{"id":53837,"date":"2018-09-27T01:00:00","date_gmt":"2018-09-30T01:49:52","guid":{"rendered":"http:\/\/www.05921.net\/index.php\/2018\/09\/30\/fda%ef%bc%9a%e5%8e%9f%e6%96%99%e8%8d%af%e6%89%b9%e5%87%86%e5%90%8e%e5%8f%98%e6%9b%b4%ef%bc%88%e6%8c%87%e5%8d%97%e8%8d%89%e6%a1%88%ef%bc%89\/"},"modified":"2018-09-30T09:49:52","modified_gmt":"2018-09-30T01:49:52","slug":"fda%ef%bc%9a%e5%8e%9f%e6%96%99%e8%8d%af%e6%89%b9%e5%87%86%e5%90%8e%e5%8f%98%e6%9b%b4%ef%bc%88%e6%8c%87%e5%8d%97%e8%8d%89%e6%a1%88%ef%bc%89","status":"publish","type":"post","link":"https:\/\/www.05921.net\/index.php\/53837\/","title":{"rendered":"FDA\uff1a\u539f\u6599\u836f\u6279\u51c6\u540e\u53d8\u66f4\uff08\u6307\u5357\u8349\u6848\uff09"},"content":{"rendered":"
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\u7ffb\u8bd1\uff1aJULIA   \u6765\u6e90\uff1a <\/span>Julia\u6cd5\u89c4\u7ffb\u8bd1<\/span><\/p>\n


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FDA\u884c\u4e1a\u6307\u5357\u8349\u6848\uff1a\u539f\u6599\u836f\u6279\u51c6\u540e\u53d8\u66f4 201809 \uff08\u8bd1\u6587\u4ec5\u4f9b\u53c2\u8003\uff09
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\u82f1\u6587\u539f\u6587\u517142\u9875\uff0c\u5e73\u53f0\u7bc7\u5e45\u53ca\u6392\u7248\u6240\u9650\uff0c\u65e0\u6cd5\u53d1\u5e03\u5168\u6587\uff0c\u5168\u6587\u53c2\u89c1\u4ee5\u4e0b\u94fe\u63a5\uff1a<\/span><\/p>\n

\u82f1\u6587\u5b98\u7f51\u94fe\u63a5\uff1ahttps:\/\/www.fda.gov\/downloads\/Drugs\/GuidanceComplianceRegulatoryInformation\/Guidances\/UCM619947.pdf<\/span><\/p>\n

\u4e2d\u82f1\u6587\u7f51\u9875\u6d4f\u89c8\uff08\u59d4\u6258\u53d1\u5e03\uff09\uff1ahttp:\/\/www.gjypzc.com\/news?page=1&q=18<\/span><\/p>\n

\u4e2d\u82f1\u6587PDF\u4e0b\u8f7d\u70b9\u51fb\u300a\u9605\u8bfb\u539f\u6587\u300b
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<\/p>\n

Post-approval Changes to Drug Substances<\/span><\/strong><\/span><\/p>\n

Guidance for Industry<\/span><\/strong><\/span><\/p>\n

\u884c\u4e1a\u6307\u5357\uff1a\u539f\u6599\u836f\u6279\u51c6\u540e\u53d8\u66f4<\/span><\/strong><\/span><\/p>\n\n\n\n
\n

This draft guidance, when finalized, will represent the  current thinking of the Food and Drug Administration (FDA or Agency) on this  topic. It does not establish any rights for any person and is not binding on  FDA or the public. You can use an alternative approach if it satisfies the  requirements of the applicable statutes and regulations. To discuss an  alternative approach, contact the FDA staff responsible for this guidance as  listed on the title page.<\/span><\/p>\n

\u672c\u6307\u5357\u8349\u6848\uff08\u5f53\u5b9a\u7a3f\u65f6\uff09\u4ee3\u8868<\/span>FDA<\/span>\u5f53\u524d\u5bf9\u6b64\u4e3b\u9898\u7684\u89c2\u70b9\u3002\u5b83\u5e76\u4e0d\u8d4b\u4e88\u4efb\u4f55\u4eba\u4efb\u4f55\u6743\u529b\uff0c\u5bf9<\/span>FDA<\/span>\u548c\u516c\u4f17\u4ea6\u4e0d\u5f62\u6210\u5f3a\u5236\u3002\u5728\u6ee1\u8db3\u672c\u9002\u7528\u6cd5\u5f8b\u6cd5\u89c4\u7684\u8981\u6c42\u65f6\u53ef\u4ee5\u4f7f\u7528\u66ff\u4ee3\u7684\u65b9\u6cd5\u3002\u5173\u4e8e\u66ff\u4ee3\u65b9\u6cd5\u7684\u8ba8\u8bba\uff0c\u8bf7\u8054\u7cfb<\/span>FDA<\/span>\u529e\u516c\u5ba4\u8d1f\u8d23\u6b64\u672c\u6307\u5357\u7684\u4eba\u5458\uff0c\u8054\u7cfb\u65b9\u5f0f\u5728\u6807\u9898\u9875\u7ed9\u51fa\u3002<\/span><\/span><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

 <\/span><\/p>\n

I.     INTRODUCTION <\/span><\/strong>\u6982\u8ff0<\/span><\/strong><\/span><\/p>\n

This guidance provides recommendations to holders of approved new drug applications(NDAs), abbreviated new drug applications (ANDAs), new animal drug applications(NADAs), and abbreviated new animal drug applications (ANADAs) and holders of drug master files (DMFs) and veterinary master files (VMFs) who want to make achange to the drug substance manufacturing process during the drug product application\u2019s postapproval period . It does not address holders of biologics license applications (BLAs) or holders of any master files cross-referenced in BLAs.<\/span><\/p>\n

\u672c\u6307\u5357\u4e3a\u5df2\u6279\u51c6\u7684<\/span>NDA<\/span>\u3001<\/span>ANDA<\/span>\u3001<\/span>NADA<\/span>\u3001<\/span>ANADA<\/span>\u3001<\/span>DMF<\/span>\u548c<\/span>VMF<\/span>\u6301\u6709\u4eba\u53d8\u66f4\u5176\u5236\u5242\u58f0\u660e\u6279\u51c6\u4e4b\u540e\u7684\u539f\u6599\u836f\u751f\u4ea7\u5de5\u827a\u63d0\u4f9b\u5efa\u8bae\u3002\u672c\u6307\u5357\u4e0d\u9002\u7528\u4e8e\u751f\u7269\u8bb8\u53ef\u7533\u62a5\uff08<\/span>BLA<\/span>\uff09\u6301\u6709\u4eba\u548c<\/span>BLA<\/span>\u4e2d\u4ea4\u53c9\u5f15\u7528\u7684\u4efb\u4f55\u4e3b\u6587\u4ef6\u7684\u6301\u6709\u4eba\u3002<\/span><\/span><\/p>\n

The guidance applies to synthetic drug substances and the synthetic steps involved in preparing semisynthetic drug substances. The guidance covers the following changes:<\/span><\/p>\n

\u672c\u6307\u5357\u9002\u7528\u4e8e\u5408\u6210\u539f\u6599\u836f\u548c\u534a\u5408\u6210\u539f\u6599\u836f\u4e2d\u7684\u5408\u6210\u6b65\u9aa4\u3002\u6307\u5357\u8986\u76d6\u4ee5\u4e0b\u53d8\u66f4\uff1a<\/span><\/p>\n

\u2022      Facility, scale, and equipment changes associated with all steps of drug substance manufacturing.<\/span><\/p>\n

\u2022      <\/span>\u4e0e\u539f\u6599\u836f\u751f\u4ea7\u6240\u6709\u6b65\u9aa4\u6709\u5173\u7684\u8bbe\u65bd\u3001\u751f\u4ea7\u89c4\u6a21\u548c\u8bbe\u5907\u53d8\u66f4<\/span><\/span><\/p>\n

\u2022      Specification changes to starting materials, raw materials, intermediates, and the unfinished and final drug substance.<\/span><\/p>\n

\u2022      <\/span>\u8d77\u59cb\u7269\u6599\u3001\u539f\u6599\u3001\u4e2d\u95f4\u4f53\u548c\u539f\u6599\u836f\u6210\u54c1\u534a\u6210\u54c1\u8d28\u91cf\u6807\u51c6\u53d8\u66f4<\/span><\/span><\/p>\n

\u2022      Synthetic manufacturing process changes.<\/span><\/p>\n

\u2022      <\/span>\u5408\u6210\u751f\u4ea7\u5de5\u827a\u53d8\u66f4<\/span><\/span><\/p>\n

\u2022      Changes in the source of the drug substance.<\/span><\/p>\n

\u2022      <\/span>\u539f\u6599\u836f\u6765\u6e90\u53d8\u66f4<\/span><\/span><\/p>\n

\u2022      Changes to the container closure system for the drug substance.<\/span><\/p>\n

\u2022      <\/span>\u539f\u6599\u836f\u5bb9\u5668\u5bc6\u95ed\u7cfb\u7edf\u53d8\u66f4<\/span><\/span><\/p>\n

This guidance does not address postapproval changes to peptides , oligonucleotides, radiopharmaceuticals; or drug substances isolated from natural sources or produced by  procedures involving biotechnology; or nonsynthetic steps (such as fermentation) for  semisynthetic drug substances. This guidance also does not address complex active ingredients  as defined in the Generic Drug User Fee Act Reauthorization Performance Goals and Program Enhancements Fiscal Years 2018-2022, known as the GDUFA II CommitmentLetter .<\/span><\/p>\n

\u672c\u6307\u5357\u4e0d\u9488\u5bf9\u591a\u80bd\u3001\u5be1\u6838\u82f7\u9178\u3001\u653e\u5c04\u836f\u54c1\u4ee5\u53ca\u4ece\u5929\u7136\u6765\u6e90\u4e2d\u5206\u79bb\u7684\u539f\u6599\u836f\u548c\u91c7\u7528\u751f\u7269\u6280\u672f\u751f\u4ea7\u7684\u539f\u6599\u836f\u3001\u534a\u5408\u6210\u539f\u6599\u836f\u7684\u975e\u5408\u6210\u6b65\u9aa4\uff08\u4f8b\u5982\u53d1\u9175\uff09\u7684\u6279\u51c6\u540e\u53d8\u66f4\u3002\u672c\u6307\u5357\u4ea6\u4e0d\u9488\u5bf9\u4eff\u5236\u836f\u4ed8\u8d39\u6cd5\u6848\u91cd\u65b0\u6388\u6743\u7ee9\u6548\u76ee\u6807\u548c<\/span>2018-2022<\/span>\u8d22\u5e74\u5f3a\u5316\u8ba1\u5212\uff08\u5e38\u79f0\u4e3a<\/span>GDUFA <\/span>\u627f\u8bfa\u51fd\uff09\u4e2d\u6240\u5b9a\u4e49\u7684\u590d\u6742\u6d3b\u6027\u6210\u5206\u3002<\/span><\/span><\/p>\n

Ingeneral, FDA\u2019s guidance documents do not establish legally enforceable responsibilities. Instead, guidances describe the Agency\u2019s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.<\/span><\/p>\n

\u4e00\u822c\u6765\u8bf4\uff0c<\/span>FDA<\/span>\u7684\u6307\u5357\u6587\u4ef6\u5e76\u4e0d\u4ea7\u751f\u6cd5\u5f8b\u5f3a\u5236\u4e49\u52a1\u3002\u76f8\u53cd\uff0c\u6307\u5357\u4e2d\u6240\u8ff0\u7684\u53ea\u662f\u836f\u76d1\u5f53\u5c40\u5bf9\u67d0\u4e2a\u4e3b\u9898\u5f53\u524d\u7684\u8003\u8651\uff0c\u5e94\u4ec5\u4f5c\u4e3a\u662f\u5efa\u8bae\uff0c\u5176\u4e2d\u5f15\u7528\u4e86\u5177\u4f53\u6cd5\u89c4\u6216\u6cd5\u5f8b\u8981\u6c42\u8005\u9664\u5916\u3002<\/span>SHOULD<\/span>\u4e00\u8bcd\u5728\u836f\u76d1\u673a\u6784\u7684\u6307\u5357\u4e2d\u51fa\u73b0\u65f6\u8868\u793a\u5efa\u8bae\u6216\u63a8\u8350\u67d0\u4e8b\u4f46\u5e76\u975e\u5f3a\u5236\u8981\u6c42\u3002<\/span><\/span><\/p>\n

II.     BACKGROUND <\/span><\/strong>\u80cc\u666f<\/span><\/strong><\/span><\/span><\/p>\n

As part of the reauthorization of the Generic Drug User Fee Amendments (GDUFA II),FDA committed to issuing a guidance on postapproval changes to Type II API DMFs and submission mechanisms for ANDA holders who reference such DMFs . This guidance is intended to fulfill that commitment, and describes the recommended documentation for master file holders or drug substance manufacturers, as appropriate. The guidance also outlines the recommended documentation to be submitted by the approved application holder, as well as references the appropriate pathways for such submissions.<\/span><\/p>\n

\u4f5c\u4e3a<\/span>GDUFAII<\/span>\u91cd\u65b0\u6388\u6743\u7684\u4e00\u90e8\u5206\uff0c<\/span>FDA<\/span>\u627f\u8bfa\u8981\u53d1\u5e03<\/span>II<\/span>\u7c7b<\/span>API DMF<\/span>\u6279\u51c6\u540e\u53d8\u66f4\u4ee5\u53ca\u5f15\u7528\u6b64\u7c7b<\/span>DMF<\/span>\u7684<\/span>ANDA<\/span>\u6301\u6709\u4eba\u7533\u62a5\u673a\u5236\u6307\u5357\u3002\u672c\u6307\u5357\u610f\u5728\u5c65\u884c\u6b64\u627f\u8bfa\uff0c\u9610\u8ff0\u4e86\u5efa\u8bae\u4e3b\u6587\u4ef6\u6301\u6709\u4eba\u548c\u539f\u6599\u751f\u4ea7\u5546\uff08\u9002\u5f53\u65f6\uff09\u9700\u63d0\u4ea4\u7684\u6587\u4ef6\u3002\u672c\u6307\u5357\u4ea6\u5217\u51fa\u4e86\u5df2\u6279\u51c6\u7684\u5236\u5242\u6279\u6587\u6301\u6709\u4eba\u6240\u5e94\u63d0\u4ea4\u7684\u6587\u4ef6\uff0c\u4ee5\u53ca\u5bf9\u6b64\u7c7b\u7533\u62a5\u7684\u9002\u5f53\u5f15\u7528\u65b9\u5f0f\u3002<\/span><\/span><\/p>\n

A.    Established Conditions and Reporting Categories <\/span><\/strong>\u5df2\u8ba2\u7acb\u7684\u6761\u4ef6\u548c\u62a5\u544a\u5206\u7c7b<\/span><\/strong><\/span><\/p>\n

Under 21 CFR 314.70, 314.97, and 514.8, application holders must notify FDA about changes to conditions established in approved applications beyond the variations already provided for in their applications. FDA\u2019s regulations identify three broad reporting categories: major changes (i.e., changes that require submission of a prior approval supplement (PAS)) ; moderate changes(i.e., changes that require submission of a changes being effected in 30 days(CBE-30) supplement or a changes being effected (CBE-0) supplement) ; and changes that must be reported in an annual report . The reporting category for a change is based on the potential risk for the change to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to its safety or effectiveness. This guidance provides recommendations on the information that should be provided to CDER, CBER, or CVM to ensure continued drug substance quality and drug product quality and performance characteristics. For the most up-to-date information on reporting categories for postapproval changes, see the referenced guidances insection XII, Reporting Category.<\/span><\/p>\n

\u5728<\/span>21CFR 314.70, 314.97<\/span>\u548c<\/span> 514.8<\/span>\u4e2d\uff0c\u7533\u62a5\u6301\u6709\u4eba\u5fc5\u987b\u901a\u77e5<\/span>FDA<\/span>\u5176\u5bf9\u5df2\u6279\u51c6\u7533\u62a5\u8d44\u6599\u4e2d\u65e2\u5b9a\u6761\u4ef6\u8d85\u51fa\u539f\u6709\u53d8\u66f4\u8303\u7574\u7684\u53d8\u66f4\u3002<\/span>FDA<\/span>\u7684\u6cd5\u89c4\u5927\u81f4\u5c06\u53d8\u66f4\u5206\u4e3a\u4e09\u79cd\u62a5\u544a\u7c7b\u522b\uff1a\u4e3b\u8981\u53d8\u66f4\uff08\u5373\u9700\u8981\u63d0\u4ea4\u9884\u5148\u6279\u51c6\u7684\u589e\u8865<\/span>PAS<\/span>\uff09\u3001\u4e2d\u7b49\u53d8\u66f4\uff08\u5373\u9700\u8981\u63d0\u4ea4<\/span>30<\/span>\u65e5\u5185\u751f\u6548\u7684\u589e\u8865<\/span>CBE-30<\/span>\u6216\u7acb\u5373\u751f\u6548\u7684\u589e\u8865<\/span>CBE-0<\/span>\uff09\uff0c\u4ee5\u53ca\u5fc5\u987b\u5728\u5e74\u62a5\u4e2d\u62a5\u544a\u7684\u53d8\u66f4\u3002\u53d8\u66f4\u7684\u62a5\u544a\u7c7b\u522b\u662f\u6839\u636e\u8be5\u53d8\u66f4\u5bf9\u836f\u54c1\u7684\u9274\u522b\u3001\u5242\u91cf\u3001\u8d28\u91cf\u3001\u7eaf\u5ea6\u6216\u6548\u4ef7\u4ea7\u751f\u7684\u4e0d\u826f\u5f71\u54cd\u786e\u5b9a\u7684\uff0c\u56e0\u4e3a\u8fd9\u4e9b\u56e0\u7d20\u53ef\u80fd\u4e0e\u5176\u5b89\u5168\u6027\u6216\u6709\u6548\u6027\u6709\u5173\u3002\u672c\u6307\u5357\u5bf9\u4e8e\u8981\u5411<\/span>CDER<\/span>\u3001<\/span>CBER<\/span>\u6216<\/span>CVM<\/span>\u63d0\u4ea4\u7684\u4fe1\u606f\u63d0\u4f9b\u4e86\u5efa\u8bae\uff0c\u4ee5\u786e\u4fdd\u539f\u6599\u836f\u8d28\u91cf\u548c\u5236\u5242\u8d28\u91cf\u548c\u6027\u80fd\u7279\u6027\u7684\u6301\u7eed\u6027\u3002\u5bf9\u4e8e\u6279\u51c6\u540e\u53d8\u66f4\u62a5\u544a\u7c7b\u578b\u7684\u6700\u65b0\u66f4\u65b0\u4fe1\u606f\uff0c\u53c2\u89c1\u7b2c<\/span>XII<\/span>\u90e8\u5206<\/span>\u201c<\/span>\u62a5\u544a\u7c7b\u522b<\/span>\u201d<\/span>\u6240\u5f15\u7528\u7684\u6307\u5357\u3002<\/span><\/span><\/p>\n

B.    Reporting Responsibilities <\/span><\/strong>\u62a5\u544a\u4e49\u52a1<\/span><\/strong><\/span><\/p>\n

Where drug substance information is provided in a DMF, a letter(s) of authorization must be provided to allow the applicant to reference the DMF . Any addition, change, or deletion of information in the master file must be submitted to the master file  in the form of an amendment. Further, the master file holder must notify each person authorized to reference the DMF of the nature of the changes , and should provide as much detail as is consistent with the confidentiality agreement between the master file holder and the authorized person, so that the authorized person can determine how to report the changes in the approved application. In turn, application holders must notify FDA of each change in each condition established in an approved application, excluding the variations already provided for in the application .<\/span><\/p>\n

\u5982\u679c\u539f\u6599\u836f\u4fe1\u606f\u662f\u5728<\/span>DMF<\/span>\u91cc\u63d0\u4f9b\u7684\uff0c\u5219\u5fc5\u987b\u63d0\u4ea4\u4e00\u4efd\u6388\u6743\u4fe1\u5141\u8bb8\u7533\u8bf7\u4eba\u5f15\u7528\u8be5<\/span>DMF<\/span>\u3002\u5bf9<\/span>DMF<\/span>\u4e2d\u4fe1\u606f\u7684\u4efb\u4f55\u589e\u52a0\u3001\u53d8\u66f4\u6216\u5220\u9664\u5747\u5fc5\u987b\u4ee5\u4fee\u8ba2\u65b9\u5f0f\u4e3a<\/span>DMF<\/span>\u63d0\u4ea4\u3002\u53e6\u5916\uff0c<\/span>DMF<\/span>\u6301\u6709\u4eba\u5fc5\u987b\u901a\u77e5\u6240\u6709\u6388\u6743\u5f15\u7528\u8be5<\/span>DMF<\/span>\u8005\u5176\u53d8\u66f4\u60c5\u51b5\uff0c\u5e76\u6839\u636e<\/span>DMF<\/span>\u6301\u6709\u4eba\u4e0e\u88ab\u6388\u6743\u4eba\u4e4b\u95f4\u7684\u4fdd\u5bc6\u534f\u8bae\u63d0\u4ea4\u8db3\u591f\u7684\u8be6\u7ec6\u4fe1\u606f\uff0c\u4f7f\u5f97\u88ab\u6388\u6743\u4eba\u53ef\u4ee5\u51b3\u5b9a\u5e94\u5982\u4f55\u5728\u62a5\u544a\u5176\u5df2\u6279\u51c6\u7684\u7533\u62a5\u53d8\u66f4\u3002<\/span><\/span><\/p>\n

When drug substance information is contained in an application, rather than in a referenced DMF, such changes must be submitted to FDA in the form of asupplement to the approved application or in an annual report, whichever is appropriate for the change being made .<\/span><\/p>\n

\u5982\u679c\u539f\u6599\u836f\u4fe1\u606f\u662f\u653e\u5728\u5236\u5242\u7533\u62a5\u8d44\u6599\u4e2d\u800c\u4e0d\u662f\u5f15\u7528<\/span>DMF<\/span>\uff0c\u5219\u5fc5\u987b\u91c7\u7528\u5bf9\u5df2\u6279\u51c6\u7533\u62a5\u8d44\u6599\u589e\u8865\u7684\u65b9\u5f0f\u5411<\/span>FDA<\/span>\u63d0\u4ea4\u6b64\u53d8\u66f4\uff0c\u6216\u5728\u5e74\u62a5\u4e2d\u63d0\u4ea4\uff08\u6839\u636e\u6240\u505a\u53d8\u66f4\u51b3\u5b9a\u6070\u5f53\u65b9\u5f0f\uff09\u3002<\/span><\/span><\/p>\n

The responsibility for reporting the types of changes described in this guidance could lie with a single party or with several parties, depending on whether the drug substance synthesis or processing is described in an application or in one or more master files. The notification to FDA should include reference to the section of this guidance under which the change is made and all pertinent information to ensure the quality of the drug substance and drug product. For example, when a master file holder makes a manufacturing process change, the change should be described in an amendment to the master file, and the application holder should provide notification of the change (citing section VIII of this guidance) in a supplement or annual report, as appropriate. The data to support the process change should be provided in an amendment to the masterfile or supplement to the approved NDA or ANDA when no master file is referenced.<\/span><\/p>\n

\u62a5\u544a\u672c\u6307\u5357\u4e2d\u6240\u8ff0\u7c7b\u522b\u53d8\u66f4\u7684\u4e49\u52a1\u53ef\u80fd\u662f\u5355\u4e00\u65b9\u7684\uff0c\u4e5f\u53ef\u80fd\u662f\u591a\u65b9\u7684\uff0c\u8fd9\u53d6\u51b3\u4e8e\u539f\u6599\u836f\u5408\u6210\u6216\u52a0\u5de5\u662f\u5728\u5236\u5242\u7533\u62a5\u4e2d\u63cf\u8ff0\u8fd8\u662f\u5728\u4e00\u4e2a\u6216\u591a\u4e2a<\/span>DMF<\/span>\u4e2d\u63cf\u8ff0\u3002\u5411<\/span>FDA<\/span>\u63d0\u4ea4\u7684\u901a\u77e5\u5e94\u5305\u62ec\u5bf9\u672c\u6307\u5357\u4e0e\u6240\u505a\u53d8\u66f4\u76f8\u5173\u90e8\u5206\u7684\u5f15\u7528\u4ee5\u53ca\u6240\u6709\u76f8\u5173\u4fe1\u606f\uff0c\u4ee5\u786e\u4fdd\u539f\u6599\u836f\u548c\u5236\u5242\u8d28\u91cf\u3002\u4f8b\u5982\uff0c\u5f53<\/span>DMF<\/span>\u6301\u6709\u4eba\u53d8\u66f4\u5176\u751f\u4ea7\u5de5\u827a\u65f6\uff0c\u53ef\u5728<\/span>DMF<\/span>\u4fee\u8ba2\u4e2d\u63cf\u8ff0\u8be5\u53d8\u66f4\uff0c\u800c\u5236\u5242\u7533\u62a5\u4eba\u5219\u5e94\u5728\u589e\u8865\u6216\u5e74\u62a5\uff08\u9002\u5f53\u65f6\uff09\u4e2d\u63d0\u4ea4\u53d8\u66f4\u901a\u77e5\uff08\u5f15\u7528\u672c\u6307\u5357\u7b2c<\/span>VIII<\/span>\u90e8\u5206\uff09\u3002\u652f\u6301\u5de5\u827a\u53d8\u66f4\u7684\u6570\u636e\u5e94\u5728<\/span>DMF<\/span>\u4fee\u8ba2\u4e2d\u63d0\u4ea4\uff0c\u6216\u5728\u5df2\u6279\u51c6<\/span>NDA<\/span>\u6216<\/span>ANDA<\/span>\u589e\u8865\u4e2d\u63d0\u4ea4\uff08\u5982\u672a\u5f15\u7528<\/span>DMF<\/span>\uff09\u3002<\/span><\/span><\/p>\n

III.   GENERAL CONSIDERATIONS <\/span><\/strong>\u4e00\u822c\u8003\u91cf<\/span><\/strong><\/span><\/p>\n

A.    Assessment of Risk <\/span><\/strong>\u98ce\u9669\u8bc4\u4f30<\/span><\/strong><\/span><\/p>\n

Any modification to drug substance manufacturing carries some risk of causing anadverse impact on quality, either in the physical properties of the drug substance or in the level or nature of impurities present, and, in some cases, to the bioequivalence or safety profile of the drug.<\/span><\/p>\n

\u5bf9\u539f\u6599\u836f\u751f\u4ea7\u7684\u4efb\u4f55\u6539\u52a8\u5747\u6709\u53ef\u80fd\u5bf9\u539f\u6599\u836f\u8d28\u91cf\u4ea7\u751f\u4e0d\u826f\u5f71\u54cd\u7684\u98ce\u9669\uff0c\u8981\u4e48\u662f\u7269\u7406\u5c5e\u6027\uff0c\u8981\u4e48\u662f\u6742\u8d28\u5728\u8d28\u4e0e\u91cf\u65b9\u9762\uff0c\u6709\u65f6\u5019\u662f\u5236\u5242\u7684\u751f\u7269\u7b49\u6548\u6027\u6216\u5b89\u5168\u6982\u51b5\u3002<\/span><\/p>\n

Certain kinds of modifications (e.g., equipment or facility changes) are viewed as less likely to result in an adverse impact than others (e.g., changes in the synthetic route). However, each drug substance manufacturer will need to assess the particular modification for their drug substance to determine the risk associated with the change . This guidance applies to changes made throughout the drug substance manufacturing process, i.e., from the starting material through the final drug substance. Late-stage changes in the drug substance manufacturing process are generally viewed as more likely to have an adverse impact on the quality of the drug substance and, consequently, on the drug product. Some late-stage changes should be evaluated not only by comparing pre-and post-modification drug substance, but also by comparing drug product prepared from pre- and post-modification drug substance. Finished drug product manufacturers should ensure that drug substances used in their products meet established specifications and, for compendial drug substances, meet United States Pharmacopeia (USP) standards.<\/span><\/p>\n

\u67d0\u4e9b\u79cd\u7c7b\u7684\u4fee\u6539\uff08\u4f8b\u5982\u8bbe\u5907\u6216\u8bbe\u65bd\u53d8\u66f4\uff09\u88ab\u8ba4\u4e3a\u76f8\u6bd4\u5176\u5b83\u53d8\u66f4\uff08\u4f8b\u5982\u5408\u6210\u8def\u7ebf\u53d8\u66f4\uff09\u5bfc\u81f4\u7684\u4e0d\u826f\u5f71\u54cd\u4f1a\u66f4\u5c0f\u3002\u4f46\u662f\uff0c\u6bcf\u4e2a\u539f\u6599\u836f\u751f\u4ea7\u5546\u90fd\u9700\u8981\u8bc4\u4f30\u5176\u539f\u6599\u836f\u7684\u7279\u5b9a\u53d8\u66f4\u4ee5\u786e\u5b9a\u8be5\u53d8\u66f4\u6240\u5e26\u6765\u7684\u98ce\u9669\u3002\u672c\u6307\u5357\u9002\u7528\u4e8e\u5bf9\u539f\u6599\u836f\u6574\u4e2a\u751f\u4ea7\u5de5\u827a\u6240\u505a\u7684\u53d8\u66f4\uff0c\u5373\u4ece\u8d77\u59cb\u7269\u6599\u5230\u539f\u6599\u836f\u6210\u54c1\u3002\u5bf9\u539f\u6599\u836f\u751f\u4ea7\u5de5\u827a\u8f83\u540e\u7684\u9636\u6bb5\u53d8\u66f4\u4e00\u822c\u4f1a\u8ba4\u4e3a\u66f4\u52a0\u6709\u53ef\u80fd\u5bf9\u539f\u6599\u836f\u8d28\u91cf\u4ea7\u751f\u4e0d\u826f\u5f71\u54cd\uff0c\u4ece\u800c\u5bf9\u5236\u5242\u4ea7\u751f\u5f71\u54cd\u3002\u4e00\u4e9b\u8f83\u540e\u9636\u6bb5\u7684\u53d8\u66f4\u4e0d\u4ec5\u5e94\u901a\u8fc7\u6bd4\u8f83\u53d8\u66f4\u524d\u540e\u539f\u6599\u836f\uff0c\u8fd8\u5e94\u901a\u8fc7\u6bd4\u8f83\u539f\u6599\u836f\u53d8\u66f4\u524d\u540e\u7684\u5236\u5242\u6765\u8fdb\u884c\u8bc4\u4f30\u3002\u51e1\u662f\u751f\u4ea7\u5546\u5e94\u786e\u4fdd\u5176\u5236\u5242\u751f\u4ea7\u6240\u7528\u539f\u6599\u836f\u7b26\u5408\u65e2\u5b9a\u6807\u51c6\uff0c\u5982\u679c\u662f\u836f\u5178\u539f\u6599\u836f\uff0c\u5219\u5e94\u7b26\u5408<\/span>USP<\/span>\u6807\u51c6\u3002<\/span><\/span><\/p>\n

Risk assessment principles are outlined in International Council for Harmonisation (ICH) guidance for industry Q9 Quality Risk Management (ICH Q9 ). As noted in ICH Q9, the level of effort, formality, and documentation of the quality risk management process should be commensurate with the level of risk. A risk assessment should be performed by the drug substance manufacturer to assess the effect of the change, as well as by the drug product manufacturer to evaluate the risks associated with drug substance manufacturing modifications. A reduction in the number of drug substance and\/or drug product batches from the recommendations provided in this guidance (see sections VI \u2013 XI) may also beacceptable if an adequate justification is provided based on the risk assessment.<\/span><\/p>\n

ICH<\/span>\u884c\u4e1a\u6307\u5357<\/span>Q9\u201c<\/span>\u8d28\u91cf\u98ce\u9669\u7ba1\u7406<\/span>\u201d<\/span>\uff08<\/span>ICH Q9<\/span>\uff09\u4e2d\u5217\u51fa\u4e86\u98ce\u9669\u8bc4\u4f30\u539f\u5219\u3002\u6b63\u5982<\/span>ICH Q9<\/span>\u4e2d\u6240\u8a00\uff0c\u8d28\u91cf\u98ce\u9669\u7ba1\u7406\u6d41\u7a0b\u7684\u5de5\u4f5c\u6c34\u5e73\u3001\u6b63\u5f0f\u7a0b\u5ea6\u4ee5\u53ca\u6587\u4ef6\u5316\u5e94\u4e0e\u98ce\u9669\u6c34\u5e73\u76f8\u5f53\u3002\u98ce\u9669\u8bc4\u4f30\u5e94\u7531\u539f\u6599\u836f\u751f\u4ea7\u5546\u6267\u884c\uff0c\u4ee5\u8bc4\u4f30\u53d8\u66f4\u7684\u5f71\u54cd\uff0c\u540c\u65f6\u4ea6\u5e94\u7531\u5236\u5242\u751f\u4ea7\u5546\u8bc4\u4f30\u539f\u6599\u836f\u751f\u4ea7\u53d8\u66f4\u6240\u5173\u8054\u7684\u98ce\u9669\u3002\u5982\u679c\u6839\u636e\u98ce\u9669\u8bc4\u4f30\u63d0\u4ea4\u4e86\u8db3\u591f\u7684\u8bba\u8bc1\uff0c\u5219\u51cf\u5c11\u672c\u6307\u5357\u4e2d\uff08\u53c2\u89c1\u7b2c<\/span>VI-XI<\/span>\u90e8\u5206\uff09\u6240\u5efa\u8bae\u7684\u539f\u6599\u836f\u548c<\/span>\/<\/span>\u6216\u5236\u5242\u6279\u6b21\u4ea6\u53ef\u63a5\u53d7\u3002<\/span><\/span><\/p>\n

The following are examples of factors to consider when conducting a risk assessment on a change to the drug substance:<\/span><\/p>\n

\u5bf9\u539f\u6599\u836f\u53d8\u66f4\u6267\u884c\u98ce\u9669\u8bc4\u4f30\u65f6\u8981\u8003\u8651\u7684\u56e0\u7d20\u4e3e\u4f8b\u5982\u4e0b\uff1a<\/span><\/p>\n

\u2022      Experience of the manufacturing facility and\/or personnel involved in the portion of the process that encompasses the proposed change.<\/span><\/p>\n

\u2022      <\/span>\u6240\u63d0\u8bae\u53d8\u66f4\u6d89\u53ca\u5de5\u827a\u90e8\u5206\u4e2d\u76f8\u5173\u751f\u4ea7\u573a\u6240\u548c<\/span>\/<\/span>\u6216\u4eba\u5458\u7684\u7ecf\u9a8c<\/span><\/span><\/p>\n

o    Changes implemented at the same facility with experienced personnel may pose less risk than a change implemented at a new facility with inexperienced personnel or involvement of a third-party vendor.<\/span><\/p>\n

O     <\/span>\u5728\u76f8\u540c\u8bbe\u65bd\u5185\u7531\u5bcc\u6709\u7ecf\u9a8c\u7684\u4eba\u5458\u6267\u884c\u53d8\u66f4\u76f8\u6bd4\u4e8e\u5728\u65b0\u8bbe\u65bd\u7531\u65e0\u7ecf\u9a8c\u7684\u4eba\u5458\u6267\u884c\u53d8\u66f4\u6216\u6d89\u53ca\u7b2c\u4e09\u65b9\u4f9b\u5e94\u5546\u65f6\u98ce\u9669\u4f1a\u66f4\u5c0f\u3002<\/span><\/span><\/p>\n

\u2022      Complexity of the manufacturing steps involved in the change.<\/span><\/p>\n

\u2022      <\/span>\u53d8\u66f4\u6240\u6d89\u53ca\u751f\u4ea7\u6b65\u9aa4\u7684\u590d\u6742\u6027<\/span><\/span><\/p>\n

o     Changes implemented to homogeneous reactions using common chemistry and reaction conditions may pose less risk than a change implemented to heterogeneous reaction steps involving unusually complex or sensitive chemistry, and\/or unusual equipment or reaction conditions.<\/span><\/p>\n

o     <\/span>\u5bf9\u91c7\u7528\u4e00\u822c\u5316\u5b66\u548c\u53cd\u5e94\u6761\u4ef6\u7684\u5747\u4e00\u53cd\u5e94\u6267\u884c\u53d8\u66f4\u76f8\u6bd4\u5bf9\u6d89\u53ca\u975e\u5e38\u89c4\u590d\u6742\u6216\u654f\u611f\u5316\u5b66\u548c<\/span>\/<\/span>\u6216\u4e0d\u5e38\u7528\u8bbe\u5907\u6216\u53cd\u5e94\u6761\u4ef6\u7684\u6210\u5206\u6df7\u6742\u7684\u53cd\u5e94\u6267\u884c\u53d8\u66f4\u98ce\u9669\u66f4\u4f4e<\/span><\/span><\/p>\n

\u2022      Physical and chemical stability of the material (intermediate or drug substance) involved in the change.<\/span><\/p>\n

\u2022      <\/span>\u53d8\u66f4\u6d89\u53ca\u7269\u6599\uff08\u4e2d\u95f4\u4f53\u6216\u539f\u6599\u836f\uff09\u7684\u7406\u5316\u7a33\u5b9a\u6027<\/span><\/span><\/p>\n

o     Changes implemented for a molecule that is physically and chemically stable may pose less risk than a change implemented for a molecule that degrades easily or has multiple or unstable physical forms.<\/span><\/p>\n

o     <\/span>\u5bf9\u7406\u5316\u7279\u6027\u8f83\u7a33\u5b9a\u7684\u5206\u5b50\u6267\u884c\u53d8\u66f4\u76f8\u6bd4\u5bf9\u6613\u4e8e\u964d\u89e3\u6216\u5177\u6709\u591a\u4e2a\u6216\u4e0d\u7a33\u5b9a\u7269\u7406\u5f62\u6001\u7684\u5206\u5b50\u6267\u884c\u53d8\u66f4\u98ce\u9669\u66f4\u4f4e<\/span><\/span><\/p>\n

\u2022      Complexity of the molecule.<\/span><\/p>\n

\u2022      <\/span>\u5206\u5b50\u590d\u6742\u6027<\/span><\/span><\/p>\n

o     Changes implemented for a small molecule with minimal structural or stereochemical isomerism may pose less risk than a change implemented for a large molecule with multiple structural or stereochemical isomers.<\/span><\/p>\n

o     <\/span>\u5bf9\u5177\u6709\u8f83\u5c11\u540c\u5206\u5f02\u6784\u6216\u5316\u5b66\u7acb\u4f53\u5f02\u6784\u4f53\u7684\u5c0f\u5206\u5b50\u6267\u884c\u53d8\u66f4\u76f8\u6bd4\u5bf9\u5177\u6709\u591a\u4e2a\u540c\u5206\u5f02\u6784\u6216\u5316\u5b66\u7acb\u4f53\u5f02\u6784\u4f53\u7684\u5927\u5206\u5b50\u6267\u884c\u53d8\u66f4\u98ce\u9669\u66f4\u4f4e<\/span><\/span><\/p>\n

\u2022      Equivalence of the entire impurity profile.<\/span><\/p>\n

\u2022      <\/span>\u6574\u4f53\u6742\u8d28\u6982\u51b5\u7684\u7b49\u540c\u6027<\/span><\/span><\/p>\n

o     Batches of post-modification material that have levels of identified impurities comparable to historical data may pose less risk than batches with higher levels of identified impurities and\/or new identified impurities.<\/span><\/p>\n

o     <\/span>\u53d8\u66f4\u540e\u7269\u6599\u6279\u6b21\u5df2\u77e5\u6742\u8d28\u6c34\u5e73\u4e0e\u5386\u53f2\u6570\u636e\u53ef\u6bd4\u7684\u60c5\u51b5\u76f8\u6bd4\u4e8e\u53d8\u66f4\u540e\u7269\u6599\u6279\u6b21\u4e2d\u5df2\u77e5\u6742\u8d28\u548c<\/span>\/<\/span>\u6216\u65b0\u5df2\u77e5\u6742\u8d28\u6c34\u5e73\u9ad8\u4e8e\u5386\u53f2\u6570\u636e\u98ce\u9669\u66f4\u4f4e<\/span><\/span><\/p>\n

o     Batches of post-modification material that have a number and level of unidentified impurities comparable to historical data may pose less risk than batches with a larger number and\/or levels of unidentified impurities.<\/span><\/p>\n

o     <\/span>\u53d8\u66f4\u540e\u7269\u6599\u6279\u6b21\u4e2d\u672a\u77e5\u6742\u8d28\u6570\u91cf\u548c\u6c34\u5e73\u4e0e\u5386\u53f2\u6570\u636e\u53ef\u6bd4\u7684\u60c5\u51b5\u76f8\u6bd4\u4e8e\u53d8\u66f4\u540e\u7269\u6599\u6279\u6b21\u4e2d\u672a\u77e5\u6742\u8d28\u6570\u91cf\u548c\u6c34\u5e73\u9ad8\u4e8e\u5386\u53f2\u6570\u636e\u98ce\u9669\u66f4\u4f4e<\/span><\/span><\/p>\n

\u2022      Comparability of physical properties when they may impact drug product performance or manufacturability (typically changes made to the drug substance at or after the final solution step would bethe most likely to impact physical properties).<\/span><\/p>\n

\u2022      <\/span>\u53ef\u80fd\u5f71\u54cd\u5236\u5242\u6027\u80fd\u6216\u53ef\u52a0\u5de5\u6027\uff08\u539f\u6599\u836f\u6700\u7ec8\u6eb6\u6db2\u6b65\u9aa4\u6216\u5176\u540e\u7684\u53d8\u66f4\u4e00\u822c\u6700\u6709\u53ef\u80fd\u5f71\u54cd\u7269\u7406\u7279\u6027\uff09\u7684\u7269\u7406\u7279\u6027\u7684\u53ef\u6bd4\u6027<\/span><\/span><\/p>\n

o     Post-modification  material that has the same physical properties may pose less risk than post-modification material with different physical properties (e.g., solid state form, particle size, solubility,bulk\/tapped density).<\/span><\/p>\n

o     <\/span>\u53d8\u66f4\u540e\u7269\u6599\u5177\u6709\u76f8\u540c\u7269\u7406\u7279\u6027\u7684\u76f8\u6bd4\u4e8e\u53d8\u66f4\u540e\u7269\u6599\u5177\u6709\u4e0d\u540c\u7269\u7406\u7279\u6027\uff08\u4f8b\u5982\uff0c\u56fa\u4f53\u5f62\u6001\u3001\u7c92\u5f84\u3001\u6eb6\u89e3\u5ea6\u3001\u5806\u5bc6\u5ea6<\/span>\/<\/span>\u51fb\u62cd\u5bc6\u5ea6\uff09\u7684\u98ce\u9669\u66f4\u4f4e<\/span><\/span><\/p>\n

B.    Other Relevant Guidances <\/span><\/strong>\u5176\u5b83\u76f8\u5173\u6307\u5357<\/span><\/strong><\/span><\/p>\n

This guidance aligns with existing FDA guidance, including the ICH guidances for industry Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients, Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients Questions and Answers, Q8(R2) Pharmaceutical Development, Q9 Quality Risk Management, Q10 Pharmaceutical Quality System, Q11 Development and Manufacture of Drug Substances, Q11 Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological\/Biological Entities)\u2014Questions and Answers, and M7 Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk.In addition to ICH Q10, which describes key systems that help establish and maintain a state of control for process performance and product quality, the FDA guidances for industry Quality Systems Approach to Pharmaceutical CGMP Regulations and Process Validation: General Principles and Practices address the current good manufacturing practice (CGMP) requirement for change control.Change control is generally understood to be the responsibility of the quality control unit . Effective change control activities are key components of any quality system. Although this guidance does not repeat the concepts and principles explained in those guidances, FDA encourages the use of modern pharmaceutical development concepts, quality risk management, and an effective pharmaceutical quality system at all stages of the manufacturing process lifecycle.<\/span><\/p>\n

\u672c\u6307\u5357\u4e0e\u5df2\u6709<\/span>FDA<\/span>\u6307\u5357\u4fdd\u6301\u4e00\u81f4\uff0c\u5305\u62ec<\/span>ICH<\/span>\u884c\u4e1a\u6307\u5357<\/span>Q7\u201cAPI<\/span>\u7684<\/span>GMP\u201d<\/span>\uff0c<\/span>Q7<\/span>\u95ee\u7b54\u3001<\/span>Q8<\/span>\uff08<\/span>R2<\/span>\uff09<\/span>\u201c<\/span>\u836f\u7269\u7814\u53d1<\/span>\u201d<\/span>\u3001<\/span>Q9\u201c<\/span>\u8d28\u91cf\u98ce\u9669\u7ba1\u7406<\/span>\u201d<\/span>\u3001<\/span>Q10\u201c<\/span>\u836f\u7269\u8d28\u91cf\u4f53\u7cfb<\/span>\u201d<\/span>\u3001<\/span>Q11\u201c<\/span>\u539f\u6599\u836f\u5f00\u53d1\u4e0e\u751f\u4ea7<\/span>\u201d<\/span>\u3001<\/span>Q11<\/span>\u539f\u6599\u836f\uff08\u5316\u5b66\u5b9e\u4f53\u548c\u751f\u7269\u5236\u54c1\u5b9e\u4f53\uff09\u5f00\u53d1\u4e0e\u751f\u4ea7\u95ee\u7b54\uff0c\u4ee5\u53ca<\/span>M7\u201c<\/span>\u836f\u7269\u4e2d<\/span>DNA<\/span>\u53cd\u5e94\u6d3b\u6027\uff08\u8bf1\u53d8\u6027\uff09\u6742\u8d28\u7684\u8bc4\u4f30\u4e0e\u63a7\u5236\u4ee5\u9650\u5236\u6f5c\u5728\u81f4\u764c\u98ce\u9669<\/span>\u201d<\/span>\u3002\u9664\u4e86<\/span>ICH Q10<\/span>\u9610\u8ff0\u5173\u952e\u7cfb\u7edf\u7528\u4e8e\u5e2e\u52a9\u5efa\u7acb\u548c\u7ef4\u62a4\u5de5\u827a\u6027\u80fd\u4e0e\u4ea7\u54c1\u8d28\u91cf\u53d7\u63a7\u5916\uff0c<\/span>FDA<\/span>\u884c\u4e1a\u6307\u5357<\/span>\u201c<\/span>\u836f\u7269<\/span>CGMP<\/span>\u6cd5\u89c4\u7684\u8d28\u91cf\u4f53\u7cfb\u5b9e\u73b0<\/span>\u201d<\/span>\u548c<\/span>\u201c<\/span>\u5de5\u827a\u9a8c\u8bc1\uff1a\u901a\u5219\u4e0e\u89c4\u8303<\/span>\u201d<\/span>\u9610\u8ff0\u4e86\u53d8\u66f4\u63a7\u5236\u7684<\/span>CGMP<\/span>\u8981\u6c42\u3002\u53d8\u66f4\u63a7\u5236\u901a\u5e38\u88ab\u7406\u89e3\u4e3a\u8d28\u91cf\u90e8\u95e8\u7684\u804c\u8d23\u3002\u6709\u6548\u7684\u53d8\u66f4\u63a7\u5236\u6d3b\u52a8\u662f\u6240\u6709\u8d28\u91cf\u4f53\u7cfb\u7684\u5173\u952e\u8981\u7d20\uff0c\u5c3d\u7ba1\u672c\u6307\u5357\u5e76\u672a\u91cd\u590d\u8fd9\u4e9b\u6307\u5357\u4e2d\u6240\u89e3\u91ca\u7684\u6982\u5ff5\u548c\u539f\u5219\uff0c\u4f46<\/span>FDA<\/span>\u9f13\u52b1\u5728\u751f\u4ea7\u5de5\u827a\u751f\u547d\u5468\u671f\u7684\u6240\u6709\u9636\u6bb5\u4f7f\u7528\u73b0\u4ee3\u5316\u836f\u7269\u5f00\u53d1\u6982\u5ff5\u3001\u8d28\u91cf\u98ce\u9669\u7ba1\u7406\u4ee5\u53ca\u6709\u6548\u7684\u836f\u7269\u8d28\u91cf\u4f53\u7cfb\u3002<\/span><\/span><\/p>\n


<\/p>\n<\/p><\/div>\n","protected":false},"excerpt":{"rendered":"

\u7ffb\u8bd1\uff1aJULIA   \u6765\u6e90\uff1a Julia\u6cd5\u89c4\u7ffb\u8bd1 FDA\u884c\u4e1a\u6307\u5357\u8349\u6848\uff1a\u539f\u6599\u836f\u6279\u51c6\u540e\u53d8\u66f4 2 […]<\/p>\n","protected":false},"author":1,"featured_media":53838,"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\/53837"}],"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=53837"}],"version-history":[{"count":1,"href":"https:\/\/www.05921.net\/index.php\/wp-json\/wp\/v2\/posts\/53837\/revisions"}],"predecessor-version":[{"id":53839,"href":"https:\/\/www.05921.net\/index.php\/wp-json\/wp\/v2\/posts\/53837\/revisions\/53839"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.05921.net\/index.php\/wp-json\/wp\/v2\/media\/53838"}],"wp:attachment":[{"href":"https:\/\/www.05921.net\/index.php\/wp-json\/wp\/v2\/media?parent=53837"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.05921.net\/index.php\/wp-json\/wp\/v2\/categories?post=53837"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.05921.net\/index.php\/wp-json\/wp\/v2\/tags?post=53837"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}