APIC发布原料药亚硝胺风险评估指南及模板！

Additional guidance on the assessment on the risk assessment for presence of N-nitrosamines in APIs

关于API中N-亚硝胺的风险评估补充指南

Table of contents

目录

1. Introduction

引言

2. Risk Assessment guidance

风险评估指南

2.1.       Prioritization of the risk assessment

风险评估的优先次序

2.2.       Management of raw materials in the risk assessment

风险评估中的原料管理

2.3.       Risk assessment

风险评估

2.3.1.           Content of risk assessment

风险评估的内容

2.3.2.           Boundaries of the risk assessment

风险评估的界限

2.3.3.           Methodology and outcome of the risk assessment

风险评估的方法及结果

2.3.4.           Collaboration with customers

与客户合作

2.3.5.           Lifecycle of the risk assessment

风险评估的生命周期

3. Analytical Testing and Lifecycle Control Strategy

分析测试与生命周期控制策略

4. References

参考资料

5. Appendix 1 – API Letter Report Template

附录1-API信件报告模板

Foreword

前言

This guidance document was prepared in 2020 by the APIC Nitrosamines Task Force on behalf of the Active Pharmaceutical Ingredient Committee (APIC)

本指南由APIC亚硝胺工作组代表于2020年由编写。

1. Introduction

引言

The EMA and other Health authorities have published requirements (EMA/189634/2019 [1] and Health Canada Letter [3] for the API industry and the MAH for drug products to expand the scope of potential sources of nitrosamines beyond that of ICH M7 [2]. This requirement is based on the fact that, as the Industry and the authorities are gathering more information about the potential ingress

欧盟药品管理局和其他卫生当局已经公布了针对API行业和麻醉药物行业的要求(EMA/189634/2019[1]和加拿大卫生部信函[3])，以扩大ICHM7以外的亚硝胺的潜在来源范围 [2]。这项规定是基于这样一个事实，即业界和当局正在收集更多关于潜在引入的信息。

• formation of such impurities in APIs, there is need to expand the evaluation of risk assessments that are needed to ensure APIs are fit for their intended use and do not pose a patient safety risk for such impurities. These requirements are new to the industry and as such APIC had devised this document to aid industry generating risk assessments as well as assistance on the level of information that is needed to be sent to the MAH for their overall drug product risk assessments.

如果API中存在这些杂质，就需要扩大对风险评估的评估，以确保API适合其预期用途，并且不会对患者的安全构成这些杂质的风险。这些要求对药品行业来说是新的，因此，APIC制定了这一文件，以帮助药品行业进行风险评估，并帮助需要向MAH提供其药物产品总体风险评估的信息的水平。

As indicated, this is a recent requirement for the Industry and authorities, and as such the level of knowledge and understanding on it may evolve with time. Therefore, in certain areas that need to be assessed detailed specific information is not practically possible to add to this guidance document, plus it may be amended with time as new information become available.

如前所述，这是业界和当局最近的一项要求，因此对它的知识和理解水平可能会随着时间的推移而发展。因此，在某些需要评估的领域，实际上不可能在本指南中增加详细的具体信息，而且随着时间的推移，随着新信息的出现，可能会对其进行修订。

2. Risk Assessment guidance

风险评估指南

The request from health authorities is to perform the assessment to all market products.

卫生当局的要求是对所有上市产品进行评估。

Due to the large numbers of products involved, EMA document [1] suggests the use of a risk-based approach to prioritize the evaluations and later the confirmatory testing (if the risk evaluation would indicate that testing would be required). The factors suggested are daily dose taken, duration of treatment, therapeutic indication and number of patients treated. However, this data is not always available at the API manufacturers side, who might use other criteria such as the ones suggested below to perform the requested risk evaluations.

由于涉及的产品数量很大，欧盟药监局文件[1]建议使用基于风险的方法对评估进行优先排序，然后进行确认性测试(如果风险评估表明需要进行测试)。建议的因素是每日用药剂量、治疗时间、治疗适应证和治疗患者人数。然而，这些数据在API制造商方面并不总是可用的，他们可能会使用其他标准来执行所要求的风险评估，例如下面建议的标准。

2.1.       Prioritization of the risk assessment

2.1.风险评估的优先次序

The following criteria might be used for prioritization (“>” meaning “higher priority than”)

下列标准可用于确定优先级(“＞”意味着“优先级高于”)

depending on the information available:

视乎现有资料而定:

• Higher daily dose taken

每日服用较高剂量

• Long duration of treatment

长期治疗

• therapeutic indication

治疗适应症

• Higher number of patients treated

接受治疗的患者人数较高

• Commercial APIs > APIs used for clinical trials

商业化API＞临床试验用API

• API manufactured in multipurpose equipment > dedicated equipment

在共线设备中生产的API＞专用设备的

• API manufactured in multipurpose equipment exposed to nitrosating agents

在暴露于硝化剂下的共线设备中生产的API

• API > Intermediate > RSM (for companies manufacturing the three categories)

API＞中间体＞RSM(用于生产这三类产品的公司)

• APIs still manufactured > APIs no longer manufactured but still on the market

API仍在生产＞不再生产但仍在市场上销售

• APIs sold to markets where risk assessment have already been requested by authorities > APIs sold to other markets

销售至市场的API已被有关当局要求进行风险评估，并已销售至其他市场

• Knowledge of the likelihood of a risk based on the chemistry of the process (presence of amine, nitro functionalities, nitrosating agents)

基于工艺化学 (存在胺，硝基功能，硝化剂) 的风险可能性知识

2.2.       Management of raw materials in the risk assessment

风险评估中的原料管理

The need and type of information to be obtained from suppliers depends on the type of material and on its use in the manufacturing process. Following factors are helpful to assess the impact of the raw materials on the risk to have nitrosamines in the API.

从供应商处获取信息的需要和类型取决于原料的类型及其在制造过程中的用途。以下因素有助于评估原料对API中含有亚硝胺风险的影响。

• Regulatory status of the raw material in the associated regulatory file (RSM, processing aid...)

原材料在相关法规文件中的法规状态(RSM，加工助剂...)

• Chemistry of the raw material such as:

原料的化学过程，例如:

• complex process

复杂过程

• use of nitrosating agents and amines

使用硝化剂和胺

• type of solvents used (e.g. recovered in house or by 3^rd party)

使用的溶剂种类(例如由内部或第三方回收)

• Number and type of chemical steps between introduction of raw material and final API stages. The evaluation should take in consideration:

原料和最终API阶段之间的化学步骤的数量和类型。评价应考虑:

• if the raw material is used in early or late steps of the API synthesis

原料用于API合成的前端还是后端步骤?

• If the next step(s) can purge the impurities or not, and if yes at which level the impurity can be purged

下一步可以清除杂质与否？如果可以，在哪一级杂质可以被清除？

• type of chemical process(es) is involved and process conditions

涉及的化学过程的类型和工艺条件

• if the next step(s) can purge the impurities or not and if yes at which level

下一步是否可以清除杂质？如果可以，在哪个水平

• if the raw material is used in later stages of the API synthesis and no further crystallization is performed

如果原料用于API合成的后期阶段，且未进一步结晶

The information from raw material suppliers can be also obtained through questionnaires, which cover chemical process and risk of contamination at the raw material supplier’s facility. The scope of the questionnaire can be very narrow and composed by just the 2 questions below to perform an efficient screening, or more complex covering all applicable potential sources of nitrosamines as described in EMA [1]. The first option does not prevent from receiving later the results of the full evaluation to confirm the conclusions achieved. If required the API risk evaluation should be revised.

原料供应商提供的信息也可以通过问卷调查获得，问卷调查包括原料供应商设施的化学过程和污染风险。调查问卷的范围可以非常狭窄，仅由以下两个问题组成，以便进行有效的筛选，或者更复杂地涵盖所有适用的亚硝胺潜在来源（如欧盟药监局[1]所述）。第一种选择并不妨碍后续收到全面评估的结果以确认所得出的结论。如需要，应修订API风险评价。

• Do you manufacture nitrosamines, amines or sources of amines in the same equipment as those used to manufacture the raw material?

贵公司是否在生产该原料的同一设备中生产亚硝胺、胺或胺的原料？

• Do you use or is there a potential presence of nitrosating agents and/or amines (secondary or tertiary amines) in your manufacturing process?

贵公司在生产过程中是否使用或可能存在硝化剂和/或胺(仲胺或叔胺)？

Examples of nitrosating agents can be found in EFPIA decision-tree for N-nitrosamine risk assessment [4] or IPEC questionnaire [5].

硝化剂的例子可以在EFPIA（欧洲制药工业协会联合会，European Federation of Pharmaceutical Industries and Associations）N-亚硝胺风险评估的决策树 [4]或IPEC问卷[5]中找到。

Information obtained from suppliers on the quality of water (especially nitrite and chloramines content) used in their process can be useful.

从供应商处获取的关于其生产过程中使用的水的质量(特别是亚硝酸盐和氯胺含量)的信息是有用的。

API manufacturers have observed that it is difficult to obtain feedback in due time as suppliers are learning on how to proceed. The API risk analysis should be clear on the depth of raw material information to be taken into account in the risk assessment.

API制造商已经注意到，由于供应商不断改进，很难及时获得反馈。API风险分析应明确原料信息的深度，以便在风险评估中加以考虑。

When the supplier’s data is not available, possible actions are:

当供应商的数据不可用时，可能采取的行动如下:

• Quote this raw material as high risk in the API risk assessment due to the absence of response, which should be later confirmed either during the EMA process Step 2 [1] (confirmatory testing) or with the information received from supplier. The API risk assessment should be reviewed and updated as applicable.

在API风险评估中，由于没有回复而将这些原料列为高风险，这些风险应在EMA程序第2步[1](确认测试)或从供应商收到的资料中加以确认。API风险评估应根据情况进行审查和更新。

• Use scientific knowledge or literature to obtain information (synthesis pathway, etc.)

利用科学知识或文献获取信息(合成路径等)

• Use alternative source of information (website, audit report…)

使用其他信息来源(网站，审计报告...)

2.3.       Risk assessment

2.3.风险评估

EFPIA decision tree [4] is a helpful tool to undertake the risk assessment.

EFPIA决策树[4]是进行风险评估的有用工具。

2.3.1    Content of the risk assessment

2.3.1风险评估的内容

The risk assessment should consider the following possible sources:

风险评估应考虑以下可能的来源:

• Raw materials: attention should be paid to recovered solvents, nitrosating agents, nitric acid, nitrites, dimethylformamide and/or other materials as per [1]. Some raw materials can be considered as low risk due to their chemical nature (e.g.: heptane due to its polarity, methanol…) Such low risk classification should be justified based on scientific literature.

原料:应注意回收的溶剂、亚硝化剂、硝酸、亚硝酸盐、丙酮及/或其他物料。一些原料由于其化学性质而被认为是低风险的(例如:正庚烷由于其极性，甲醇...)。这种低风险分类应基于科学文献。

• Manufacturing process and reaction conditions: conditions forming or suppressing nitrosamines must be assessed such as temperature, pH, carbon treatment [6], chemical reduction [6] or excess of alcohol [7]. Purging factors, if known, can be useful to review the risk level [5].

制造过程和反应条件:必须评估形成或抑制亚硝胺的条件，如温度、pH值、碳处理[6]、化学还原[6]或过量的酒精[7]。清除因素，如果知道，可以用于审查风险水平[5]。

• Structural study and potential subsequent degradation of the structural fragments: amine, nitro… The degradation pathway depends on the process.

结构研究和潜在的后续降解的结构片段:胺，硝基...降解途径取决于工艺。

• Water:

水:

• Well-water and tap-water can contain nitrites and nitrates. Nitrite content is limited on a country by country basis. In EU the limits are typically between 0.1 and 0.5 ppm for well-water and tap water, as other global countries. If in house treatment (e.g. addition of chloramines) is used the impact on the level of nitrosamines formation should be assessed. For APIs manufactured in countries outside Europe, specific analysis of the nitrite or nitrate content in water might be considered.¹

井水和自来水可能含有亚硝酸盐和硝酸盐。亚硝酸盐含量限度不同国家有所不同。与全球其他国家一样，欧盟的井水和自来水的限值通常在0.1至0.5ppm之间。如果采用企业内处理(例如加入氯胺)，应评估对亚硝胺形成水平的影响。对于在欧盟以外国家生产的API，可考虑对水中的亚硝酸盐或硝酸盐含量进行专门分析

• It is generally agreed that the level of nitrite in purified water is typically low, therefore purified water is considered as a low risk. In particular, steps ofwater carbon treatment are known to lower the nitrosamine content. On the contrary, ozonation of the water (containing traces of secondary amines) can theoretically lead to formation of nitrosamines.

一般认为，纯化水的亚硝酸盐水平通常是低的，因此纯化水被认为是一个低风险。特别是，水的碳处理步骤已知可降低亚硝胺含量。相反，臭氧理论上可以导致水(含有微量的仲胺)中亚硝胺的形成。

• Some suppliers are not controlling nitrite content in their water system, therefore in such cases nitrite or Nitrosamine presence (if amines involved) should be assessed, considering that in general no nitrite limit is stablished for tap-water.

有些供应商没有控制其供水系统的亚硝酸盐含量，因此在这些情况下，应评估是否含有亚硝酸盐或亚硝胺(如果含有胺类)，因为自来水通常是没有设定亚硝酸盐含量限度的。

• Cross contamination and cleaning of equipment:

交叉污染和设备清洁:

• The question to be addressed is whether the equipment (used for synthesis/storage/transport) is dedicated or multipurpose. In case of multipurpose equipment, the potential carryover (nitrites, nitrosating agents, amines, etc.) should be assessed and if there is a risk, it should be mitigated by setting appropriate cleaning limits and (e.g. by a corresponding control strategy).

需要解决的问题是设备(用于合成/储存/运输)是专用的还是共用的。就共用设备而言，应评估潜在的残留物(亚硝酸盐、亚硝化剂、胺等)，如有风险，应设定适当的清洗限度及(例如采取相应的控制措施)，以减低风险。

• Some cleaning solvents (such as dimethylformamide) should also beexpressly considered in the risk assessment.

一些清洁溶剂(如丙酮)也应在风险评估中明确考虑。

• Steam, cleaning agents other than solvents, and consumables (gaskets…)should also be considered as applicable, depending on the chemical processes involved.

根据所涉及的化学过程，蒸汽、除溶剂以外的清洁剂和耗材(垫圈...)也应视为适

1. Purified water according Ph. Eur. complies with a nitrates level of maximum 0.2 ppm

根据欧盟药典，纯化水的硝酸盐水平最高0.2ppm.

• Nitrogen should be considered in the risk assessment because of the presence of NOx (nitric oxides) which might be considered as nitrosating agents, alternatively the demonstration of a proper control of nitrogen to prevent the presence of NOx can be relevant.

在风险评估中应考虑氮，因为氮氧化物(一氧化氮)的存在可能被视为硝化剂，否则，应证明氮得到适当控制以防止氮氧化物。

• Primary packaging: The most used material is polyethylene. Particular attention might be paid to the ones with additives such as antistatic packaging (which might contain specific additives) or packaging for liquid APIs by assessing potential interactions between packaging and API.

内包装:最常用的材料是聚乙烯。评估包装与API之间的潜在相互作用，特别注意包含添加剂的包装，如抗静电包装(可能包含特定的添加剂)或液体API包装。

2.3.2.   Boundaries of the risk assessment

风险评估的界限

As the risk assessment has to address routine and accidental presence of nitrosamines in APIs, the definition of the boundaries of the risk assessment should be justified. A difference should be made between “possibility” to have nitrosamine and “likelihood” to have nitrosamines.

由于风险评估必须处理API中亚硝胺的普遍和意外存在，因此风险评估的界限的定义应当合理。在“possibility”（ 指较小的可能性）有亚硝胺和“likelihood”（ 侧重从表面迹象观察，某事或现象有相当大的可能性。）有亚硝胺之间应作出区分。

Some potential helpful criteria are listed below:

下面列出一些可能有帮助的标准:

• Number of synthesis steps where critical components are used (e.g. sodium nitrite and secondary amines) by calculating the theoretical value, assuming that all nitrites and amines a converted in nitrosamines

使用关键组分(例如亚硝酸钠和仲胺)的合成步骤的数目，假设所有亚硝酸盐和胺都转化为亚硝胺，计算理论值

• Number of synthesis steps after potential nitrosamine formation and if they are able to purge the potential impurities formed

在亚硝胺（可能）形成之后的合成步数以及能否清除潜在的杂质

While the number of N-nitrosamines listed by regulators is limited, a useful reference on nitrosamine, some of their properties and toxicological data can be found on the National Institutes of Health website [8].

虽然监管机构列出的亚硝胺数量有限，但有关亚硝胺的一些有用参考资料及其一些性质和毒理学数据可在国立卫生研究院卫生组织的网站上找到。

2.3.3.   Methodology and outcome of the risk assessment

2.3.3.风险评估的方法及结果

The risk assessment can be performed:

风险评估可以:

• Through a FMEA-type tool with different scores assigned to various risk levels

通过一个FMEA类型的工具，不同的风险水平分配不同的分数

• Through a yes/no questionnaire which has the benefit of better orienting the result. An example of such a questionnaire can be found in the IPEC questionnaire [5].

通过一个是/否的问卷，以更好地定位结果。这种调查问卷的一个例子可以在IPEC的调查问卷[5]中找到。

The outcome of the risk assessment can be:

风险评估的结果可以是:

• A high/medium/low risk to further establish planning and priority of next steps (in particular analytical testing), so that the API producer can prioritize further mitigation measures

划分高/中/低风险，以进一步确定下一步计划和优先级(特别是分析测试)，以便API生产商能够按优先级考虑进一步的缓解措施

• A negligible/potentially present outcome for external use to provide a clear position to the MAH (see next paragraph).

-结果为可忽略/可能存在，为MAH提供了明确的立场（请参阅下一段）。

The decision to proceed to analytical testing should be taken, only when a risk is confirmed, and the associated testing strategy can be unambiguously established. An ICH M7 assessment is also a useful step to undertaken before proceeding to any analytical testing.

只有当风险得到确认，并且相关的测试策略可以明确建立时，才应该作出进行分析测试的决定。在进行任何分析测试之前，进行ICHM7评估也是一个有用的步骤。

2.3.4.   Collaboration with customer

与客户合作

The collaboration with the customer depends on the type of contract and product.

与客户的合作取决于合同和产品的类型。

Generic API manufacturers will mostly establish themselves a methodology for risk assessment and inform the customer about the outcome. A Letter template to formalize the results of the risk assessment to be shared with customers is in Appendix 1.

通用API制造商大多会建立自己的风险评估方法，并通知客户有关结果。与客户共享风险评估结果的信函模板见附录1。

Contract API manufacturers may receive risk assessment methodology of their customers. The decision on which risk assessment to perform depends on the company policy and on its contractual and quality agreements with the customer.

合同API制造商可能会收到其客户的风险评估方法。进行何种风险评估的决定取决于公司政策及其与客户的合同和质量协议。

Examples of authorities’ expectations regarding the information to be supplied by our customers to their authorities can be found on [1], [3] and [9], (no risk identified response template and risk identified response template) websites.

有关当局期望客户向其当局提供的资料的例子，可在[1]、[3]和[9](没有风险识别反馈模板)网站上找到。

2.3.5.   Lifecycle of the risk assessment

风险评估的生命周期

The risk assessment is a living document which will be updated whenever additional knowledge is obtained on the API or process change is conducted (when risk assessment may need repeated). Mitigation actions should be defined if a risk is identified.

风险评估是一份动态的文件，一旦获得关于API的额外知识或进行工艺变更时(当可能需要再次进行风险评估时)，该文件将被更新。如果确定了风险，则应确定缓解措施。

If new information is obtained, such as late supplier information, and such information increases the risk level versus the previous version of the risk assessment, such new information will have to be communicated to the customers accordingly.

如果获得了新的信息，例如供应商迟交的信息，而且这种信息相对于以前版本的风险评估而言增加了风险水平，则必须相应地向客户传达这种新的信息。

The results of analytical testing change control and investigation systems should also feed the risk assessment. The analytical testing lifecycle is described below.

分析测试变更控制和调查系统的结果也应为风险评估提供依据。下面描述了分析测试的生命周期。