加拿大新药和已上市药品实施ICH Q3D通知

Q3D Notice: Health Canada recommendations for implementation of the ICH Harmonised Guideline for Elemental Impurities (Q3D) for new and marketed products

Q3D通知：加拿大药监对新药和已上市药品的ICH Q3D实施建议

原文链接：http://hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/ich/qual/q3d-rec-eng.php

Notice

July 22, 2016
Our file number: 16-108149-319

Health Canada recommendations for implementation of the International Council for Harmonisation (ICH) Harmonised Guideline for Elemental Impurities (Q3D) for new and marketed products

加拿大新药和已上市药品实施ICH Q3D通知

The ICH Harmonised Guideline for Elemental Impurities Q3D has been recommended for adoption to the regulatory bodies of the European Union, Switzerland, Japan, USA, and Canada. Canadian drug products should comply with the guideline as follows:

ICH指南Q3D“元素杂质”已经被ICH建议欧盟、瑞士、日本、美国和加拿大采纳。加拿大药品应在以下实施日期内符合该指南：

Table 1: Dates for implementation of ICH Q3D in Canada
表1：加拿大实施ICH Q3D时间表
Document	Implementation date
文件	实施日期
Submission of a new abbreviated new drug submission (ANDS) or drug identification number (DIN) application for a drug product should include the content requirements as per Q3D	Submissions received after December 31, 2016
简略新药申报（ANDS）和药品识别号（DIN）申报药品应按Q3D要求提交相关内容。	2016年12月31日之后收到的申报
Submission of a new Supplemental (A)NDS or Post-DIN Change for a major change to an existing Drug Product as a result of the risk assessment per Q3D Submission of a new Supplemental (A)NDS for a quality related major change to a marketed drug product should include the content requirements as per Q3D for a new drug product	Submissions received after December 31, 2016
新的补充申报（A）NDS和现有药品批准后DIN主要变更按Q3D进行风险评估认为需要申报的。 已上市药品与质量相关的主要变更进行新的补充申报（A）NDS时应包括新药品Q3D内容要求。	在2016年12月31日之后收到的申报
Completion of the risk assessment for elemental impurities Implementation of any manufacturing changes to control the levels of elemental impurities Updated drug product specifications with a statement confirming compliance with ICH Q3D	By January 1, 2018
完成元素杂质风险评估 实施所有控制元素杂质水平的生产变更 更新药品标准，同时提交符合ICH Q3D的确认声明	2018年1月1日之前

Implementation of elemental impurity risk assessments for new submissions for drug products (ANDS or NDS, S(A)NDS and DIN Applications):

药品（ANDS或NDA，S(A)NDS和DIN申报）新申报中元素杂质风险评估的实施

Submissions received by Health Canada after December 31, 2016 should include a risk assessment for elemental impurities. Submissions received after December 31, 2016 that do not have a risk assessment will be requested to submit the missing information.

加拿大药监在2016年12月31日之后收到的申报资料应包括元素杂质风险评估。自2016年12月31日起收到的申报中如果缺失风险评估，则会被要求补充提交缺失的信息。

Risk assessments will be evaluated during the assessment process. The scope of the risk assessment to be submitted for assessment should be based on the principles outlined in the ICH Q3D guideline and related training materials being developed by the ICH Q3D Implementation Working Group. Case studies are currently under development and will be published on the ICH website, when available. Detailed risk assessments and data supporting these risk assessments should be documented and available upon request by the Regulator (e.g., at the inspection stage).

在审评过程中要对风险评估进行评价。所需提交的风险评估范围应根据ICH Q3D指南中列出的原则和ICHQ3D实施工作组所制订的相关培训材料来确定。案例研究目前正在制订中，完成后会在ICH官网上发布。详细的风险评估和支持这些风险评估的数据应记录，并在法规人员要求时提供（例如，在现场检查阶段）。

The locations where the elemental impurities-related information can be found in Module 3 should be clearly summarized in Module 2.3.P.5: Control of Drug Product of the Quality Overall Summary. The overall risk assessment summary for elemental impurities should be placed in Module 3.2.P.5.6 Justification of Specifications. The risk assessment for the container closure system may be cross-referenced to a master file. If toxicology data is submitted to support limits above the ICH Q3C Permitted Daily Exposure or for routes of administration not covered by ICH Q3D, it should be placed in Module 4.2.3.7.6 Other Toxicity Studies: Impurities.

元素杂质相关的信息在模块3中的位置应在模块 2.3.P.5：“质量综述制剂控制”中清楚总结。元素杂质总体的风险评估总结应放置在模块3.2.P.5.6“质量标准论证”里。在主文中可以交叉引用容器密闭系统的风险评估。如果提交毒性数据来支持高于ICH Q3C允许日暴露值（PDE）的限度，或者是常规摄入途径不在ICH Q3D列表中，则应该放置在模块4.2.3.7.6“其它毒性研究：杂质”中。

Compliance with the ICH Q3D guideline should be documented after the risk assessment has been completed and any necessary controls have been implemented. For example, a statement confirming ICH Q3D compliance should be included on the drug product specifications and reflected in the updated Certified Product Information Document (CPID). Additional evidence of compliance should be available on request.

在风险评估完成之后，以及所有必要控制都实施后应记录是否符合ICH Q3D指南。例如，在药品质量标准中提供ICH Q3D符合性声明，并包括在更新后的认证产品信息文件（CPID）中。如果要求，则应提交额外证据。

Implementation of elemental impurity risk assessments for Canadian marketed drug products:

已在加拿大上市的药品的元素杂质评估的实施

S(A)NDSs or Post-DIN Changes for any quality related major change to a drug product submitted after December 31, 2016 should include a risk assessment for elemental impurities to allow for review and authorisation of the S(A)NDS or Post-DIN changes by January 1, 2018. A risk assessment should be performed in accordance with the ICH Q3D guideline and any training materials published as a result of work currently being done by the ICH Q3D implementation working group. Case studies are currently under development and will be published on the ICH website, when available. The risk assessment should be documented and available for inspection and any controls should be implemented, if applicable, by January 1, 2018.

2016年12月31日之后提交的药品S(A)NDS或Post-DIN所有质量相关主要变更应包括一份元素杂质风险评估供2018年1月1日之前审核和批准。风险评估应根据ICH Q3D指南和ICH Q3D指南工作组制作公布的培训材料实施。案例研究目前正的制作中，完成时会在ICH官网上公布。风险评估应有书面记录，并在检查时提供，在2018年1月1日前，应实施所有适用的控制。

If the risk assessment indicates that previously manufactured and unexpired batches have levels of elemental impurities that could pose a potential risk to health, the appropriate Directorates in Health Canada should be notified. Where appropriate this may include notification to the Health Product Compliance Directorate (formerly known as the Inspectorate) and/or the Biologics and Genetic Therapies Directorate (BGTD) for lot releases of biologics. If necessary, appropriate corrective action should be taken, such as: conducting recalls of any affected lots in accordance with recall procedures, developing an action plan to avoid a product shortage situation and filing a drug submission with appropriate manufacturing changes to effectively address the potential safety concerns.

如果风险评估显示之前生产的和仍在有效期内的批次中元素杂质可能对健康有潜在风险，则应通知加拿大药监相关部门。适当时，应包括通知卫生产品符合性部门（之前称为检查部）和/或生物和基因治疗部门（BGTD）以放行生物制品。必要时，应采取适当的纠正措施，例如，对所有受影响批次根据召回程序进行召回，制订行动计划以避免产品短缺情形发生，提交药品申报，对生产工艺进行适当变更以有效解决潜在的安全问题。

ICH Q3D compliance should be included on the drug product specifications and reflected in the updated Certified Product Information Document (CPID). Additional evidence of compliance should be available on request. Consult Health Canada's Guidance Documents, Post-Notice of Compliance (NOC) Changes: Quality or Post-Drug Identification Number (DIN) Changes for the appropriate type of drug submission to file respective of the proposed change(s).

ICH Q3D符合性应包括在药品质量标准中，并反映在更新后的认证药品信息文件（CPID）中。官方索取时应提供符合性额外证据。相关药品注册变更申报要求，参见加拿大药监文件“批准通知（NOC）变更：质量”或“药品识别码变更”。

In the following cases, the filing of a post-NOC or post-DIN change may be appropriate:

在以下案例中，适合提交一份批准后NOC或批准后DIN变更：

• Where there is a need for the replacement of the active pharmaceutical ingredient (API), API starting materials, synthesis intermediates or the excipients in order to comply with the ICH Q3D guideline and the requirements of thePost-NOC/ Post-DIN Changes guidance document.
  如果有必要更换原料药（API）、API起始物料、合成中间体或辅料以符合ICH Q3D指南和批准后NOC/批准后DIN变更指南文件的要求。
• Where there is a need for major changes to the manufacturing process to reduce and control the levels of elemental impurities and the changes are such that the requirements of the Post-NOC/Post-DIN Changes guidance document would deem that a S(A)NDS should be submitted.
  如果有必要对生产工艺进行主要变更来降低和控制元素杂质的水平，根据批准后NOC/批准后DIN变更指南文件要求提交S(A)NDS时。
  

The Post-NOC or Post-DIN change should contain a summary of the risk assessment, the conclusions drawn and appropriate data to support any changes made in order to comply with the ICH Q3D guideline and/or in accordance with the Post-NOC/Post DIN Changes guidance document. The overall risk assessment summary for elemental impurities should be placed in Module 3.2.P.5.6 Justification of Specifications. In Module 2.3.P.5 of the Quality Overall Summary, provide a summary of the Module 3 locations where the elemental impurities-related information can be found.

批准后NOC或批准后DIN变更应包括风险评估总结，所做出的结论以及适当的数据来支持任何为符合ICH Q3D指南和/或符合批准后NOC/批准后DIN变更指南文件所做的所有变更。元素杂质全面风险评估总结应放置在模块3.2.P.5.6“质量标准论证”中。在质量综述的模块2.3.P.5中，要提供在模块3的哪儿能找到元素杂质相关信息。

As an outcome of the risk assessment, rather than the need for a major chemistry and manufacturing change, one or more of the following scenarios may apply:

应该根据风险评估的结果，而不是根据主要研发和生产变更，应用以下一个或多个情景：

• Additional controls are added to specifications to ensure levels of elemental impurities meet the ICH Q3D limits. Where a control of an elemental impurity is warranted, an elemental specific method is applied. A non-specific compendial test for heavy metals is not acceptable for control of elemental impurities. Consult Health Canada's Post-NOC Changes guidance document to determine if the filing of a Notifiable Change or an Annual Notification is necessary for any minor change(s) that are implemented.
  为保证元素杂质水平符合ICH Q3D限度，在质量标准中增加额外控制。如果要保证对元素杂质的 控制，则需要采用元素专属方法。一个非专属的药典重金属方法用于控制元素杂质是不可接受的。参考加拿大药监NOC批准后变更指南文件来决定针对所实施的轻微变更是应该提交通知性变更或年报。
• No further controls or updates to the Specifications for elemental impurities are needed for materials such as the API (or the API starting material and synthesis intermediates), excipients or the finished product.
  不需要对物料，如API（或API起始物料和合成中间体）、辅料或成品的元素杂质质量标准进行更多控制或更新。
• No replacement or change of the quality of materials such as the API, the API starting materials, synthesis intermediates, excipients or the manufacturing equipment is needed.
  不需要替换或变更物料质量，例如API、API起始物料、合成中间体、辅料或生产设备。
• No change to the manufacturing process is needed.
  不需要对生产工艺进行变更。
  

Periodic re-assessments of the risks associated with elemental impurities, and corresponding compliance activity, may be appropriate throughout the lifecycle of the product.

定期对元素杂质相关风险和对应的符合性活动进行定期再评估，可能需要贯穿在整个产品生命周期。

Questions regarding this implementation should be directed to bps_enquiries@hc-sc.gc.ca.

关于此实施的问题请直接发送到上述邮箱。

Additional guidance regarding implementation of elemental impurity risk assessments for Over-the-Counter Drug Products (OTC) and Natural Health Products (NHPs):

关于非处方药（OTC）和营养保健品（NHP）元素杂质风险评估实施的附加指南

OTCs that are classified under the Food and Drugs Act as drug products should comply with ICH Q3D guidance by the dates presented above. Generally risk assessments for elemental impurities do not need to be submitted for assessment unless a Chemistry and Manufacturing portion of the submission is reviewed by the Therapeutic Products Directorate (e.g., Risk Assessments should be submitted for certain OTCs which are submitted as Applications for Drug Identification Numbers (DINA)). For product submissions for which chemistry and manufacturing data is not submitted (e.g., DINF Category IV monographs), risk assessments should be held on file.

根据食品药品法案为归类为药品的OTC截止上述日期时应符合ICH Q3D指南。如果申报资料中的研发和生产部分没有被治疗产品委员会（例如，指定的OCT需提交风险评估，该申报提交是为了做药品识别码（DINA））进行审核，则一般来说不需要提交元素杂质风险评估。对于没有提交研发和生产申报的药品（例如，DINF类别IV各论），则应该在文件中放入风险评估。

Natural Health Products have been excluded from meeting the requirements of the ICH Q3D guidance. They should meet the requirements for elemental impurities presented in the Quality of Natural Health Products guideor subsequent updates. NHPs which claim USP standards, should also meet the USP requirements by the date of implementation for USP <2232> (January 1, 2018).

自然保健药品不需要符合ICH Q3D指南的要求。他们应符合“自然保健药品质量指南”和之后更新中给出的元素杂质要求。声明符合USP标准的NHP自USP<2232>实施日（2018年1月1日）开始还要符合USP的要求。

Questions regarding NHPs should be directed to NNHPD_DPSNSO@hc-sc.gc.ca.

关于NHP的问题应直接发送邮件至上述邮箱。

Additional guidance regarding implementation of elemental impurity risk assessments for drugs listed in Schedule C and Schedule D to the Food and Drugs Act:

关于列在食品和药品法案计划C和计划D中药品的元素杂质风险评估实施的附加指南

Although "cold kits" (for reconstitution with a radiopharmaceutical) are regulated as Schedule C drugs, they do not meet the definition of a "radiopharmaceutical" and so are considered to be within the scope of ICH Q3D.

尽管“冷包”（放射性药品组合用）是按C计划药品来管理，他们并不符合“放射性药品”的定义，因此被认为是包括在ICH Q3D的范围内。

The risk assessment for elemental impurities should be conducted for Schedule D (biologics) drugs that are covered within the scope of the ICH Q3D guideline.

被ICH Q3D指南范围所覆盖的D计划药品（生物制品）应实施元素杂质的风险评估。

For biologics, additionally consult Section 5.7 of the ICH Q3D guideline and the biologics-specific case study (under development). Where implementation of manufacturing changes is considered, Appendix 3 (Biologics) and Appendix 4 (Schedule C drugs) of the Post-NOC Changes: Quality guidance document should be consulted.

对于生物制品，还需参照ICH Q3D指南的第5.7部分和生物特定案例研究（制订中）。如果考虑进行生变变更，则要参照

Questions regarding this implementation should be directed to bgtd_ora@hc-sc.gc.ca.

关于此实施的问题请直接发送到上述邮箱。