FDA行业指南：人药中亚硝胺杂质的控制202009

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FDA行业指南：人药中亚硝胺杂质的控制202009

FDA发布本指南立即生效，有建议可通过书面或电子方式提交。

要求化学合成API和制剂生产商进行风险评估（不需提交，需留文件备查），如识别出风险则进行确认性检测；如检出结果高于可接受限度，则立即通知FDA。识别出风险但不高于可接受限度者应根据情况提交变更或与FDA沟通。

具体参见指南全文。

I.     INTRODUCTION 概述

II.    BACKGROUND 背景

A.    Nitrosamine Impurities 亚硝胺杂质

B.    General Root Causes for the Presence ofNitrosamine Impurities in APIs 原料药中出现亚硝胺杂质的常见根本原因

C.   Nitrosamine Impurities in Drug Products FromSources Other Than API Contamination 药品中非API污染的其它来源亚硝胺杂质

III.   RECOMMENDATIONS 建议

A.    Acceptable Intake Limits 可接受日摄入限度

B.    Recommendations to API Manufacturers 对API生产商的建议

C.   Recommendations to Drug Product Manufacturers对制剂生产商的建议

IV.   MAINTAINING THE DRUG SUPPLY 维持持药品供应

V.    REPORTING CHANGES TO FDA 向FDA报告变更

A.    Recommended Timeline for Risk Assessment,Confirmatory Testing, and Submission of Required Changes 风险评估、确认性检测和所需变更提交的建议时间表

APPENDIXA. ADDITIONAL RESOURCES 附录A：其它资源

APPENDIXB. FDA DETERMINATION OF ACCEPTABLE INTAKE LIMITS

附录B：FDA对可接受摄入限度的确定

II.    BACKGROUND背景

FDA has been investigating the presence of nitrosamine impurities in certain drug products. Since 2018, several drug products including ARBs, ranitidine,nizatidine, and metformin have been found to contain unacceptable levels of nitrosamines.

FDA已经对特定药品中出现亚硝胺杂质的情况进行了调查。自2018年以来，已发现有几种药品包括ARB、雷尼替丁、尼扎替丁和二甲双胍中含有不可接受水平的亚硝胺。

In June 2018, FDA was informed of the presence of an impurity identified as N-nitrosodimethylamine (NDMA) in the ARB valsartan . Through investigation, the Agency determined that numerous lots of valsartan and a few other ARB drug products from different manufacturers contained unacceptable levels of nitrosamines. The drug product manufacturers voluntarily recalled the affected batches of these drug products , which led to a drug shortage in some of the affected products . In addition, FDA evaluated processes that use common amines in API synthesis and learned that common synthetic pathways could also introduce other types of nitrosamine impurities besides NDMA.

2018年6月，FDA收到通知说在ARB缬沙坦中检出NDMA杂质。通过调查，FDA发现来自不同生产商的大量批次缬沙坦和几种其它ARB药品中含有不可接受水平的亚硝胺。药品生产商自愿召回了这些药品的受影响批次，这样导致了有些受影响药品的短缺。另外，FDA评估了API合成中使用常见胺的工艺，了解到常规的合成路径亦会引入NDMA以外其它类别的亚硝胺杂质。

In September 2019, FDA learned that some common heartburn products (ranitidine, commonly known as Zantac, and nizatidine, commonly known as Axid) contained unacceptable levels of NDMA . FDA recommended that manufacturers voluntarily recall ranitidine and nizatidine products with NDMA levels above what the Agency considers acceptable  . Recently,preliminary findings from FDA stability testing raised concerns that NDMA levels in some ranitidine products stored at room temperature can increase with time to unacceptable levels.

2019年9月，FDA了解到有些常见胃灼烧药品（雷尼替丁，通常称为善胃得，尼扎替丁，通常称为爱希得）中含有不可接受水平的NDMA。FDA建议生产商主动召回NDMA水平超出FDA认为可接受水平的雷尼替丁和尼扎替丁药品。最近，FDA稳定性测试中初步发现有些室温下存贮的雷尼替丁药品中NDMA水平会随时间推移升高至不可接受的水平。

FDA’s preliminary results using accelerated stability testing demonstrated that elevated levels of NDMA were measured in all products after 2 weeks. FDA’s testing suggests that NDMA levels increase with storage time. On April 1, 2020, FDA requested that all ranitidine products be withdrawn from the U.S. market.

FDA的加速稳定性测试得到初步结果显示在2周后所有药品中NDMA水平均有所升高。FDA的检测说明NDMA水平随着存贮时长增加而增加。2020年4月1日，FDA要求从美国市场上召回所有雷尼替丁药品。

In December 2019, FDA became aware that some metformin diabetes medicines in other countries were reported to have NDMA. In light of this information, FDA acquired samples of metformin to test for NDMA. By February 2020, the Agency had identified NDMA in some samples but did not find levels exceeding the acceptable intake limit. In May 2020, further FDA testing revealed that certain lots of metformin extended-release formulation contained NDMA above the Agency’s recommended acceptable intake limit. Based on that testing, FDA requested that identified applicants voluntarily recall these lots of the extended-release metformin. FDA continues to investigate possible NDMA impurities in metformin and other drug products and will advise companies on appropriate action.

2019年12月，FDA了解到其它国家有些二甲双胍糖尿病药品报道含有NDMA。根据该消息，FDA索取了一些二甲双胍样品进行NDMA检测。截止2020年2月，FDA已在多个样品中检出NDMA，但并未发现超出可接受摄入限度。2020年5月，FDA进一步检查发现有些批次的二甲双胍缓释制剂含有NDMA超出FDA建议的可接受摄入限度。基于该检测结果，FDA要求所识别出的申报人主动召回这些批次的缓释二甲双胍。FDA正在继续调查二甲双胍中可能的NDMA杂质，未来会给公司提出相应措施建议。

Because the nitrosamine impurity issue extends beyond the U.S. drug supply, FDA and other regulatory authorities have partnered to share information, coordinate inspection efforts, communicate effective analytical methods to detect and identify various nitrosamines, and to develop rapid solutions to ensure the safety and quality of the drug supply.

由于亚硝胺杂质问题扩散到美国药品供应以外范围，FDA和其它药监机构已合作共享信息，协调进行检查工作，沟通有效的分析方法从而检出和识别不同的亚硝胺，同时建立快速解决方案来确保药品供应的安全和质量。

英文FDA官网下载

https://www.fda.gov/media/141720/download

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syhorchid

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研究研究，谢谢