FDA行业指南：人用药物中亚硝胺杂质控制指南（中英文对照版）！

Control of Nitrosamine Impuritiesin Human Drugs

人药中亚硝胺杂质的控制

Guidance for Industry

行业指南

Preface 

前言

FDA is implementing this guidance without prior public comment becausethe Agency has determined that prior public participation is not feasible orappropriate (see Section 701(h)(1)(C)(i) of the Federal Food, Drug, andCosmetic Act (FD&C Act) and 21 CFR 10.115(g)(2) and (g)(3)). FDA made this determination because of theimportance of providing timely information to manufacturers regarding riskassessments, testing, and other appropriate actions they should take to reduceand mitigate nitrosamine impurities in active pharmaceutical ingredients (APIs)1 and drugproducts. This guidance document is being implemented immediately, but itremains subject to comment in accordance with the Agency’s good guidancepractices.

FDA 立即执行本指南没有事先征询公众意见，因为 FDA 已确定公众事先参与是不可行或不适当的（请参见《联邦食品，药品和化妆品法》第 701(h)(1)(C)(i)节和 21 CFR10.115(g)(2) 和 (g)(3))。FDA 之所以做出这一决定，是因为必须及时向制造商提供有关风险评估、检测以及他们应采取的减少和缓解活性药物成分（API）和制剂中亚硝胺杂质的其他适当措施的信息。该指导文件将立即执行，但仍会根据 FDA 的优良指南规范接受各方意见。

Comments may be submitted at any time for Agency consideration. Submitwritten comments to the Dockets Management Staff (HFA-305), Food and DrugAdministration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. Submitelectronic comments to https://www.regulations.gov. Allcomments should be identified with the docket number FDA-2020-D-1530 andcomplete title of the guidance in the request.

如的意见和建议，可以随时提交给 FDA 考虑。书面建议请发送至 Dockets Management Staff (HFA-305), Food and DrugAdministration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852。电子建议请提交到 https://www.regulations.gov。所有建议均应标上档案编号 FDA-2020-D-1530，并写明指南的完整标题。

I.  INTRODUCTION

介绍

II. BACKGROUND

背景

A. Nitrosamine Impurities

亚硝胺杂质

B. General Root Causes for the Presence of NitrosamineImpurities in APIs

原料药中亚硝胺杂质存在的一般根源

C. Nitrosamine Impurities in Drug Products From Sources Other Than API Contamination

药品中除原料药污染以外的亚硝胺杂质来源

III.      RECOMMENDATIONS

建议

A. Acceptable Intake Limits

可接受的摄入量限值

B. Recommendations to API Manufacturers

对原料药制造商的建议

C. Recommendations to Drug Product Manufacturers

对药品制造商的建议

IV.  MAINTAINING THE DRUGSUPPLY

维持药物供应

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、确认测试及必要变更的提交

APPENDIX A.ADDITIONAL RESOURCES

附录A 拓展资源

APPENDIX B. FDA DETERMINATION OF THE ACCEPTABLE INTAKE

附录B FDA对可接受摄入量的测定

Controlof Nitrosamine Impurities in Human Drugs

Guidance for Industry

行业指南：人药中亚硝胺杂质的控制

This guidance represents the current thinking of the Food and DrugAdministration (FDA or Agency) on this topic. It does not establish any rightsfor any person and is not binding on FDA or the public. You can use analternative approach if it satisfies the requirements of the applicablestatutes and regulations. To discuss an alternative approach, contact the FDAstaff responsible for this guidance as listed on the title page.

本指南代表了 FDA 关于此主题的最新观点。它不为赋予任何人任何权利，对 FDA 或公众均无约束力。如果满足适用法规的要求，则可以使用其他方法。要讨论替代方法，请联系标题页上列出的负责本指南的 FDA 工作人员。

I.   INTRODUCTION

概述

This guidance recommends steps manufacturers of APIs and drug productsshould take to detect and prevent unacceptable levels of nitrosamine2impurities in pharmaceutical products3. The guidance also describesconditions that may introduce nitrosamine impurities. The recent unexpectedfinding of nitrosamine impurities, which are probable human carcinogens, indrugs such as angiotensin II receptor blockers (ARBs4),ranitidine5, nizatidine6, and metformin7, has made clear the need for arisk assessment strategy for potential nitrosamines in any pharmaceuticalproduct at risk for their presence.

本指南为 API 和制剂生产商提供了检出和防止药品中出现不可接受水平亚硝胺杂质所需采取措施的建议。本指南亦介绍了可能引入亚硝胺杂质的条件。最近在如 ARB、雷尼替丁、尼扎替丁和二甲双胍药品中意外发现的亚硝胺杂质是可能的人类致癌物，使得大家清楚需要对所有存在风险的药品采取潜在亚硝胺风险评估策略。

The discovery of nitrosamines in some types of drug products led FDA andother international regulators to conduct a detailed analysis of theseimpurities in affected APIs and drug products89. Based on the Agency’s current understanding, this guidance discussespotential root causes of nitrosamine formation and advises API and drug productmanufacturers that they should (1) conduct risk assessments of their approvedor marketed products and products with pending applications, and (2) takeappropriate actions to reduce or prevent the presence of nitrosamines in APIsand drug products.

在一些类型的药品中发现亚硝胺促使 FDA 和其它国际药品监管机构对这些影响 API 和制剂的杂质进行了详细的分析。根据 FDA 目前的了解，本指南讨论了亚硝胺形成的可能根本原因，建议 API 和制剂生产商（1）对其已批准和已上市药品及在审药品进行风险评估，（2）采取恰当措施降低或防止 API 和制剂中出现亚硝胺。

Although nitrosamine impurities have been found in only some drugproducts, and batches of those products have been recalled when there wereunacceptable levels10 of these impurities, nitrosamine impurities mightexist in other APIs and drug products due to use of vulnerable processes andmaterials that may produce nitrosamine impurities. Therefore, therecommendations made in this guidance apply to all chemically synthesized APIs.They also apply to drug products containing chemically synthesized APIs and todrug products at risk due to other factors described in this guidance (seesections II.B and C), and not just to the drug products that have beenidentified in FDA announcements.

虽然只在几种药品中检出了亚硝胺杂质，并且已经召回了杂质水平高于可接受水平的药品批次，但由于工艺易受影响，原料可能生成亚硝胺杂质，因此亚硝胺杂质有可能亦存在于其它 API 和制剂中。所以本指南建议适用于所有化学合成 API，同时应适用于含有化学合成API 的制剂，和因为本指南中所述的其它因素（参见第 II.B 和 C 部分）而处于风险中的药品，不是仅针对 FDA 公告中已发现的那些药品。

In general, FDA’s guidance documents do not establish legallyenforceable responsibilities. Instead, guidances describe the Agency’s currentthinking on a topic and should be viewed only as recommendations, unlessspecific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means thatsomething is suggested or recommended, but not required.

一般来说，FDA 的指南文件并不构成法律强制义务。相反，指南只是说明 FDA 当前对某个问题的观点，应仅作为是建议，引用了具体法律法规要求者除外。FDA 指南中 SHOULD 一词的使用表示建议或推荐某事但不是强制要求。

II.  BACKGROUND

背景

FDA has been investigating the presence of nitrosamine impurities incertain drug products. Since 2018, several drug products including ARBs,ranitidine, nizatidine, and metformin have been found to contain unacceptablelevels 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 identifiedas N-nitrosodimethylamine (NDMA) in the ARB valsartan11. Throughinvestigation, the Agency determined that numerous lots of valsartan and a fewother ARB drug products from different manufacturers contained unacceptablelevels of nitrosamines. The drug product manufacturers voluntarily recalled theaffected batches of these drug products12, which led to a drug shortage insome of the affected products13. In addition, FDA evaluated processes that usecommon amines in API synthesis and learned that common synthetic pathways couldalso 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 NDMA14. FDA recommended thatmanufacturers voluntarily recall ranitidine and nizatidine products with NDMAlevels above what the Agency considers acceptable1516. Recently, preliminary findingsfrom FDA stability testing raised concerns that NDMA levels in some ranitidineproducts stored at room temperature can increase with time to unacceptablelevels.

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 testingdemonstrated that elevated levels of NDMA were measured in all products after 2weeks. FDA’s testing suggests that NDMA levels increase with storage time. OnApril 1, 2020, FDA requested that all ranitidine products be withdrawn from theU.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 somemetformin diabetes medicines in other countries were reported to have NDMA. Inlight 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 notfind levels exceeding the acceptable intake limit. In May 2020, further FDAtesting revealed that certain lots of metformin extended-release formulationcontained NDMA above the Agency’s recommended acceptable intake limit. Based on that testing, FDArequested that identified applicants voluntarily recall these lots of theextended-release metformin. FDA continues to investigate possible NDMAimpurities in metformin and other drug products and will advise companies onappropriate 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. drugsupply, FDA and other regulatory authorities have partnered to shareinformation, coordinate inspection efforts, communicate effective analyticalmethods to detect and identify various nitrosamines, and to develop rapidsolutions 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。

A.  NitrosamineImpurities

亚硝胺杂质

The term nitrosamine describesa class of compounds having the chemical structure of a nitroso group bonded toan amine (R1N(-R2)-N=O), as shown in Figure 1. The compounds can form by a nitrosatingreaction between amines (secondary, tertiary, or quaternary amines) and nitrousacid (nitrite salts under acidic conditions).

术语亚硝胺指的是一类化合物，它们含有亚硝基结构，与胺基相连（R1N(-R2)-N=O），见图1。此类化合物可通过胺（伯胺、叔胺或季胺）和亚硝酸（酸性环境下的亚硝酸盐）发生亚硝胺化反应生成。

Figure 1. Representative Reactionto Form Nitrosamines

图 1 亚硝胺形成的代表性反应

FDA has identified seven nitrosamine impurities that theoretically couldbe present in drug products: NDMA, N-nitrosodiethylamine (NDEA),N-nitroso-N-methyl-4-aminobutanoic acid (NMBA), N-nitrosoisopropylethyl amine(NIPEA), N-nitrosodiisopropylamine (NDIPA), N-nitrosodibutylamine (NDBA), andN-nitrosomethylphenylamine (NMPA) (Figure 2). Five of them (NDMA, NDEA, NMBA,NIPEA, and NMPA) have actually been detected in drug substances or drugproducts.

FDA 已识别出 7 种亚硝胺杂质，理论上它们都有可能出现在药品中：NDEA、NMBA、NIPEA、NDIPA、NDBA 和 NMPA（见图 2）。其中 5 种（NDMA、NDEA、NMBA、 NIPEA 和 NMPA）已在原料药或制剂中实际检出。

Figure 2.Chemical Structures of Seven Potential Nitrosamine Impurities in APIs and DrugProducts

图 2 API 和制剂中 7 种可能亚硝胺杂质的化学结构

Nitrosamine compounds are potent genotoxic agents in several animalspecies and some are classified as probable or possible17 humancarcinogens by the International Agency for Research on Cancer (IARC18). Theyare referred to as “cohort of concern” compounds in the ICH guidance forindustry M7(R1) Assessment and Control ofDNA Reactive (Mutagenic) Impurities in PharmaceuticalsTo Limit Potential Carcinogenic Risk (March 201819). Theguidance recommends control of anyknown mutagenic carcinogen, such as nitroso-compounds, at or below a level suchthat there would be a negligible human cancer risk associated with the exposureto potentially mutagenic impurities. Following the discovery of nitrosaminecontaminants in ARBs, FDA published interim acceptable limits for theseimpurities20. FDA recommended that manufacturers take action to quantify nitrosaminelevels in their drugs and to reduce or remove these impurities when above theinterim limit; FDA has used the interim limits to guide immediatedecision-making for additional evaluation and product recalls21 while balancing the risks of potential long-term carcinogen exposure withdisruption to clinical management of patients.

亚硝胺化合物在几种动物中是高效基因毒性试剂，有些被 IARC 归类为可能的人类致癌物质。它们在 ICH 行业指南 M7（R1）“评估和控制药品中的 DNA 反应性（诱变性）杂质以限制潜在致癌风险”（2018年3月）中被称为“关注群”化合物。该指南建议控制所有已知诱变性致癌物，如亚硝类化合物，等于或低于某个水平，暴露于该水平的潜在诱变杂质时人类癌症风险可忽略。在发现了 ARB 中的亚硝胺污染物之后，FDA 发布了这些杂质的临时可接受限度。FDA 建议生产商采取措施对其药品中的亚硝胺进行定量检测，并降低或清除这些超出临时限度的杂质。FDA 已使用临时限度指导快速做出更多评估和产品召回决策，同时在致癌物长期暴露潜在风险与患者临床用药中断之间取得平衡。

B.   GeneralRoot Causes for the Presence of Nitrosamine Impurities in APIs 

原料药中出现亚硝胺杂质的常见根本原因

Recent information gathered by FDA suggests several general root causesof the presence of nitrosamine impurities in APIs:

FDA 最近收集到的信息显示 API 中出现亚硝胺杂质有几种共同根本原因：

1.   GeneralConditions That Lead to Nitrosamine Formation

导致亚硝胺形成的共同条件

Formation of nitrosamines is possible in the presence of secondary,tertiary, or quaternary amines22 and nitrite salts23 under acidic reactionconditions. Under these conditions, nitrite salts may form nitrous acid, whichcan react with an amine to form a nitrosamine (see Figure 1). There is agreater risk of nitrosamine formation if nitrous acid is used to quenchresidual azide (a reagent commonly used in tetrazole ring formation orintroduction of azide functional group into a molecule) in the presence ofprecursor amines.

如果在酸性反应条件下出现仲胺、叔胺或季胺和亚硝酸盐，则有可能形成亚硝胺。在这些条件下，亚硝酸盐可能会形成亚硝酸，亚硝酸有可能与胺反应形成亚硝胺（见图 1）。如果在淬灭残留叠氮化物（生成四唑环或引入叠氮基团至分子结构时常用的试剂）时使用了亚硝酸，同时有胺的前体出现时，则形成亚硝胺的风险会更高。

Nitrites used as reagents in one step can carry over into subsequentsteps, despite purification operations, and react with amines to generatenitrosamine impurities. Therefore, whenever nitrite salts are present,carryover into subsequent steps cannot be ruled out. In general, processes thatuse nitrites in the presence of secondary, tertiary, or quaternary amines areat risk of generating nitrosamine impurities.

即使有精制操作，但在一个步骤中所用的亚硝酸盐仍有可能会带入后续步骤，并与胺反应生成亚硝胺杂质。因此，只要有亚硝酸盐存在，就不能排除其会带入后续步骤的可能性。一般来说，在有仲胺、叔胺或季胺出现时使用亚硝酸盐的工艺都有产生亚硝胺杂质的风险。

2.  Sourcesof Secondary, Tertiary, and Quaternary Amines That Can Form Nitrosamines

可能形成亚硝胺的伯胺、叔胺和季胺来源

Amines may be present in a manufacturing process for a variety ofreasons. The API (or API degradants), intermediates, or starting materials maycontain secondary or tertiary amine functional groups. Tertiary and quaternaryamines may also be added intentionally as reagents or catalysts.

胺有可能因多种原因出现在生产工艺中。API（或 API 降解产物）、中间体或起始物料有可能含有仲胺或叔胺基团。叔胺和季胺亦有可能被有意加入作为试剂或催化剂。

All of these types of amines can react with nitrous acid or othernitrosating agents to form nitrosamines242526.

所有这些类别的胺均可能与亚硝酸或其它亚硝化试剂反应生成亚硝胺。

Amide solvents, which are susceptible to degradation under certainreaction conditions, are another source of secondary amines. For example, underhigh reaction temperatures for an extended reaction period,N,N-dimethylformamide can degrade into dimethylamine, which can react withnitrous acid to form NDMA (see Figure 3). N-methylpyrrolidone,N,N-dimethylacetamide, and N,N-diethylacetamide also have similar degradationpathways to form secondary amines that can react with nitrous acid to formnitrosamine impurities. Secondary amines could also be present as impurities inamide solvents. For example, dimethylamine, which can react with nitrous acidto form NDMA, may exist as an impurity in N,N-dimethylformamide.

酰胺类溶剂在特定反应条件下易于降解，它们是另一种仲胺来源。例如，在高温条件下反应较长时间时，N,N 二甲基甲酰胺可能降解为二甲胺，二甲胺可与亚硝酸反应形成 NDMA （见图 3）。N-甲基吡咯烷酮，N,N-二甲基乙酰胺和 N,N-二乙基乙酰胺亦有类似的降解途径，会形成仲胺，仲胺可与亚硝酸反应形成亚硝胺杂质。仲胺亦可能在酰胺类溶剂中作为杂质出现。例如，二甲胺可能作为杂质存在于 N，N-二甲基甲酰胺中，它可与亚硝酸反应形成 NDMA。

Figure 3. Formation of NDMA FromN,N-Dimethylformamide

图3 从 N,N-二甲基甲酰胺形成 NDMA

Tertiary and quaternary amines used as reagents in the synthesis of APIsmay contain other amine impurities. Tertiary amines, such as triethylamine,have been shown to contain low levels of other secondary amines (such asdipropylamine and isopropylethylamine). Secondary and tertiary amines may bepresent as impurities or degradants formed by dealkylation of quaternaryamines. For example, a common phase-transfer catalyst, tetrabutylammoniumbromide, may contain tributyl- and dibutylamine impurities. The amine impuritylevel that may lead to nitrosamine contamination of the API is processdependent and should be determined by each API manufacturer.

用作 API 合成试剂的叔胺和季胺可能含有其它胺类杂质。叔胺如三乙胺被证明会含有低水平其它仲胺（如二丙胺和异丙基乙胺）。仲胺和季胺可能会作为季胺的脱烷基杂质或降解产物出现。例如，常用的转相催化剂四丁基溴化铵应可能含有三丁胺和二丁胺杂质。可能会导致 API 受亚硝胺污染的胺杂质水平依工艺不同而不同，应由各 API 生产商来确定。

This list of the aforementioned sources is not exhaustive, as aminereagents can be used to mediate a wide range of synthetic transformations.Manufacturers should evaluate other reagents containing amine functional groupsfor potential risk of nitrosamine formation.

前面所提到的来源的清单并非穷尽清单，因为胺试剂可能会被用于介导很多合成转化反应。生产商应评估其它含有胺基的试剂是否有形成亚硝胺的可能性。

3.   Contaminationin Vendor-Sourced Raw Materials

供应商来源原料的污染

Nitrosamine impurities can be introduced when vendor-sourced materials,including starting materials and raw materials, are contaminated. The Agencyhas observed the following contaminations due to this root cause:

如果从供应商处采购的原料，包括起始物料和原料受到污染，也可能会引入亚硝胺杂质。FDA 已发现该根本原因导致的以下污染情况：

• Nitrosaminecontamination has occurred when fresh solvents (ortho-xylene, toluene, and methylene chloride) were contaminatedduring shipment from vendors (e.g., during transfer between storage vessels).

• 新鲜溶剂（邻二甲苯、甲苯和二氯甲烷）从供应商处运输（例如，不同贮罐之间转移）时被污染，导致亚硝胺污染

• Sodiumnitrite is a known impurity in some starting materials (such as sodium azide)and may be present and react with amines under acidic conditions to formnitrosamines. Nitrate-containing raw materials, such as potassium nitrate, maycontain nitrite impurities. The amount of nitrite impurity that can be toleratedis process dependent and should be determined by each API manufacturer.

• 亚硝酸钠在有些起始物料中的已知杂质（例如，叠氮化钠），可能会出现并在酸性环境下与胺反应生成亚硝胺。受到亚硝酸盐污染的原料如亚硝酸钾可能含有亚硝酸盐杂质。可以容许的亚硝酸盐杂质的数量因工艺而异，应由各 API 生产商决定

• Secondaryor tertiary amines have been reported as impurities in some raw materials (seedetails in section II.B.2 in this guidance) and in fresh solvents such astoluene.

• 有些原料和新鲜溶剂如甲苯中已报道含有仲胺或叔胺杂质（参见本指南第 II.B.2 部分）

• Startingmaterials or outsourced intermediates may be at risk throughcross-contamination if they are manufactured at sites where nitrosamineimpurities are produced in other processes.

• 如果生产场所有其它工艺会产生亚硝胺杂质，则起始物料或外购中间体可能有交叉污染的风险

Awareness of the supply chain of raw materials is an important factor inpreventing contamination. For example, API producers may not be aware ofnitrosamine contamination in raw or starting materials they have sourced fromvendors; a producer whose manufacturing process is not normally susceptible tonitrosamine formation may not realize that vendor-sourced material may have hadimpurities introduced during production or transport.

了解原料供应链对于防止污染来说是非常重要的。例如，API 生产商可能并不了解其从供应商外采购的原料或起始物料的亚硝胺污染情况；自己的生产工艺一般不易形成亚硝胺的生产商可能意识不到其外购的原料可能会在生产或运输过程中已被杂质污染。

4.  RecoveredSolvents, Catalysts, and Reagents as Sources of Contamination

回收溶剂、催化剂和试剂作为污染来源

Recovered materials such as solvents, reagents, and catalysts may pose arisk of nitrosamine impurities due to the presence of residual amines (such astrimethylamine or diisopropylethylamine). If the recovery process involves aquenching step (i.e., nitrous acid used to decompose residual azide),nitrosamines could form during solvent recovery. These nitrosamines may beentrained if they have boiling points or solubility properties27 similarto the recovered materials, depending on how recovery and subsequentpurification takes place (e.g., aqueous washes or distillation). This furtherincreases the risk of contamination in material recovery. For these reasons,some drug products using APIs manufactured by certain “low” risk processes28 werefound to be contaminated. The Agency has observed the following contaminationsdue to this root cause:

回收物料如溶剂、试剂和催化剂可能会因为有残留胺（例如，三甲胺或二异丙基乙胺）而具有亚硝胺杂质风险。如果回收工艺涉及到淬灭步骤（即使用亚硝酸分解残留叠氮化物），在溶剂回收过程中则有可能形成亚硝胺。如果这些亚硝胺的沸点或溶解特性与被回收物料相似，则有可能进入回收物料中，具体依回收工艺和后续精制步骤而不同（例如，水性溶液冲洗或蒸馏）。这会进一步增加原料回收中污染风险。因此，有些使用含“低”风险工艺生产的 API 的药品被发现受到污染。FDA 已发现因为该根本原因而受到污染的情况有：

• Amanufacturing site may produce the same API by more than one synthetic processthat uses common solvents. If any of those synthetic processes producesnitrosamines or contains precursor amines, the solvents sent for recovery areat risk. The use of recovered solvents that are comingled from differentprocesses or across manufacturing lines without control and monitoring canintroduce nitrosamine impurities. If a recovered solvent is contaminated inthis way and then used to manufacture an API, the API will be contaminated evenif the synthetic route is not normally susceptible to nitrosamine formation.

• 一个生产场所可能采用多个合成工艺生产同一 API，使用相同的溶剂。如果这些合成工艺中有任何一步会产生亚硝胺或含有胺的前体，则送去回收的溶剂就有风险。使用来自不同工艺或不同产线的混合回收溶剂而不加控制和监测应可能引入亚硝胺杂质。如果一种回收溶剂受到此种方式的污染，然后再用于生产一种 API，即使该 API 的合成路线正常情况下并不容易形成亚硝胺，该 API 亦会受到污染。

• Recoveryof raw materials (e.g., solvents, reagents, and catalysts) is often outsourcedto third-party contractors. Process outsourcing can pose a risk if thethird-party recovery facility does not receive enough specific information onthe contents of the materials they are processing and relies solely on routinerecovery processes.

• 原料回收（例如溶剂、试剂和催化剂）通常会外包给第三方合同生产商。如果第三方回收场所未曾收到关于其处理的原料成分的足够具体的信息，仅依赖于常规的回收工艺，则工艺外包可能会有风险

• Rawmaterials can be contaminated if adequate cleaning of equipment between customers,or between different materials, is not carried out or is not validated ascapable of removing each impurity of concern. It was reported that ortho-xylene and toluene werecontaminated during recovery due to inadequate cleaning and to use of shared storageequipment between different customers. Inadequate and unvalidated cleaningprocedures can also lead to cross- contamination if precautions to avoidnitrosamine contamination are not in place before materials from differentcustomers are combined for recovery. For example, the catalyst tri- N-butyltinchloride (used as a source of tri-N-butyltin azide) was contaminated at athird- party contractor facility due to the combination of this catalyst fromdifferent customers.

• 如果不同客户，不同原料之间未对设备进行足够的清洁，或者没有经过验证足以清除每种受关注的杂质，则原料有可能被污染。有报道发现邻二甲苯和甲苯在回收过程中因清洁不足，并且不同客户物料使用了共用存贮设备而受到污染。如果在将来自不同客户的原料合并回收之前没有小心地避免亚硝胺污染，清洁程序不充分以及未经过验证亦可能导致交叉污染。例如，在第三方合同生产场所处，催化剂三正丁基氯化锡（用作三正丁基叠氮化锡的来源）因为与来自不同客户的同一催化剂合并而受到污染。

5.  QuenchingProcess as a Source of Nitrosamine Contamination

亚硝胺污染来源的淬灭工艺

There is a risk of nitrosamine formation when a quenching step isperformed directly in the main reaction mixture (i.e., when nitrous acid isadded to the reaction mixture to decompose residual azide). This allows nitrousacid to come into direct contact with residual amines in the raw materials usedin the manufacturing process. The nitrosamine impurities could be carried tothe subsequent steps if there are not adequate removal or purificationoperations in place, or if the operations are not optimized for removingspecific impurities of concern. This can contaminate the entire downstreamprocess once they are introduced. Even if the quenching process is conductedoutside of the main reaction mixture (see section II.B.4 in this guidance),there is a risk if contaminated recovered materials are introduced into themain process.

如果直接在反应液中执行淬灭操作（即，将亚硝酸加入反应液降解残留叠氮化合物）会有形成亚硝胺的风险。这种操作会让亚硝酸与生产工艺中所用原料中的残留胺直接接触。如果没有足够的清除或精制操作，或者清除所讨论的特定杂质的操作没有优化，则亚硝胺杂质可能会被带入后续步骤；而一旦引入，这些杂质就可能会污染整个下游工艺。即使淬灭工艺在主反应液以外执行（参见本指南第 II.B 部分），如果被污染的回收物料被引入了主工艺，还是会存在风险。

6.  Lack ofProcess Optimization and Control

缺少工艺优化和控制

Another potential source of formation of nitrosamine impurities is lackof optimization of the manufacturing process for APIs when reaction conditionssuch as temperature, pH, or the sequence of adding reagents, intermediates, orsolvents are inappropriate or poorly controlled. FDA has seen instances inwhich reaction conditions varied widely between batches and even betweendifferent processing equipment in the same facility for the same API.

另一个亚硝胺杂质的可能形成来源是在反应条件（如温度、pH 值或加入试剂、中间体或溶剂的顺序）控制不当或控制不良时缺少对 API 生产工艺的优化。FDA 发现有时甚至在同一 API 同一生产场所不同工艺设备上批间反应条件变化都非常大。

The multiple root causes of nitrosamine contamination listed above canoccur within the same API process. Therefore, multiple strategies may benecessary to identify all potential sources of contamination. Typical routinetests (e.g., HPLC) for API purity, identity, and known impurities are unlikelyto detect the presence of nitrosamine impurities. Further, each failure modecould result in different nitrosamines in different amounts across batches fromthe same process and the same API producer, with contamination detected in somebatches but not all.

上述多个亚硝胺污染的根本原因均可能会在同一 API 工艺中发生。因此，有必要采用多种策略识别出可能的污染来源。API 纯度、鉴别和已知杂质的典型常规检测（例如 HPLC）不可能检出存在的亚硝胺杂质。另外，每种失效模式均可能导致同一生产商同一工艺 API 在不同批次中有不同数量的不同种类亚硝胺，这样在有些批次中但不是全部批次中检出污染情况。

C.  NitrosamineImpurities in Drug Products From Sources Other Than API Contamination 

药品中非 API污染的其它来源亚硝胺杂质

Nitrites are common nitrosating impurities that have been reported inmany excipients at ppm levels. Nitrite impurities are found in a range ofcommonly used excipients, which may lead to nitrosamine impurities forming indrug products during the drug product manufacturing process and shelf-lifestorage period. The supplier qualification program29 should take into account thatnitrite impurities vary across excipient lots and may vary by supplier. Drugproduct manufacturers should also be aware that nitrite and nitrosamineimpurities may be present in potable water.

亚硝酸盐是常见的亚硝化杂质，已有多种辅料报道检出 ppm 级亚硝酸盐。在大量常用辅料中检出亚硝酸盐杂质，这可能导致在制剂生产工艺和货架期存贮过程中在药品内形成亚硝胺杂质。供应商确认程序应考虑亚硝酸盐杂质在不同辅料批次和不同供应商中的波动情况。制剂生产商还应了解亚硝酸盐和亚硝胺杂质可能会在自来水中出现。

Some drug products may undergo degradation pathways that formnitrosamine impurities; this could potentially occur during drug productstorage.

有些药品可能会经过降解途径形成亚硝胺杂质，在药品存贮过程中有可能会发生这种情况。

III.   RECOMMENDATIONS

建议

Becausenitrosamines are probable or possible human carcinogens, FDA recommends thatmanufacturers consider the potential causes of nitrosamine formation describedin this guidance as well as any other pathways observed and evaluate the riskfor nitrosamine contamination or formation in their APIs and drug products.Manufacturers should prioritize evaluation of APIs and drug products based onfactors such as maximum daily dose, duration of treatment, therapeuticindication, and number of patients treated.30As new information becomes available and FDA’s understandingof nitrosamines in drugs evolves, the Agency may recommend that certain drugproducts become higher priorities for risk assessment.

因为亚硝胺是人类致癌物质，FDA 建议制造商考虑本指南中描述的亚硝胺形成的潜在原因以及发现到的其他途径，并评估其原料药和药品中亚硝胺污染或形成的风险。制造商应根据每日最大剂量、治疗时间、治疗适应症和接受治疗的患者人数等因素（30），优先评估原料药和药物产品。随着新资料的获得和FDA对药物中亚硝胺不断了解，FDA可能建议某些药物产品优先进行风险评估。

Manufacturersshould refer to the ICH guidance for industry Q9 Quality Risk Management(June 2006) for details related to quality risk identification, analysis, andmanagement. Manufacturers of APIs and drug products should take appropriatemeasures to prevent unacceptable levels of nitrosamine impurities in theirproducts.

有关质量风险识别、分析和管理的详细信息，制造商应参考 ICH Q9质量风险管理(2006年6月)。原料药和药品制造商应采取适当措施，防止其产品中亚硝胺杂质达到不可接受的水平。

A.   Acceptable Intake Limits

可接受的摄入量限值

FDArecommends the following acceptable intake (AI) 31limits for the nitrosamine impurities NDMA, NDEA, NMBA,NMPA, NIPEA, and NDIPA (Table 1). We further recommend that manufacturers usethese AIs when determining limits for nitrosamine impurities in APIs and drugproducts.32

FDA建议的亚硝胺杂质NDMA，NDEA，NMBA，NMPA，NIPEA 和 NDIPA的可接受摄入量(AI)31如下(表1)。我们还建议制造商在设定原料药及药物产品中亚硝胺杂质含量限值时，应使用这些可接受摄入量（AI）32。

Table 1. AI Limits for NDMA, NDEA, NMBA, NMPA,NIPEA, and NDIPA in Drug Products

表1. 药品中 NDMA，NDEA，NMBA，NMPA，NIPEA 和 NDIPA 的 AI 限值

Nitrosamine  亚硝胺	AI  Limit (ng/day)1,2 可接受摄入限值(ng/天)1,2
NDMA	96
NDEA	26.5
NMBA	96
NMPA	26.5
NIPEA	26.5
NDIPA	26.5

1. The AI limit is adaily exposure to a compound such as NDMA, NDEA, NMBA,NMPA, NIPEA, or NDIPAthat approximates a 1:100,000 cancer risk after 70 years of exposure. AppendixB includes a description of the AI derivation for NDMA, which is an example ofhow FDA applied ICH M7(R1) to set a limit.

   AI限值是每天暴露在一种化合物中，比如 NDMA，NDEA，NMBA，NMPA，NIPEA，或 NDIPA，在暴露70年后，患癌症的风险大约为1:100,000。附录B 包含了 NDMA 的 AI 推导的描述，这是 FDA 如何应用 ICH M7(R1)来设置限值的一个例子。

2. The conversion of AIlimit into ppm varies by product and is calculated based on a drug’s maximumdaily dose (MDD) as reflected in the drug label (ppm = AI (ng)/MDD (mg)).

   AI限值转换为ppm单位因产品不同而不同，可根据药物标签上所反映的每日最大剂量(ppm = AI (ng)/MDD (mg))计算。

Theselimits are applicable only if a drug product contains a single nitrosamine. Ifmore than one of the nitrosamine impurities identified in Table 1 is detectedand the total quantity of nitrosamine impurities exceeds 26.5 ng/day (the AIfor the most potent nitrosamines) based on the maximum daily dose (MDD), themanufacturer should contact the Agency for evaluation. For drug products withan MDD of less than 880 mg/day, a recommended limit for total nitrosamines of0.03 ppm is not more than 26.5 ng/day and is considered acceptable. For drugproducts with an MDD above 880 mg/day, the limit for total nitrosamines shouldbe adjusted so as not to exceed the recommended limit of 26.5 ng/day.33

这些限值只适用于药品中含有单一亚硝胺的情况。如发现表一所列的多个亚硝胺杂质，而根据每日最大剂量计算，总亚硝胺杂质超过26.5ng/天(即亚硝胺的最大可接受摄入量) ，制造商应联络本署作出评估。对于每日最大剂量（MDD）少于880毫克/天的药物，推荐的总亚硝胺含量限值为0.03ppm，不超过26.5 ng/天，这是可以接受的。对于MDD大于880毫克/天的药物，应调整总亚硝胺的限量，以避免超过26.5 ng/天的推荐限值。

Ifnitrosamines without published AI limits are found in drug products,manufacturers should use the approach outlined in ICH M7(R1) to determine therisk associated with the nitrosamine and contact the Agency about theacceptability of any proposed limit.34

如果在药品中发现未公布 AI 限值的亚硝胺，制造商应使用 ICH M7(R1)中概述的方法来确定与亚硝胺有关的风险，并就任何拟设限值的可接受性与当局联系。

Generally, sensitive methodswith limits of quantitation (LOQ) in the parts-per-billion (ppb) range areneeded to meet the low AIs recommended for nitrosamines. Manufacturers of APIsand drug products should usemethods with LOQs at or below 0.03 ppm.35Manufacturersshould establish methods for which the LOQ and limit of detection (LOD) are aslow as reasonably practical for products for which the maximum daily dose ishigh (e.g., greater than 1 g). If more than one nitrosamine listed in Table 1is detected, then the analytical method should be validated for LOQs below 0.03ppm to accurately quantify a total nitrosamine level of not more than 26.5ng/day. For example, if the MDD is 1200 mg, the LOQ should be below 0.02 ppm.FDA’s public webpage includes validated analytical test methods recommended fordetecting nitrosamine impurities in several different APIs and products.36,37

一般来说，需要使用定量限（LOQ）为十亿分之一（ppb）级别的高灵敏度方法，以满足建议的亚硝胺AIs。API和药物产品的制造商应使用定量限（LOQ）≤0.03 ppm的方法。对于最大日剂量高的产品(例如，大于1克)，制造商应建立定量限（LOQ）和检测限（LOD）尽可能低的方法。如果检测到不止一种表1所列亚硝胺，则应验证分析方法的LOQ是否低于0.03ppm，以准确定量亚硝胺总含量不超过26.5ng/天。例如，如果MDD 为1200毫克，检测限应低于0.02 ppm。FDA官网包含了多种不同原料药及产品中亚硝胺杂质的推荐的经验证的分析测试方法。

API and drug product manufacturers should take the followingsteps to mitigate nitrosamine impurities in their products:

原料药和药品制造商应采取以下步骤，以减少其产品中的亚硝胺杂质:

1. Assess the risk ofnitrosamine impurities in APIs, marketed products, and products under approvedand pending applications. Risk assessments should be conducted in a timelymanner based on the prioritization of drugs.38 Manufacturers do not need to submit risk assessmentdocuments to the Agency, but they should retain these documents so that theyare available if requested.

   评估原料药、市售产品和已批准和待批准申请的产品中亚硝胺杂质的风险（38）。制造商不需要向FDA提交风险评估文件，但应保留这些文件，以便需要时可以提供。

2. Conduct confirmatorytesting39when there is any risk for the presence of nitrosamineimpurities. Due to nitrosamines’ physiochemical properties (low molecularweights, some volatility and high toxicity), the analytical methods fornitrosamines need to have specificity, excellent chromatographic separation,and highly sensitive detection capability.

   当有亚硝胺杂质存在的风险时，进行确认性测试。由于亚硝胺的理化性质(低分子量、某些挥发性和高毒性) ，亚硝胺的分析方法需要具有专一性、良好的色谱分离性和高灵敏度的检测能力。

3. Report changesimplemented to prevent or reduce nitrosamine impurities in APIs and drugproducts to FDA. This includes submission of any drug master file (DMF)amendments in accordance with 21 CFR 314.420(c) and changes to approvedapplications as required under 21 CFR 314.70 and 314.97 and pendingapplications under 21 CFR 314.60 and 314.96.

   向 FDA 报告为防止或减少原料药和药品中的亚硝胺杂质而实施的变更。这包括根据21 CFR 314.420(c)提交任何药物主文件(DMF)修订，以及根据21CFR 314.70和314.97对已批准申请的变更和根据21 CFR 314.60和314.96提交中期申请。

B.   Recommendationsto API Manufacturers 

对 API生产商的建议

While nitrosamines are not expected to form during the manufacture ofthe vast majority of APIs, all manufacturers of chemically synthesized APIsshould take appropriate actions to mitigate the risk of nitrosamine contaminationfor APIs where there is a potential for nitrosamine impurities.

虽然在大多数 API 的生产过程中预期并不会产生亚硝胺，但所有化学合成 API 的生产商均应在可能出现亚硝胺杂质时采取恰当措施缓解 API 的亚硝胺污染风险。

API manufacturers should review their API manufacturing processes andperform risk assessments to identify the potential for nitrosamine impurities.If a risk of nitrosamine impurities is identified, confirmatory testing ofbatches should be conducted using sensitive and appropriately validatedmethods. If the risk assessment determines that there is no potential fornitrosamine impurities, there is no need to take further action. If a nitrosamine impurity isdetected, API manufacturers should investigate the root cause. They shouldimplement changes in the manufacturing process to reduce or prevent nitrosamineimpurities40.

API 生产商应审核其 API 生产工艺，并执行风险评估，识别是否有可能存在亚硝胺杂质。如果发现亚硝胺杂质存在风险，则应采用经过恰当验证的灵敏方法对批次执行确认性检测。如果风险评估认为没有亚硝胺杂质存在风险，则不需要采取进一步措施。如果检出一种亚硝胺杂质，则 API 生产商应调查其根本原因，应对其生产工艺执行变更，从而降低或防止亚硝胺杂质

1.  Mitigatingthe Presence of Nitrosamine Impurities in APIs

缓解 API中出现亚硝胺杂质的情形

FDArecommends that API manufacturers take the following actions:

FDA 建议 API 生产商采取以下步骤：

APImanufacturers should optimize the design of the manufacturing process for APIsduring route of synthesis (ROS) development to minimize or prevent theformation of nitrosamine impurities. API manufacturers should refer to the recommendationsin ICH M7(R1) and the ICH guidances for industry Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (September 2016) and Q11 Development and Manufacture of DrugSubstances (November 2012) in this respect. The following factors should be considered during processdevelopment:

API 生产商应在合成路线（ROS）开发过程中优化 API 生产工艺设计，尽可能降低或防止形成亚硝胺杂质。API 生产商应参考 ICH M7（R1）和 ICH Q7（API GMP 2016 年 9 月）以及 Q11（原料药开发和生产，2012 年 11 月）中在这些方面的建议。在工艺开发过程中应考虑以下因素：

• Avoidingreaction conditions that may produce nitrosamines whenever possible; when notpossible, demonstrating that the process is adequately controlled and iscapable of consistently reducing nitrosamine impurities through appropriate androbust fate and purge studies.

• 尽可能避免可能产生亚硝胺杂质的反应条件；如果不能避免，要通过恰当稳健的去向和清除研究证明对工艺有足够的控制，可以持续降低亚硝胺杂质

• Usingbases other than secondary, tertiary, or quaternary amines (when possible) ifROS conditions may form nitrosamines.

• 如果 ROS 的条件可能形成亚硝胺时，尽可能使用非伯胺、叔胺或季胺的其它碱

• Usingcaution when the ROS involves the use of amide solvents (e.g.,N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone).

• 如果 ROS 要使用酰胺类溶剂（例如，N,N-二甲基甲酰胺，N,N-二甲基乙酰胺和 N-甲基吡咯烷酮），要谨慎

• Replacingnitrites with other quenching agents for azide decomposition processes.

• 在叠氮分解工艺中采用其它淬灭试剂替代亚硝酸盐

• Optimizingand consistently controlling the sequences of reactions, processes, and reactionconditions (such as pH, temperature, and reaction time).

• 优化并持续控制反应顺序、工艺和反应条件（例如，pH 值，温度和反应时间）

• Designinga manufacturing process that facilitates the purge of nitrosamine impurities inthe subsequent processing steps.

• 设计生产工艺促进在后续工艺步骤中清除亚硝胺杂质

APImanufacturers should consider removing quenching steps (when there is a risk ofnitrosamine formation, e.g., using nitrous acid to decompose residual azide)from the main reaction mixture to reduce the risk of nitrosamine formation. TheAPI, or an intermediate formed through a reaction using an azide salt, can beseparated from the mother liquor into the organic phase. The aqueous wastephase separated from the organic phase should then be quenched with nitrousacid without contacting the API, its intermediate, or solvents intended forrecovery.

API 生产商应考虑从主反应线中拿掉淬灭步骤（如果有形成亚硝胺的风险，例如，使用亚硝酸分解残留叠氮），降低亚硝胺形成的风险。将使用叠氮盐反应生成的API 或中间体可以先从母液中分离出来到有机相中。从有机相中分离出来的水相废液再用亚硝酸进行淬灭，不需要接触 API、中间体或待回收溶剂。

APImanufacturers should audit their supply chains and monitor them for any at-riskraw materials, starting materials, and intermediates41. APImanufacturers should maintain records including the name of the raw material manufacturerand its supplier42,42 roles of the actual manufacturers of suchmaterials, and any repackers and distributors who handle the materials beforeAPI manufacture. When appropriate, API manufacturers should establish controls and consider additionalspecifications for at-risk materials to prevent nitrosamine contamination.

API 生产商应对其供应链进行审计，监控其有风险的原料、起始物料和中间体。API生产商应保存记录，包括原料生产商及其供应商的名称、该原料实际生产商的角色，以及在 API 生产之前处理这些原料的再包装商和分销商。适当时，API 生产商应建立有风险原料的控制措施，考虑建立附加质量标准，从而防止亚硝胺污染。

To avoidcross-contamination when recovered materials such as solvents, reagents, andcatalysts are used in the manufacturing process, recovered material should beused only in the same step or in an earlier step (if there is sufficientpurification) of the same process from which it was collected. The recoveredmaterials should meet appropriate standards before reuse. If the recovery ofmaterials is outsourced to third-party contractors, the API manufacturer shouldaudit the contractors’ validation of cleaning procedures. API manufacturersshould follow recommendations in ICH Q7 for ensuring that cross-contaminationwith nitrosamine or nitrosamine precursors can be prevented. API manufacturersshould also verify with their suppliers whether the purchased materials used intheir processes are recovered.

为避免在生产工艺中使用回收物料如溶剂、试剂和催化剂时产生交叉污染，只应在同一工艺同一步骤或更早步骤中回收物料（如有足够的精制）。回收物料在使用之前应符合恰当的标准。如果物料的回收外包给了第三方，则 API 生产商应审计受托方的清洁方法验证。API 生产商应遵守 ICH Q7 中的建议，确保防止被亚硝胺或亚硝胺前体交叉污染。API 生产商还应对其供应商进行核查，确定所购买用于工艺生产的原料是否回收原料。

APImanufacturers should be aware that potable water used in API manufacture maycontain low levels of nitrite and even nitrosamines from environmentalcontamination43.43 The existence of nitrites in processing water may lead to nitrosaminecontamination in API manufacture. Therefore, to avoid unacceptable levels ofnitrosamine impurities in APIs, API manufacturers should analyze nitrite andnitrosamine levels in water and use water that has been purified to removeunacceptable impurities.

API 生产商应了解 API 生产中所用的自来水可能含有较低水平的亚硝酸盐，甚至是环境污染中亦可能有亚硝胺。工艺用水中存在亚硝酸盐可能会导致 API 生产受到亚硝胺污染。因此，为避免 API 中亚硝胺杂质水平达到不可接受的高度，API 生产商应对水中的亚硝酸盐和亚硝胺水平进行分析，并使用经过纯化的水清除不可接受的杂质。

If a nitrosamine is introduced to the API throughexogenous sources44 that can be avoided, manufacturers shouldeliminate the source of contamination.

如果亚硝胺是通过可避免的外部来源引入 API 的，生产商应消除污染来源。

APIbatches may be reprocessed or reworked to control the level of nitrosamineimpurities as provided in ICH Q7 for amending and controlling such operations.If a batch is found to contain nitrosamine and is reprocessed or reworked inany way, these operations should be conducted under oversight of the qualityunit.

API 批次被返工或再加工，从而控制亚硝胺杂质，此时需要遵守 ICH Q7 中所述的要求修改和控制此类操作。如果发现一个批次含有亚硝胺，但仍进行了返工或再加工，则应在质量部门监管下进行这些操作。

2.  Controlof Nitrosamine Impurities in APIs

原料药中亚硝胺杂质的控制

If a nitrosamine impurity is detected above the LOQ, the APImanufacturer should develop a strategy to ensure that the nitrosamine levelremains within the AI limit. Manufacturers should develop an appropriatecontrol strategy, which should include specification limits, to ensure that thenitrosamine level reliably remains well below the AI limit in the API. Givenexisting uncertainties regarding nitrosamine impurities and their presence indrugs, for APIs with an impurity detected above the LOQ or at-risk APIs,testing of each batch on release should be conducted. Alternate approaches(e.g., upstream test of an intermediate) should be supported by sufficientprocess understanding and evidence of adequate statistical control and should besubmitted to FDA in a supplement prior to implementation45.

如果检出一种亚硝胺杂质超出 LOQ，则 API 生产商应制订策略确保亚硝胺水平保持在 AI 限度以下。生产商应制订恰当的控制策略，其中应包括有质量标准限度，从而确保亚硝胺水平可靠保持在 API 的 AI 限度以下。考虑到亚硝胺杂质及其在药品中的存在有不确定性，因此在其中检出一种杂质高于 LOQ 的 API 或者是有风险的 API，放行时应对每个批次进行检测。替代方法（例如，对中间体进行上游检测）需要有对工艺的足够了解和充分的统计学控制证据作为支持，并应在实施之前在增补文件中提交给 FDA。

Any API batch found to contain levels of nitrosamine impurities abovethe recommended AI should not be released by the API manufacturer fordistribution unless, with prior FDA agreement, the API is needed to prevent ormitigate a shortage of a drug.

未得到 FDA 认可该 API 需要用于防止或缓解药品短缺的预先同意时，API 生产商不得放行销售任何检出亚硝胺杂质高于建议 AI 水平的 API 批次。

C.   Recommendationsto Drug Product Manufacturers 

对制剂生产商的建议

Drug product manufacturers should conduct riskassessments to determine the potential for nitrosamine impurities in drugproducts. A risk assessment should involve collaboration with the APImanufacturer to aid in the identification of the API ROS or other processconditions of the API’s manufacture that put the drug product at risk fornitrosamine impurities. The risk assessment should also include evaluation ofany pathway (including degradation) that may introduce nitrosamines during drugproduct manufacture or storage. If the risk assessment determines that there isno potential for nitrosamine impurities, there is no need to take furtheraction.

制剂生产商应进行风险评估，确定制剂中出现亚硝胺杂质的可能性。风险评估应涉及到与 API 生产商的合作，协助识别出可能将制剂置于亚硝胺杂质风险下的 API ROS 或 API 生产其它工艺条件。该风险评估还应包括对制生产和存贮过程中所有可能引入亚硝胺的途径（包括降解）的评估。如果风险评估发现没有可能存在亚硝胺杂质，则不需要采取进一步措施。

If a risk of nitrosamines in a drug product is identified, confirmatorytesting of batches should be conducted using sensitive and appropriatelyvalidated methods46. If a nitrosamine impurity is detected,manufacturers should investigate the root cause and implement changes in themanufacturing process to mitigate or reduce nitrosamine impurities47.

如果发现制剂中存在亚硝胺风险，则应采用经过恰当验证的高灵敏度方法对制剂批次进行确认性检测。如果检出亚硝胺杂质，则生产商应调查根本原因，并对生产工艺进行变更以缓解或降低亚硝胺杂质。

1.  Controlof Nitrosamine Impurities in Drug Products

制剂中的亚硝胺杂质的控制

Drug product manufacturers must test representative samples of allincoming components, including lots of at-risk API, prior to use, as requiredunder 21 CFR 211.8448. To meet the CGMP regulations in 21 CFR 211subpart E and be consistent with the ICH guidance for industry Q10 PharmaceuticalQuality System (April 2009), drug product manufacturers should continuetesting API lots until they haveverified that the API supplier can consistently manufacture API withoutunacceptable levels of nitrosamine.

制剂生产商在使用所有进厂组份前必须按 21 CFR 211.84 的要求检测代表性样品，包括有风险的 API 批次。为符合 21 CFR 211 子章 E 中的 CGMP 要求，并与 ICH Q10 指南（药物质量体系，2009 年 4 月）保持一致，制剂生产商应继续检测 API 批次，直到能够确定 API 供应商可持续生产出不含有不可接受水平亚硝胺的 API。

Drug product manufacturers, when designing their control strategy,should evaluate whether nitrites could be present during manufacturingprocesses where at-risk APIs are used. They should also evaluate whethernitrosamines could form in a finished drug product over the drug product’sshelf life. If a nitrosamine is introduced to the drug product throughexogenous sources that can be avoided, manufacturers should eliminate the sourceof contamination.

制剂生产商在设计其控制策略时，应评估在使用有风险 API 时生产工艺中是否会出现亚硝酸盐。生产商还应评估制剂货架期中制剂是否会形成亚硝胺。如果制剂中的亚硝胺是通过可避免的外部来源引入，则生产商应消除污染来源。

If a nitrosamine impurity is detected above the LOQ, the manufacturershould develop a strategy to ensure that the nitrosamine level remains withinthe AI limit. The control strategy should include specification limits for theidentified nitrosamine. Such a control strategy is also recommended when theintroduction of nitrosamine is inherent due to the API structure, the API ROS,or the manufacturing process of the API or drug product. Given existinguncertainties regarding nitrosamine impurities and their presence in drugs,testing of each batch on release should be conducted. Alternate approachesshould be supported by sufficient process understanding and evidence ofadequate statistical control and should be submitted to FDA in a supplementprior to implementation49.

如果检出的亚硝胺杂质高于 LOQ，则生产商应制订策略确保亚硝胺水平保持低于 AI 限度。控制策略应包括所识别的亚硝胺的质量标准限度。如果亚硝胺的引入是由于 API 结构、API ROS 或 API 或制剂生产工艺使然，亦建议采取此种控制策略。考虑到亚硝胺的不确定性及其在药品中出现的不确定性，对每个批次应进行放行检测。替代方法需要有对工艺的足够了解和充分的统计学控制证据作为支持，并应在实施之前在增补文件中提交给 FDA。

If drug product batches with unacceptable levels of nitrosamineimpurities are already in distribution, drug product manufacturers shouldcontact FDA so the Agency can determine the regulatory action for the specificdrug products. Any drug product batch found to contain levels of nitrosamineimpurities at or above the recommended AI should not be released by the drugproduct manufacturer for distribution. Manufacturers should contact the Agencyif a recall is initiated50. Under section 501 of the Food, Drug, and CosmeticAct (FD&C Act51), a drug that is not manufactured, processed,packed, or held in conformity with CGMP to ensure that the drug meets certainquality and purity standards is considered adulterated. FDA may exerciseregulatory discretion when warranted to prevent or mitigate a shortage of adrug.

如果已销售的药品批次中存在不可接受水平的亚硝胺杂质，则药品生产商应联系 FDA，这样FDA 可以决定是否需要针对特定的药品采取强制措施。所有检出亚硝胺杂质水平等于或高于建议 AI 限度的药品批次均不应放行销售。生产商如果启动召回应联系 FDA。根据 FDCA 第 501 条款，药品的生产、加工、包装或保存如果不符合 CGMP，不能确保药品符合特定的质量和纯度标准，则会被认定为掺假药品。FDA 可能会根据情况自由裁定法规措施，防止或缓解药品短缺。

IV.        MAINTAINING THE DRUG SUPPLY 

维持持药品供应

If any manufacturing changes or recalls are likely to lead to adisruption in the drug supply, manufacturers should immediately contact CDER’sDrug Shortage Staff at [e-mail]; FDA can work with manufacturers to mitigate the risk ofnitrosamineimpurities in APIs and drug productswhile avoiding interruptions in the drug supply. Contacting the Drug ShortageStaff can assist manufacturers in meeting any obligations to reportdiscontinuances or interruptions in their drug manufacture under section 506Cof the FD&C Act and implementing regulations under 21 CFR314.81(b)(3)(iii). It also allows FDA to consider, as soon as possible, whatactions, if any, may be needed to avoid shortages and protect the health ofpatients who depend on the affected products.

如果生产商的变更或召回有可能导致药品供应短缺，生产商应立即联系 CDER 的药品短缺人员。FDA 可与生产商一起缓解 API 和制剂中亚硝胺杂质风险，同时避免药品供应中断。联系药品短缺人员可帮助生产商履行 FDCA 第 506C 款规定的报告其所生产的药品中断的义务，并执行 21 CFR 314.81(b)(3)(iii)规定的要求。这样还能让 FDA 尽快考虑需要采取什么措施（如有）来避免药品短缺，保护依赖于受影响药品的患者健康。

V.   REPORTINGCHANGES TO FDA 

向 FDA报告变更

Drug manufacturers must report changes implemented to prevent or reducenitrosamine impurities in accordance with FDA regulations (21 CFR 314.60,314.70, 314.96, and 314.97).

药品生产商必须根据 FDA 法规（21 CFR 314.60, 314.70, 314.96, 和 314.97）向 FDA 报告其为防止或降低亚硝胺杂质所执行的变更。

If an API DMF holder makes process changes in the ROS as a result of therisk assessment and confirmatory testing, the DMF holder must submit amendmentsand inform each drug product manufacturer that references the DMF (includingpending and approved applications), in accordance with 21 CFR 314.420(c). Ifthe API is manufactured by the applicant and not covered by a DMF, themanufacturer must report such ROS changes in the application in accordance with21 CFR 314.70 and 21 CFR 314.97. If a batch of API is found to contain anitrosamine and is reprocessed or reworked in any way, these operations shouldbe reported in the DMF or application (as applicable).

如果 API DMF 持有人因为风险评估和确认性检测的结果需要对其 ROS 进行工艺变更，则 DMF 持有人必须根据 21 CFR 314.420(c)提交修订并通知所有引用其 DMF（包括在审和已批准申报）的制剂生产商。如果该 API 是由申报人生产的，未提交 DMF，则生产商必须根据 21 CFR 314.70 和 21 CFR 314.97 在药品申报资料中报告其 ROS 变更。如果检出一批 API 含有亚硝胺，并且进行了任何形式的返工或再加工，则应在 DMF 或药品申报资料（适用时）中报告这些操作。

Although each DMF may contain only a single synthetic route, if a changein synthetic process is needed to avoid nitrosamine contamination and it is notpossible to immediately stop using the original manufacturing process, the APImanufacturer should submit both processes in the DMF and provide an estimatefor the earliest feasible timeframe for the removal of the original process.The different synthetic processes should be identified by separate codes todesignate batches manufactured through each process. If the original processcannot be discontinued within a reasonable timeframe, the new or revisedprocess should be submitted in a separate DMF.

虽然每份 DMF 都只有一种合成路线，但如果需要对合成工艺进行变更从而避免亚硝胺污染，而无法立即停止使用原来的生产工艺的，此时 API 生产商应在 DMF 中提交两种工艺，并提交删除初始工艺的最早可行时间框架预测。要采用不同代码来区分采用不同合成工艺生产的批次。如果在合理时间段时不能停止使用原始工艺，则应使用另一份 DMF 提交新的或修订后的工艺。

If changes to the drug product are needed to prevent nitrosamineformation, application holders must submit a supplement to notify FDA of anychanges to conditions established in the approved applications beyond thevariations already provided for in their applications, as required by 21 CFR314.70 and 314.97. Holders of pending applications must update theirapplications through submission of an amendment according to 21 CFR 314.60 and314.96.

如果需要对制剂进行变更从而防止形成亚硝胺，申报资料持有人必须按 21 CFR 314.70 和 314.97 的要求提交补充资料，告知 FDA 对已批准申报资料中既定条件超出其申报资料中波动的变更。在审申报资料的持有人必须根据 21 CFR 314.60 和 314.96 通过提交修订申请更新其申报资料。

Section V of this guidance includes additional information on reportingchanges in APIs and drug products.

本指南第 V 部分有 API 和制剂中变更报告的更多信息。

A.  RecommendedTimeline for Risk Assessment, Confirmatory Testing, and Submission of RequiredChanges

风险评估、确认性检测和所需变更提交的建议时间表

FDA recommends different implementation timelines depending on theregulatory status of the drug product52.

FDA 建议根据药品的注册状态执行不同时间表。

1.   Approvedor Marketed Drug Products 已批准或已上市药品

To ensure the safety of the U.S. drug supply, manufacturers shouldconclude a risk assessment of approved or marketed products within 6 months of publication of thisguidance. Confirmatory testing should start as soon as the risk of nitrosamineis identified from the risk assessment and should begin immediately forproducts considered at high risk. To ensure the safety of the U.S. drug supply,confirmatory testing of drug products and submission of required changes indrug applications should be concluded within3 years of the date of publication of this guidance. FDA acknowledges thatthe implementation timeline includes investigating the root cause of thecontamination or formation, identifying changes that will eliminate the rootcause (e.g., change in manufacturing process, change in supplier), andconfirming that any proposed changes will minimize the risk of nitrosaminecontamination or formation without otherwise adversely affecting productquality. The timelines also include activities conducted by API manufacturers(i.e., risk assessment and testing) to support the drug products in which theyare used. FDA may request an expedited risk assessment, confirmatory testing,or other regulatory action based on information available to the Agency.

为确保美国药品供应安全，生产商应在本指南发布后 6 个月内对已批准和已上市的药品得出风险评估结论。对于风险评估识别出亚硝胺风险的药品，应尽快展开确认性检测，高风险药品应立即进行确认性检测。为确保美国药品供应安全，药品的确认性检测和提交必要的注册变更应在本指南发布日起 3 年内完成。FDA 知道执行时间表包括污染和形成根本原因调查、识别可清除根本原因的变更（例如生产工艺变更，供应商变更）、确认所有提议的变更能够尽可能降低亚硝胺污染或形成的风险，而不会对药品质量产生不良影响。时间表还包括 API 生产商所采取的支持其所用于的制剂的措施（即风险评估和检测）。FDA 可能会根据其所获得的信息要求加快风险评估、确认性检测或其它法规措施。

2.   PendingApplications 在审申报

a.  Pre-Submission Stage 申报前阶段

FDA recommends that applicants conduct a risk assessment for nitrosamineimpurities in APIs and proposed drug products and conduct confirmatory testingas needed prior to submission of an original application. However, the riskassessment and submission of confirmatory testing, if needed, and changes tothe DMF or application may be submitted in an amendment if they are notavailable at the time of the original submission filing. Such an amendmentshould be submitted as quickly as possible after the original submission filingto minimize any potential adverse impact on the application assessment timeline53.

FDA 建议申报人在初始申报提交之前对 API 和所提议的制剂中的亚硝胺杂质进行风险评估，必要时进行确认性测试。当然，如果在初始申报时无法获得这些资料，申报人可以在之后进行风险评估并提交确认性检测结果，必要时在修订文件中提交 DMF 或申报资料变更。此类修订应在初始申报提交之后尽快提交，以尽可能降低对申报资料审评时间表的潜在的不良影响。

b.  Applications Pending With theAgency 正在 FDA处审评的申报

Applicants with pending applications should conduct the risk assessmentexpeditiously and inform FDA if confirmatory testing finds nitrosamine levelsabove the AI limit54.54 If a nitrosamine impurity is detected above theLOQ but is within the AI limit, the applicant should amend the application asappropriate. The Agency will work with the applicant to resolve issues duringthe review cycle or immediately after approval, and before distribution, if determinedto be necessary by the Agency55.

申报资料已经在审的申报人应尽快进行风险评估，如果确认性检测发现亚硝胺水平高于 AI 限度时应通知 FDA。如果有亚硝胺杂质检出水平高于 LOQ，但仍在 AI 限度内，则申报人应对其申报资料进行适当修订。如果认为有必要，FDA 会与申报人一起在各审评环节中或在批准之后销售之前立即解决这些问题。

FDA generally will adhere to review goals established as part of thePrescription Drug User Fee Act reauthorization for years 2018–2022 (PDUFA VI)and the Generic Drug User Fee Amendments Reauthorization of 2017 (GDUFA II).

FDA 一般会遵守 PDUFA VI 制订的 2018-2022 审评目标和 GDUFA II 2017 的审评目标。

APPENDIXA. ADDITIONAL RESOURCES 附录 A：其它资源

略

APPENDIX B. FDA DETERMINATION OFACCEPTABLE INTAKE LIMITS

附录 B：FDA 对可接受摄入限度的确定

Identification of the acceptable intake (AI) values listed in sectionIII of this guidance follows the procedures recommended in the ICH guidance forindustry M7(R1) Assessment and Controlof DNA Reactive (Mutagenic) Impurities inPharmaceuticals To Limit Potential Carcinogenic Risk (March 20181). Acompound-specific AI can be calculated based on rodent carcinogenicity potency data such as TD50 values(doses giving a 50% tumor incidence equivalent to a cancer risk probabilitylevel of 1:2) identified in the public literature. Linear extrapolation to aprobability of 1 in 100,000 (i.e., the accepted lifetime risk level used) isachieved by simply dividing the TD50 by 50,000. The AI (in mg/kg/day units) can then beconverted to mg/day by multiplying by the human body weight (50 kg is theassumed body weight identified in the referenced guidance). Linearextrapolation from a TD50 value is considered appropriate to derive an AIfor M7 Class 1 impurities (known mutagenic carcinogens) with no establishedthreshold mechanism. In many cases, the carcinogenicity data are available fromthe Carcinogenicity Potency Database (CPDB). When the CPDB contains apre-calculated TD50 value for a selected chemical, this value may be used to calculate theAI. Where carcinogenicity study data for an impurity are of lesser quality asdescribed in ICH M7, a surrogate compound with carcinogenicity data may be usedto derive an acceptable intake but should be scientifically justified.

本指南第 II 部分所列的可接受摄入（AI）值是依据 ICH 行业指南 M7（R1）评估和控制药品中 DNA 反应性（诱变性）杂质以限制潜在致癌风险（2018 年 3 月）计算的。化合物专用的 AI 值可根据公开文献中报道的啮齿动物致癌效价数据如 TD50 值（给药剂量会导致 50%的肿瘤发生，等于患癌风险可能性水平为 1/2）计算。将 TD50 除以 50000 线性外推至十万分之一的可能性（即所用可接受终生风险水平），然后乘以人类体重（50kg为参考指南中识别的假定体重）将 AI（mg/kg/天单位）转换为 mg/天。如果没有既定的阈值机理，从 TD50 值线性外推对于 M7 的一类杂质（已知诱变致癌物）来说是恰当的 AI 计算方法。在许多案例中，致癌性数据可以从 CPDB 中获取。如果 CPDB 中已有所选化合物的 TD50 计算值，则可使用该值计算 AI 值。如果某个杂质的致癌性研究数据质量达不到 ICH M7 所述质量要求，则可使用具有致癌性数据的相似化合物来计算 AI 但需要进行科学论证。

A summary of the AI derivation for NDMA is provided as an example. NDMAwas identified as a mutagenic carcinogen in several species and is listed as aprobable human carcinogen by the Environmental Protection Agency’s (EPA’s)Integrated Risk Information System (IRIS) program. TD50 values for NDMA are 0.0959mg/kg/day (rat, based on Peto et al.2) and 0.189 mg/kg/day (mouse)according to the CPDB3. For the AI calculation, the lower (moreconservative) value of the rat is used. The resulting AI associated with a 1 in100,000 cancer risk over 70 years of exposure is calculated by dividing theTD50 by 50,000 and then multiplying by 50 to account for a patient with a 50-kgbody weight, resulting in 0.0000959 mg/day NDMA, or approximately 96 ng/dayNDMA.

此处举 NDMA 为例说明 AI 计算的过程。NDMA 被识别为几个物种的诱变致癌物，被EPA 的 IRIS 项目列为可能的人类致癌物。NDMA 的 TD50 值为 0.0959mg/kg/天（大鼠，根据 Peto et al.），根据 CPDB 为 0.189mg/kg/天。在 AI 计算时，使用了较低的大鼠TD50 值（更保守）。将 TD50 除以 50000 得到 70 年暴露时长后十万分之一患癌风险的AI 值，然后乘以50（患者体重），得到 NDMA 的 AI 值为 0.0000959mg/天，即 96ng/天。

Hence, a daily lifelong intake of 96 ng/day NDMA corresponds to atheoretical cancer risk of 10-5 and therefore represents an AI when present as animpurity.

这样，终生每日摄入 96 ng/天的 NDMA 对应于理论患癌风险为十万分之一，作为 NDMA 以杂质出现时的 AI 值。