EMA于20200625发布的人药中亚硝胺杂质审查报告，因较长，因翻译时间跨度较长，可能同一术语中文表述不一，仅供参考。
由于文件较长，未制作文内目录，仅制作了PDF书签作为索引。
本报告为CHMP出具。以下为最后的建议部分，是CHMP的建议。文中提到其它专家组有SWP（安全工作组）、QWP（质量工作组）、ad-hocexpertgroup（特设专家组）、PRAC（欧盟药物警戒风险评估委员会），在个别专业方面意见有分歧。
5 Recommendations建议
Based on the above assessment of the available data, the CHMP recommends that:
根据上述已有数据评估情况，CHMP建议：
1. The presence of N-nitrosamines in human medicinal products shall be mitigated as much as possible and shall be at or below a limit based on ICH M7(R1) principles for substances of the “cohort of concern” defined in this guideline and calculated considering a lifetime daily exposure.
人药中含有N-亚硝胺的风险应尽可能降低，应低于根据ICH M7（R1）原则订立的本指南中定义为“关注群”的限度，并在计算时考虑终生日暴露情形
This should be achieved by an appropriate control strategy and by the design oradaptation of the manufacturing processes aiming to prevent formation of and contamination with nitrosamines whenever possible.
应采用适当的控制策略和设计或调整生产工艺，从而尽可能防止亚硝胺的形成和污染来达到此目标。
2. The risk of presence of nitrosamines must be evaluated by the MAHs/Applicants. In case of risk, confirmatory testing must be performed.
MAH/申办人必须对亚硝胺出现的风险进行评估，如果存在风险，则必须进行确认性检测。
• A risk evaluation/risk assessment for the presence of nitrosamines must be submitted for new marketing authorization applications at the time of submission, and for already authorized medicinal products containing chemically synthesised active pharmaceutical ingredients (APIs) as per the ‘call for review’ andfor biological medicinal products in a similar exercise as per instructions to be published in a Questions and Answers document .
•新上市许可申报资料提交时，以及已批准含“要求审核的”的化学合成API的药品和按所发布的问答文件要求执行类似措施的生物制品必须提交亚硝胺出现的风险评估，
• The approach for risk evaluation/risk assessment should cover manufacturing processes of active substance and finished product in consideration of the root-causes, and subsequent confirmatory testing in the finished product.in case a risk is identified
•风险评估的根本原因考量应包括API和制剂的生产工艺，如果发现有风险，则应对制剂进行确认性检测
• Although the overall risk of presence of nitrosamines in biological medicinal products is considered very low, the following risk factors should be taken into consideration: biologicals containing chemically synthesized fragments, where risk factors similar to chemically synthesized active substances are present, biologicals using processes where nitrosating reagents are deliberately added, or those packaged in certain primary packaging material, such as blister packs containing nitrocellulose.
•虽然生物制品中亚硝胺出现的整体风险相对低，但仍应考虑以下风险因素：含有化学合成片断的生物制品、使用了有意添加亚硝化试剂的工艺的生物制品，或其它包装在特定内包材中，如含硝化纤维的泡罩包装
3. Where a nitrosamine has been detected, alimit based on the above mentioned ICH M7(R1) principles for “cohort of concern” substances considering a lifetime daily exposure should be calculated.
如果检出亚硝胺，则应根据上述ICH M7（R1）针对“关注群”物质原则，同时考虑终生日暴露情形计算制订一个限度
The following limits have been established for some specific N-nitrosamines and should be applied:
应使用以下为一些特定N-亚硝胺杂质制订的限度
N-Nitrosamine (CAS number)N-亚硝胺（CAS号）ng/day***NDEA*(55-18-5) 26.5 DIPNA**(601-77-4) 26.5 MeNP**(16339-07-4) 26.5
These limits are applicable only if a finished product contains a single N-nitrosamine.
这些限度仅适用于含有一种N-亚硝胺杂质的制剂。
*Limit calculated on the basis of harmonic mean TD50 derived from carcinogenic potency database (CPDB)
限度是基于致癌效力数据库（CPDB）的调和平均TD50计算的
**Limit derived using SAR/read-across approach
使用SAR/交叉参照方法计算的限度
***The conversion to a specification limit in ppm for a particular medicinal productis calculated by dividing the respective above limit (ng) by the maximum daily dose (mg) of a given product as reflected in the SmPC .
转化为特定制剂质量标准限度（单位ppm）是将上述对应限度（ng）除以指定药品SmPC中载明的最大日剂量（mg）得到的。
• The limit as calculated above will usually need to be included in the finished product specification.
•上述计算所得限度通常需要放在制剂质量标准中
• Skip testing is only justified if it can be shown that the levels of the respective nitrosamine are consistently ≤ 30% of the limit defined above and the root cause is identified and well-understood.
•只有在证明相应亚硝胺水平一直≤ 30%上述规定限度并且已找出根本原因还有深入了解时，才可以进行跳检
• Omission from the specification is only justified if it can be shown that the levels of the respective nitrosamine are consistently ≤ 10% of the limit defined above and the root cause is identified and well-understood.
•只有证明相应亚硝胺水平一直≤ 10%上述规定限度并且已找出根本原因还有深入了解时，才可将该杂质不放在质量标准中
4. If more than one N-nitrosamine is identified in a given finished product (or its API), it must be ensured that the totalrisk level of the sum of all detected N-nitrosamines does not exceed 1 in100,000 life-time risk. An alternative approach where the sum of all detected N-nitrosamines does not exceed the limit of the most potent N-nitrosamine identified may also be used. The approach chosen for a particular case needs to be duly justified by the applicant/MAH.
如果在指定制剂（或其API）中识别出有不止一种N-亚硝胺杂质，则必须确保所有检出N-亚硝胺总和风险水平不超过十万分之一终生风险。如果所有检出N-亚硝胺杂质总和未超过活性最高的N-亚硝胺的限度，可采用替代方法。特定情形下所选方法需要由申办人/MAH进行合理论证。
5. Exceptionally, when a single N-nitrosamine cannot be kept below the limit defined in 3. or the total risk level of the sumof more than one detected N-nitrosamine cannot be kept below a 1 in 100,000 life-time risk, the MAH should submit to the relevant competent authorities forthwith an investigation report including the potential/identified root cause(s), preventive/corrective actions and a thorough discussion on the impacton the benefit/risk balance including all relevant considerations (e.g. medical need, daily dose, duration of administration and treatment alternatives, potential patient risk in case of drug shortage). Acceptability of limits higher than those defined in 3 and 4. is then decided by the relevant competent authorities on a case-by-case basis, after having performed a benefit/risk evaluation. In such instances, the “less-than-lifetime” (LTL) concept in ICH M7(R1) may be considered by the competent authorities for the range of a temporarily acceptable exposure until further measures can be implemented to reduce the contaminant at or below the limits defined in point 3. and 4 .
例外情况下，如果单个N-亚硝胺杂质不能低于3中所规定的限度，或者是不止一种检出N-亚硝胺杂质的总和风险水平不能保持在十万分之一终生风险以下，则MAH应向药监当局提交一份调查报告，在其中包括潜在/已识别出的根本原因、CAPA和对利弊平衡影响性的彻底讨论，包括所有相关考量（例如，医疗需求，日给药剂量，给药时长和治疗替代品，药品短缺时的潜在患者风险）。高于3和4中所规定值的限度的可接受度应由相关药监当局在进行利弊评估之后各案决定。在此情形下，药监当局可考虑ICH M7（R1）中的“短于终生”（LTL）概念制订临时可接受暴露范围，直到能够实施进一步措施将污染物降低至等于或低于3和4所规定的限度。
6. Exceptions to sections 3. and 4. include some products falling outside the scope of the ICH M7(R1) guideline, i.e.certain active substances and finished products intended for advanced cancer indications or when the active substance is itself genotoxic. For finished products intended only for advanced cancer, N-nitrosamine impurities should be controlled according to ICH Q3 A(R2) and ICH Q3B(R2), as specified in the Q&A document to ICH S9. When the active substance itself is genotoxic at therapeutic concentrations, N-nitrosamine impurities could be controlled at limits for non-mutagenic impurities according to ICH M7(R1).
3和4的例外情形包括有些药品不在ICH M7（R1）指南范围的情况，即用于晚期癌症的API和制剂，或API本身具有基因毒性时。仅用于晚期癌症的制剂，N-亚硝胺杂质应根据ICH Q3A（R2（和ICH Q3B（R2）按ICH S9问答文件的说明进行控制。如果API本身在治疗浓度即具有基因毒性，则可按ICH M7（R1）中非诱变性杂质的限度控制N-亚硝胺杂质。
7. When N-nitrosamines are identified with sufficient substance specific animal carcinogenicity data to calculate a reliable TD50 then this should be used to derive a substance specific limit for lifetime exposure as recommended in ICH M7(R1).
如果检出的N-亚硝胺杂质有足够的动物致癌数据，可计算可靠的TD50，则应使用该数据按ICH M7（R1）所建议的终生暴露期计算该杂质的特定限度。
8. When N-nitrosamines are identified within sufficient substance specific data to derive a substance specific limit for lifetime exposure as recommended in ICH M7(R1), a class specific TTC for nitrosamines of 18 ng/d can be used as default option. This TTC has been derived from the Lhasa carcinogenic potency database and is considered a conservative and acceptable approach. If a MAH intends using a higher limit than 18 ng/day, an approach based on structure-activity-relationship (SAR) considerations is acceptable. The approach taken needs to be duly justified bythe applicant/MAH.
如果检出的N-亚硝胺没有足够的数据按ICH M7（R1）所建议的计算物质专用的终生暴露限度，则可使用18 ng/天作为该级别特定TTC的默认值。该TTC已通过Lhasa致癌性数据库进行计算，并认为是可接受的保守方法。如果MAH准备使用高于18 ng/天的限度，则可以根据构效关系（SAR）考量。所采用的方法应由申报人/MAH进行合理论证。
9. MAHs should implement a control strategy regarding N-nitrosamines for their active substances and finished products, which should include current and prospective measures to minimise the risk of generation/contamination with any nitrosamine (e.g. change of manufacturing process, introduction of appropriate specifications and development of appropriate methods, measures related to the premises and equipment e.g.cleaning procedures, environmental monitoring,…) and control any future change that may impact on this risk (e.g. change of supplier, change of manufacturing process, change of packaging…)
MAH应对其API和制剂中的N-亚硝胺采取措施策略，其中应包括现行和前瞻性的措施（例如，生产工艺变更，引入适当的质量标准，开发适当的方法，与设施和设备有关的措施，例如，清洁程序，环境监测……），以降低任何亚硝胺杂质的生成/污染风险，控制未来可能对该风险产生影响的任何变更（例如，供应商变更、生产工艺变更、包装变更……）。
In order to fulfil their obligations above, MAH/applicants shall:
为了履行其上述义务，MAH/申报人应：
• carry out risk evaluation/risk assessment of manufacturing processes of API (route of synthesis, starting materials, intermediates, raw materials) in view of potential formation of or contamination with N-nitrosamines, taking into account potential and confirmed root causes for the presence of N-nitrosamines in APIs.
•对API生产工艺从可能形成N-亚硝胺或受其污染的角度进行风险评估（合成路线、起始物料、中间体、原料），同时考虑API中出现N-亚硝胺杂质的潜在和已确认根本原因
• carry out risk evaluation/risk assessmentof finished product (degradation of API, primary packaging material, excipients, etc.), taking into account the root-causes for the presence of N-nitrosamines in finished products.
•对制剂进行风险评估（API降解、内包材、辅料等），同时考虑N-亚硝胺在制剂中出现的根本原因
• ensure that, in accordance with Article 23 and Annex I of Directive 2001/83/EC and Article 16 of Regulation (EC) No 726/2004, their medicinal products are manufactured and controlled by means of processes and methods in compliance with the latest state of scientific and technical progress. As a consequence, MAHs/ Applicants shall design their manufacturing processes and controls to prevent if possible or mitigate as much as possible the presence of N-nitrosamines in their API and finished product(s) and shall introduce any subsequent changes to their manufacturing process as needed.
•根据指令2001/83/EC第23条和附录1和法案(EC) No 726/2004第16条，确保其药品根据工艺生产和控制，并符合最新的科学和技术进展声明。因此，MAH/申报人对工艺的设计和控制应能尽可能防止（如可能）或降低N-亚硝胺在其API和制剂中出现的可能性，应对其生产工艺进行必要的变更
• ensure that active substances and excipients used in their finished products are manufactured in compliance with good manufacturing practices as laid down in Article 46(f) of Directive 2001/83/EC.
•确保其制剂所用API和辅料生产符合指令2001/83/EC第46(f)条规定的GMP要求
• MAHs’/Applicants’ compliance with the above-mentioned obligations is subject to regular controls by competent authorities including during inspections.
•履行上述义务的MAH/申报人需由药监当局进行定期检查
10. With regard to the analytical method(s) employed the following is advised:
关于所用分析方法，建议如下
• The limit of quantitation (LoQ) provides the minimum level at which an analyte can be quantified with acceptable accuracy and precision and should thus be used to define the required analytical sensitivity for impurity testing.
•定量限（LOQ）是分析对象可被定量的最低水平，同时具备可接受的准确性和精密度，并用于定义杂质检测所需的分析灵敏度
• If quantitative testing is performed as a routine control, the LoQ should be at or below the limit for the respective nitrosamine impurity defined in 3.
•如果常规检测中进行定量检测，则LOQ应等于或低于3项中规定的相应亚硝胺杂质限度
• If quantitative testing is performed to justify skip testing, the LoQ of the analytical procedure employed should be ≤30% of the limit defined in 3.
•如果使用了定量检测来论证跳检，则所用分析方法的LOQ应≤ 30%第3项中规定的限度
• If quantitative testing is performed to justify omission of specification, the LoQ of the analytical method employed should be ≤ 10% of the limit defined in 3.
•如果使用了定量检测来论证不包括该杂质在质量标准中，则所用分析方法的LOQ应≤ 30%第3项中规定的限度
• Higher sensitivity of analytical methodsmay be needed for medicinal products used at high daily doses (, or in case more than one nitrosamine is anticipated or identified in a given medicinal product. Such cases should be discussed with the relevant competent authority/ies.
•制剂日给药剂量较大时可能需要更高灵敏度的分析方法（或者如果指定制剂中有或检出不止一个亚硝胺杂质），则应与相关药监当局讨论
• Different analytical methods may be usedfor determination of multiple nitrosamines. If the same analytical method is used for multiple nitrosamines, the selectivity of the method should be demonstrated at the LoQ for each nitrosamine.
•可使用不同分析方法来检测多个亚硝胺杂质。如果使用了同一分析方法检测多个亚硝胺杂质，则应在各亚硝胺的LOQ水平证明方法的选择性
11. Although further epidemiological studies wouldbe useful to better characterize the relationship between nitrosamine exposure from medicinal products and cancer risk, critical challenges have been identified such as large sample size, long study duration, determination of exposure, identification of confounding factors and adequate control group which would be necessary to achieve meaningful and interpretable results.Nationwide registries or large healthcare database might be the most promising approach but may not contain all important information. In such cases, data linkage to other data sources that may contain the missing information should be checked prior to study initiation. Furthermore, the possibility of a meta-analytical approach may be considered in case of insufficient patient numbers in a given data source.
虽然流行病学研究有助于更好地研究暴露于制剂中亚硝胺和患癌风险之间的关系，但要达到有意义可解释的结果，需要面对多个关键挑战如样本量过大，研究时间过长，暴露时长难确定，干扰因子难识别，需要足够的控制组。全国范围内注册或较大的卫生数据库可能是最有效的方式，但这些数据库可能没有全部重要信息。在此情形下，应在研究开始之前检查是否有与其它数据源相连接的数据可能含有缺失信息。另外，如果在指定的数据源中没有足够的患者数量，可考虑是否能采用元分析方法。
英文原文官方下载
https://www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490-assessment-report_en.pdf
中英文下载
nitrosamines-emea-h-a53-1490-assessment-report_en 中英
另外EMA的亚硝胺专题页面为
https://www.ema.europa.eu/en/human-regulatory/post-authorisation/referral-procedures/nitrosamine-impurities
文章来源：Julia法规翻译
