FDA发布《亚硝胺污染控制指南》！

近日，FDA发布了《行业指南：人用药物中亚硝胺污染控制指南》，该指南自发布起生效。包含一下内容：

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

部分翻译如下：

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。

注释：

29 In accordance with the ICH guidance for industry Q10 PharmaceuticalQuality System (April 2009), the manufacturer’s pharmaceutical qualitysystem extends to control of the quality of purchased materials. The supplierqualification program is a manufacturer’s system (e.g., audits, materialevaluations, qualification) for selecting material suppliers who can providematerials using a defined and approved supply chain.

根据 ICH Q10药品质量体系(2009年4月) ，制造商的药品质量体系包含对所采购物料的质量控制。供应商确认程序是制造商选择物料供应商一个体系(例如，审计，物料评估，确认)，这些物料供应商使用一个明确的和批准的供应链提供物料。

30 For example, a drug product with a maximum daily dose (MDD)of 2000 mg with the same detected level of the same type of nitrosamine wouldpose a greater risk than a drug product with a maximum daily dose of 200 mg. Adrug product intended for only short-term use (e.g., a 7-day course of anantibiotic) poses less risk than a drug product intended for chronic use.

举例来说，检出相同含量的亚硝胺两种药物，每日最高剂量（MDD）为2000毫克的药物，其风险要比每日最高剂量为200毫克的药物高。一种只打算短期使用的药品(如7天的抗生素疗程)比一种打算长期使用的药品造成的风险要小。

31 The term acceptable intake (AI) is used in ICH M7(R1)to indicate the threshold of toxicological concern (TTC) considered for theimpurity to be associated with negligible risk of carcinogenicity or othertoxic effects. FDA announcements regarding limits for nitrosamines used theterm acceptable daily intake (ADI). For the purposes of this guidance,the term AI is used rather than ADI.

ICH M7（R1）中使用的术语“可接受摄入量（AI）”表示认为该杂质与可忽略的致癌风险或其他毒性作用相关的毒理学阈值（TTC）。FDA关于亚硝胺限量的公告使用了可接受的每日摄入量（ADI）。在本指南中，使用的是AI而非ADI。

32 API manufacturers should control nitrosamine impurities toensure that the drug products in which the APIs are used will meet therecommended AI limits.

原料药制造商应控制亚硝胺杂质，以确保使用原料药的药品符合建议的AI 限值。

33 Manufacturers shouldcontact [e-mail] multiple nitrosamine impurities are detected in an API ordrug product in which the total nitrosamine level exceeds 26.5 ng/day based onMDD. Inquiries submitted to this mailbox will be routed to the appropriate FDAoffice.

如果在某种原料药或药品中检测到多种亚硝胺杂质，而其总亚硝胺含量按MDD 计算超过26.5ng/天，制造商应与 cder-opq-inquiry@fda. hhs. gov 联系。提交到这个邮箱的询问将被发送到相应的 FDA 办公室。

34 See footnote 33 for contact information.

联系方式见脚注33。

35The LOQ may be considered the reporting threshold fornitrosamine impurities (i.e., the limit above which an impurity should bereported in the certificate of analysis).

检测限可视为亚硝胺杂质的报告阈值(即超过该限度的杂质应在检验报告中报告)。

36      FDA-recommendedanalytical methods for detecting nitrosamine impurities can be found at https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-ndma-zantac-ranitidine, at https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-ndma-metformin, and in the 12/12/2018 update athttps://www.fda.gov/Drugs/DrugSafety/ucm613916.htm.

FDA推荐的亚硝胺杂质检测方法可以在https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-ndma-zantac-ranitidine、https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-ndma-metformin和2018年12月12日更新的 https://www.fda.gov/drugs/drugsafety/ucm613916.htm中找到。

37      Manufacturers orlaboratories are encouraged to make validated test methods publicly available(e.g., by posting on the method developer’s website) to facilitate fastertesting of other similar products. FDA also accepts requests to post privatelydeveloped methods at FDA’s website if FDA’s review of the method protocol findsit is scientifically sound, and if the method owner provides writtenauthorization for posting by FDA. The manufacturers or laboratories should sendtheir test methods to [e-mail].

鼓励制造商或实验室公布经验证的测试方法(例如，在方法开发者的网站上张贴) ，以便对其他类似产品进行更快的测试。如果 FDA 对该方法方案的审查认为科学可靠，并且该方法所有者提供了FDA 发布的书面授权，FDA 也会接受在 FDA 网站上公布私人开发的方法的请求。制造商或实验室应将他们的测试方法发送到 cder-opq-inquiry@fda. hhs. gov。

38In accordance with quality management principles,manufacturers should consider manufacturing changes and shifts over the productlifecycle that may impact the potential for nitrosamine impurities, includingnew sources of raw materials or excipients. Risks should be reassessedperiodically (see ICH Q9).

根据质量管理原则，制造商应考虑在产品生命周期中可能影响亚硝胺杂质的生产变更和变化，包括原料或辅料的新来源。应定期重新评估风险(见 ICH Q9)。

39 Testing using appropriately validated methods may beconducted by the API manufacturer or by a qualified laboratory.

可由原料药制造商或经确认的实验室使用经适当验证的方法进行测试。