e2a\u7a33\u5065\u7684\u706d\u83cc\u65b9\u6cd5\u548c\u4e25\u5bc6\u7684\u9a8c\u8bc1\u65b9\u6848\uff0c\u786e\u4fdd\u65b0\u65b9\u6cd5\u53ef\u8fbe\u5230<\/span>10-6<\/sup> <\/span>\u6216\u66f4\u9ad8\u7684\u65e0\u83cc\u4fdd\u8bc1\u6c34\u5e73\uff08\u4f8b\u5982\uff0c\u63d0\u4f9b<\/span>XX<\/span>\u706d\u83cc\u65b9\u6cd5\u7684<\/span>XX<\/span>\u548c<\/span>XX<\/span>\u6570\u636e\uff09\uff0c\u5e76\u4f7f\u7528\u4ee3\u8868\u4f1a\u5728\u4f60\u4eec\u73af\u5883\u548c\u4ea7\u54c1\u4e2d\u53d1\u73b0\u7684\u6700\u5dee\u60c5\u5f62\u5fae\u751f\u7269\u8010\u53d7\u6027\u7684\u9002\u5f53\u7684\u8010\u53d7\u6027\u751f\u7269\u6307\u793a\u5242\u3002\u5173\u4e8e\u540e\u8005\uff0c\u8bf7\u5305\u62ec\u6bcf\u4e2a\u5fae\u751f\u7269\u6307\u793a\u5242\u6279\u6b21\u7684<\/span>XX<\/span>\u68c0\u6d4b\u4ee5\u8bc1\u660e\u5176\u8010\u53d7\u4f60\u516c\u53f8\u6240\u7528\u7684\u7279\u5b9a\u706d\u83cc\u65b9\u6cd5\u3002<\/span><\/span><\/p>\n

If you plan to continue use of your current (b)(4) <\/strong>step at the conclusion of processing, describe the facility and process improvements that will ensure that units subjected to that step are first produced by aseptic processing.<\/span><\/p>\n

 <\/span>\u5982\u679c\u4f60\u4eec\u5728\u5de5\u827a\u7ed3\u8bba\u4e2d\u8ba1\u5212\u6301\u7eed\u4f7f\u7528\u4f60\u4eec\u5f53\u524d\u7684<\/span>XX<\/span>\u6b65\u9aa4\uff0c\u8bf7\u63cf\u8ff0\u5bf9\u8bbe\u65bd\u548c\u5de5\u827a\u7684\u6539\u8fdb\uff0c\u786e\u4fdd\u8be5\u6b65\u9aa4\u7684\u5355\u5143\u9996\u5148\u662f\u7531\u65e0\u83cc\u5de5\u827a\u6240\u751f\u4ea7\u7684\u3002<\/span><\/span><\/p>\n

Also include the microbiological testing procedures that you will be using in your process validation studies for in-process and finished product testing. Regarding (b)(4) <\/strong>sterility testing, provide your test method, validation protocol, and validation report.<\/span><\/p>\n

 <\/span>\u4ea6\u8bf7\u5305\u62ec\u4f60\u4eec\u5c06\u5728\u5de5\u827a\u9a8c\u8bc1\u7684\u4e2d\u63a7\u548c\u6210\u54c1\u68c0\u6d4b\u4e2d\u4f7f\u7528\u7684\u5fae\u751f\u7269\u68c0\u6d4b\u7a0b\u5e8f\u3002\u5173\u4e8e<\/span>XX<\/span>\u7684\u65e0\u83cc\u68c0\u6d4b\uff0c\u8bf7\u63d0\u4ea4\u4f60\u4eec\u7684\u68c0\u6d4b\u65b9\u6cd5\u3001\u9a8c\u8bc1\u65b9\u6848\u548c\u9a8c\u8bc1\u62a5\u544a\u3002<\/span><\/span><\/p>\n

In addition, provide sterility testing results for all batches of your purportedly sterile (b)(4) <\/strong>batches that have been released and are within expiry. If such testing reveals substandard quality drug products, provide your corrective actions, including notifying customers and product recalls.<\/span><\/p>\n

\u6b64\u5916\uff0c\u4f60\u4eec\u8bf7\u63d0\u4ea4\u4f60\u4eec\u5df2\u653e\u884c\u4e14\u4ecd\u5728\u6548\u671f\u5185\u7684\u636e\u79f0\u65e0\u83cc\u7684<\/span>XX<\/span>\u6279\u6b21\u7684\u6240\u6709\u6279\u6b21\u65e0\u83cc\u68c0\u6d4b\u7ed3\u679c\u3002\u5982\u679c\u6b64\u68c0\u6d4b\u7ed3\u679c\u663e\u793a\u836f\u54c1\u8d28\u91cf\u4e0d\u7b26\u5408\u6807\u51c6\uff0c\u5219\u63d0\u4ea4\u4f60\u4eec\u7684\u7ea0\u6b63\u63aa\u65bd\uff0c\u5305\u62ec\u901a\u77e5\u5ba2\u6237\u548c\u53ec\u56de\u4ea7\u54c1\u3002<\/span><\/span><\/p>\n

2.   Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).<\/span><\/strong><\/span><\/p>\n

\u4f60\u516c\u53f8\u672a\u80fd\u5f7b\u5e95\u8c03\u67e5\u6240\u6709\u5df2\u9500\u552e\u6216\u672a\u9500\u552e\u7684\u6279\u6b21\u4ea7\u54c1\u6216\u5176\u7ec4\u4efd\u672a\u7ecf\u89e3\u91ca\u7684\u4e0d\u7b26\u5408\u5176\u8d28\u91cf\u6807\u51c6\u7684\u60c5\u51b5\uff08<\/span><\/strong>21 CFR 211.192<\/span><\/strong>\uff09\u3002<\/span><\/strong><\/span><\/p>\n

You failed to conduct thorough investigations into customer complaints for your (b)(4) <\/strong>drug products which purport to be sterile. You did not evaluate all potential causes for customer complaints or extend the investigation to other potentially affected batches and other products.<\/span><\/p>\n

 <\/span>\u4f60\u4eec\u672a\u80fd\u5bf9\u4f60\u4eec\u5e94\u4e3a\u65e0\u83cc\u7684<\/span>XX<\/span>\u4ea7\u54c1\u7684\u5ba2\u6237\u6295\u8bc9\u8fdb\u884c\u5f7b\u5e95\u8c03\u67e5\u3002\u4f60\u4eec\u672a\u8bc4\u4f30\u5ba2\u6237\u6295\u8bc9\u6240\u6709\u53ef\u80fd\u7684\u539f\u56e0\uff0c\u6216\u6269\u5c55\u8c03\u67e5\u81f3\u5176\u5b83\u53ef\u80fd\u53d7\u5f71\u54cd\u7684\u6279\u6b21\u6216\u5176\u5b83\u4ea7\u54c1\u3002<\/span><\/span><\/p>\n

For example, you received complaints AR-17-49 (October 23, 2017) and AR-17-50 (October 25, 2017) due to a significant number of leaking (b)(4)<\/strong> of (b)(4)<\/strong>. Your investigation found that the (b)(4)<\/strong> seals leaked due to pinholes in the package caused by debris that had accumulated on the sealing (b)(4)<\/strong> of the packaging machine. However, your investigation did not include your assessment of the following: <\/span><\/p>\n

\u4f8b\u5982\uff0c\u4f60\u4eec\u6536\u5230\u7531\u4e8e\u5927\u91cf<\/span>XX<\/span>\u7684<\/span>XX<\/span>\u6cc4\u6f0f\u5bfc\u81f4\u7684\u6295\u8bc9<\/span>AR-17-49 (2017<\/span>\u5e74<\/span>10<\/span>\u6708<\/span>23<\/span>\u65e5<\/span>)<\/span>\u548c<\/span> AR-17-50 (2017<\/span>\u5e74<\/span>10<\/span>\u6708<\/span>25<\/span>\u65e5<\/span>)<\/span>\u3002\u4f60\u4eec\u7684\u8c03\u67e5\u53d1\u73b0\u7531\u4e8e\u5305\u88c5\u673a\u7684\u5bc6\u5c01<\/span>XX<\/span>\u4e0a\u7d2f\u79ef\u7684\u788e\u7247\u5bfc\u81f4\u5305\u88c5\u4e0a\u7684\u9488\u5b54\u800c\u5f15\u53d1<\/span>XX<\/span>\u5bc6\u5c01\u6cc4\u6f0f\u3002\u4f46\u662f\uff0c\u4f60\u4eec\u7684\u8c03\u67e5\u5e76\u672a\u5305\u62ec\u4f60\u4eec\u5bf9\u4ee5\u4e0b\u7684\u8bc4\u4f30\uff1a<\/span><\/span><\/p>\n