ANDA申报常见缺陷 第1部分：原料药

转载文章4年前更新 菜芽君
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作者：潘宪伟 来源：药研数据库

Pharmaceutical Technology; Jan 2010; 34, 1; ABI/INFORM Global pg. 50

Common Deficiencies in Abbreviated New Drug Applications

Part 1: Drug Substance

Aloka Srinivasan and Robert Iser

仿制药申报常见缺陷信解读

第一部分：原料药

Team leaders in the US Food and Drug Administration’s Office of Generic Drugs provide an overview of common deficiences cited throughout the Chemistry, Manufacturing, and Controls section of abbreviated new drug applications (ANDAs).

The reviewers aim to assist ANDA sponsors in building quality into their submissions by clarifying components of the applications

食品和药品管理局（FDA）仿制药办公室（Office of Generic Drugs）的团队负责人提供了一份概述，列举了简化新药/仿制药申请（ANDAs）中化学、制造和控制部分的常见缺陷

评审员的目标是通过澄清申请的组成部分来帮助ANDA发起者，提高其申报的质量

Aloka Srinivasan, PhD., and Robert Iser, M.S., are team leaders at the Office of Generic Drugs within the Office of Pharmaceutical Science, under the US Food and Drug Administration’s Center for Drug Evaluation and Research。

[email protected].

‘ To whom all correspondence should be addressed

Aloka Srinivasan 博士和医学硕士 Robert Iser 是食品和药品管理局（FDA）药物审评与研究中心下属的仿制药办公室（Office of Generic Drugs）的团队负责人。

所有的信件都可以寄给：[email protected]。

 

The ever increasing workload at the Office of Generic Drugs (OGD) within the US Food and Drug Administration’s Center for Drug Evaluation and Research (CDER) has led the office to develop a number of strategies to streamline the review process. One such strategy was the introduction of Question-Based Review-Quality Overall Summary (QbR-QOS). Another strategy involves asking sponsors of abbreviated new drug applications (ANDAs) to provide a Pharmaceutical Development Report with their application.

美国食品和药物管理局（FDA）的医药评价和研究中心（CDER）下属的仿制药办公室（OGD）不断增加的工作量，促使OGD制定一系列策略，以简化审评流程。其中一个策略是，引进基于问题审评的质量总体概述（QbR-QOS）。另一个策略是，要求简化新药/仿制药申请（ANDAs）申报者的提供一份药物开发报告。

The QbR is a platform for implementation of CDER’s Pharmaceutical CGMPs for the 21st Century: A Risk-Based Approach and a springboard to quality by design (QbD). It also provides the sponsors with an opportunity to discuss the development of their product. The summary report in QbR-QOS can be referenced by the reviewers as a snapshot of the ANDA before they review the entire application (Le., the body of data). Adequate information provided in the QbR-QOS and the Pharmaceutical Development Report reduces the application assessment time, minimizes transcriptional errors, and helps the review process at all levels (primary, secondary, and tertiary).

基于问题审评（QbR）是CDER面向21世纪的药品CGMPs的实施平台：基于风险的方法和质量源于设计的出发点（QbD）。它还为申报者提供了一个讨论其产品开发的机会。QbR-QOS中的总结报告可由审阅人员在审阅整个申请（即，主体数据）前，作为ANDA的快照引用。在QbR-QOS和药物开发报告中提供的充分的信息，可以减少申请评估时间、最小化转录错误，和帮助所有级别的申请过程（一级、二级和三级）

Also. by seeking sponsors’ responses to critical questions regarding the quality of their drug product, the QbR has helped to reduce the number of deficiencies cited for an application. This process of knowledge sharing has improved the overall review quality. However, it has not met the expectation of the Office of Generic Drugs (OGD) because applications are being submitted with minimal justification in establishing product quality. Despite OGD’s efforts, the number of amendments submitted in response to FDA’s deficiency letters, have still been staggering.

另外，通过查阅申报者对其药品质量的关键问题的答复，QbR已经帮助减少了申请中所提到的缺陷的数量。这些知识的共享也提高了整体的评审质量。但是，它还没有达到仿制药办公室（OGD）的期望，因为提交申请时，未对产品质量的确立，提供充分的理由。尽管OGD做出了努力，但针对FDA缺陷信提交的修正案数量仍然惊人。

With this as prologue, a series of articles are forthcoming in an effort to be more transparent and to assist sponsors to submit applications with adequate justification for drug substance and drug product (DS and DP) specifications, in-process controls, choice of formulation, product design, and manufacturing processes. Our experience shows that having justification in the original submission reduces the number of deficiencies and provides assurance to the agency in the sponsors’ ability to manufacture high quality drug products.

作为一个序言，一系列的文章即将发表，以使其更加透明，并帮助申请人为其原料药（DS）和制剂（DP）的申请提供充分的理由，如为质量标准、过程控制、处方选择、产品设计和生产工艺提供理由。我们的经验表明，在最初提交的材料中提出正当理由可以减少缺陷的数量，并为该机构提供保证，使其能够生产高质量的药品。

These articles will attempt to clarify the intent and criticality of some of the common deficiencies cited throughout the Chemistry, Manufacturing, and Controls (CMC) portion of ANDA submissions. Sponsors may use this information to build quality into their submissions. As background for this work, the authors have surveyed a representative sample of deficiency letters issued by each chemistry team within OGD over the past six months. The surveyed deficiencies were cited for ANDAs submitted in the QbR-QOS format. However, this article is not intended to be a discussion of all common deficiencies in ANDAs. The article focuses exclusively on the drug substance portions of the ANDA submissions using the Common Technical Document (CTD) and QbR format as a guide. For a partial list of some common drug substance related deficiencies. see the sidebar “Examples of commonly cited drug-substance related deficiencies.”

这些文章将试图澄清，在ANDA提交的化学、制造和控制（CMC）部分中引用的一些常见缺陷的意图和重要性。申报者可以使用这些信息，提高其申报的质量。作为这项工作的背景，作者调查了过去6个月，仿制药办公室（OGD）每个化学小组发表的有代表性的缺乏信样本。在以QbR-QOS格式提交的ANDAs申报中，可以参考调查的这些缺陷信。然而，本文不打算讨论ANDAs中的所有常见缺陷。本文以通用技术文件（CTD）和QbR格式为指南，专门关注ANDA提交的原料药部分。查阅部分常见的与原料药有关的缺陷。请参阅侧栏“ADNA申报中与原料药相关的缺陷信举例”。
Examples of commonly cited drug-substance related deficiencies in ANDAs (as paraphrased by the authors)ADNA申报中与原料药相关的缺陷信举例（正如作者所述）
  1. The Drug Master file (DMF) related to the drug substance is deficient, and the holder has been notified. Please do not respond until the DMF holder has responded to all the deficiencies.和原料药相关的DMF存在缺陷，已通知DMF持有者，请在DMF持有者回应了所有的缺陷问题后，再回复FDA

  2. The general properties section (S.1) of the ANDA fails to contain all relevant information. Please provide hygroscopicity, solubility as a function of pH, and melting range for the drug substance.

    ANDA申报资料的一般属性项（S.1）下未包括所有相关信息。请提供原料药的引湿性、pH、溶解性和熔点信息

  3. Please revise the characterization section (S.3) to include full IUPAC names, structures, and classification of the impurities as process related and/or degradation products.

    请修订特性鉴定部分（S.3），以包括全部IUPAC名称（International Union of Pure and Applied Chemistry国际伦理和应用化学联合会）、结构，以及按照工艺相关和/或降解产物的杂质分类情况

  4. Please tighten or justify the proposed limits for the specified impurities based on ICH Q3A on impurities in new drug substances recommendations taking into account maximum daily dose (MDD).

    请按照ICH Q3A关于新原料药杂质指南所推荐应考虑的最大日剂量（MDD），严控特定杂质的限度或提供设定现有限度的合理性

  5. Please revise the unknown impurities criteria to be in-line with ICH Q3A recommendations based on the MDD. Impurities observed above the recommended identification threshold should be identified, and impurities observed above the recommended qualification threshold should be suitably qualified.

    请按照ICH Q3A指南推荐的最大日剂量（MDD）来修订未知杂质限度。所观察到的杂质高于推荐的鉴定限度应进行鉴定，高于推荐的界定限度应进行适宜的确认

  6. Residual solvent criteria should be in line with the DMF holder’s limits, as they are process related impurities. Please ronsult your DMF holder and revise your criteria accordingly.

    残留溶剂标准应与DMF持有者的限度一致，因为它们是工艺相关杂质。请咨询你的DMF持有者并相应的修订你的标准

  7. Please consult your DMF holder to ensure all potential process impurities (e.g., metal catalysts or reagents) are included or controlled in the proposed specifications.

    请咨询你的DMF持有者以确保所有的潜在工艺杂质（如：金属催化剂或试剂）已在建议的标准中被包含或被控制

  8. Please add justified specifications for the full range of particle size distribution. Alternatively, please provide justification that particle size is not critical to the manufacturing process and drug product performance.

    请增加粒径分布全范围的合理标准，或者提供粒径大小对于生产工艺和制剂性能不是关键性的合理理由

  9. Based on the literature, multiple polymorphic forms are possible. Please provide the form used and add a suitable control to ensure consistency in the drug substance.

    根据文献，可能存在多晶型，请提供所用的晶型并增加适宜的控制，以确保原料药的一致性

  10. Please include a suitable test and justified criterion for water content of the drug substance.

    请在原料药标准中增加水分的适宜检测方法和合理的标准

  11. Please add a quantitative control of the counter-ion in your drug substance.

    请增加你的原料中对应离子的定量控制

  12. Based on the chiral nature of the drug substance, please include a control for the relevant enantiomer and diastereomers.

    根据原料药的手性属性，请包含有关对映体和非对映体的控制

  13. In view of the chiral nature of the drug substance, please indude a chiral identity.

    鉴于原料药的手性属性，请包含手性鉴别方法

  14. We recommend a chiral assay of your drug substance, since it is prone to racemization on storage.

    因为你们的原料药在贮藏中有消旋化的倾向，我们建议采用手性含量测定方法

  15. As validated methods were transferred from the DMF holder, please provide verification data to demonstrate that the methods can be performed at the proposed facility.

    由于已验证的方法是从DMF持有者处转移过来的，请提供确认数据，以证明这些方法可以在拟议的工厂中执行

  16. Please provide a USP cross-over study for the assay method to demonstrate the proposed method is equivalent or better than the compendial method.

    请提供含量测定方法和USP方法的交叉研究，以证实所提议的方法相当或优于药典方法

  17. We recommend that a chromatographic method be proposed for the analysis of drug substance assay.

    我们建议采用色谱方法来分析原料药的含量

  18. Please revise the certificate of analysis to report impurity results as discrete numerical values instead of as “conforms.” If results are below the method limit of quantltation (LOQ), please report as less than LOQ; and if results are below the limits of detection (LOD), please report as less than LOD or “none detected.”

    请修订分析报告书，以具体数字来替换“符合规定”来报告杂质结果。如果结果低于方法的定量限（LOQ），请报告为小于LOD；如果结果小于检测限（LOD），则报告为小于LOD或“未检出”

  19. Please provide LOD and LOO for all specified impurities and residual solvents.

    请提供所有特定杂质和残留溶剂的LOD和LOQ

  20. Please provide information on all impurity reference standards used, including lot number, source of the standard, and purity.

    请提供所用的所有杂质标准品的信息，包括批号、标准品的来源和纯度

One area that will not be expanded on in this article is the common deficiency that the referenced Drug Master File (DMF) is inadequate and, as such, the ANDA sponsor should not respond until they have been informed that the DMF deficiencies have been addressed. The deficiency in itself is rather clear and its criticality is obvious as the drug substance is the key ingredient in the product. However a recommendation to ANDA sponsors is that they “do their homework” when selecting a DMF partner and be aware of the information available to them with regard to drug-substance characterization, properties, purity, and methodology as well as the regulatory history of the DMF holder. The upcoming International Conference on Harmonization (ICH) Q11 guideline on drug substances should provide clarity for both DMF holders and ANDA sponsors with respect to the critical aspects of the drug substance. Schwartz provides another helpful resource with respect to critical information to be gleaned from the referenced DMF (1).

本文中未涉及的一个领域是，所引用的药物主文件（DMF）不充分这一常见缺陷，因此，ANDA申报者在被告知DMF缺陷已得到解决之前不应做出响应。其缺陷相当明显，且重要性也是显而易见的，因为原料药是制剂的关键成分。然而，对ANDA申报者的建议是，他们在选择DMF合作伙伴时“做足功课”，并了解他们可获得的原料药的物质特性、性质、纯度和方法学的信息，以及DMF持有者的监管历史。即将召开的关于药物协调的国际会议ICH Q11指南将可能为DMF持有者和ANDA申报者提供关于药物关键方面的明确信息。对于要从引用的DMF收集的关键信息，Schwartz提供了另一个有用的资源。

A second topic not discussed in this article is the issue of polymorphism. It is again a frequently cited deficiency where the ANDA sponsor has been requested to include information and a control for polymorphic identity and its impact on the performance of the drug product. The sponsors are highly recommended to address criticality of controls of polymorphism in the drug substance and/or the drug product based on an evaluation of drug substance characteristics, proposed formulation, proposed manufacturing process, and its impact on the product performance. For more details on the Significance of polymorphism in ANDAs, please refer to the following publications (2, 3).

本文中未讨论的另外一个主题是多晶型问题。这又是一个经常被引用的缺陷，即要求ANDA申报者提供多晶型的信息、控制和对药物产品性能的影响。高度鼓励，申报者根据对原料药特性、拟定处方、拟定生产工艺和对制剂性能影响的评估，阐述原料药和/或制剂中对晶型控制的重要性。有关ANDAs中多晶型重要性的详细信息，请参阅以下出版物（2，3）。

2.3.S /3.2.S Drug Substance 原料药

2.3.S.1 General Information 一般信息

The second question in the QbR-QOS pertains to drug-substance properties. This question is inconsistently answered by the sponsors of most applications. A full understanding of the drug-substance properties is essential in the development of formulation, manufacturing process, analytical methodology, and product stability. In many instances, this critical information is lacking and triggers a question requesting the identification of crucial aspects of the drug substance that are essential in making a quality drug product. An understanding of the drug-substance properties is paramount to ascertaining the critical material attributes (CMA). The properties may or may not be CMAs based on the intended use or performance, the formulation. manufacturing process, analytical methodology, and product stability. Examples are as follows:

在QbR-QOS中关于原料药性能的第二个问题。这个问题大多数申报者的回答不太一致。在处方开发、生产工艺、分析方法学以及制剂稳定性中对原料药特性的全面了解至关重要。在多个例子中，缺乏这个关键的信息，而且引发了一个问题：要求对制剂中决定质量的重要的原料药的关键项目进行鉴别。对原料药性能的了解首要在于确定关键物料的属性。这些特性可能是，也可能不是关键物料属性，这要根据其用途或性能、处方、生产工艺、分析方法和产品稳定性。举例如下：

  • Solubility may be critical to determining the formulation, the process, and the performance of the product. A study of pH-related solubility and solubility in various organic solvents can also be used to justify manufacturing process steps and in providing information useful for developing suitable analytical methods.

    溶解性对于确定处方、工艺以及制剂的性能方面可能至关重要。溶解性与pH相关的研究和不同的有机溶剂中溶解性的研究，也可用于证实生产工艺步骤的合理性并且为开发合适的分析方法提供有用的信息

  • Knowledge of hygroscopicity may have an impact on choices made in the formulation or the manufacturing process; and may also provide insight into potential stability challenges if the drug substance or the formulation is sensitive to moisture.
    吸湿性的知识可能在处方选择或生产工艺中有一定的影响，而且如果原料药或处方对湿度敏感，它也可以在潜在的稳定性挑战方面提供一些认识
Providing an answer to this question and identifying the drug-substance aspects that are critical to product quality can eliminate this request coming from the reviewer.

对这个问题给出答复，并标识出对制剂的质量，起至关重要的原料药的属性，可减少审核者对这个问题的疑问。

2.3.S.2 Manufacture 生产

With respect to section 2.3.S.2, reference is usually made to the associated DMF(s). If questions are asked regarding the manufacturing of the drug substance, it is because of additional processing of the drug substance by the ANDA sponsor such as micronization. If the ANDA sponsor performs post-DMF drug substance processing such as micronization, the effect of such processes on drug substance stability should be addressed.

关于2.3.S.2部分，通常参考相关的DMF。如果问到关于原料药制造的问题，那是由于ANDA申报者附加的原料药的工艺，例如微粉化工艺。如果ANDA申报者采用后批准的DMF原料药工艺，例如微粉化，那么应讨论这种工艺对原料药稳定性的影响

An additional question that is often asked by reviewers in this section is whether the drug substance will be manufactured at multiple manufacturing sites. It is recommended that the DMF holder be consulted to address which site will be used to supply commercial material and if multiple sites will likely be used. This fact should be included in the exhibit batch information (i.e .. the possibility of manufacturing multiple exhibit batches). If there is a possibility of a change in source site after approval, this information should be included in the ANDA sponsor’s regulatory strategy.

在这部分，审核者经常会问到的另外一个问题，那就是原料药是否在多个生产地址生产。如果多个生产地址都可能涉及到，建议DMF持有者商议选择一个生产地址用于供应商业化的原料。展示批信息中也应包括该事实（即生产多个批次的展示批的可能性）。如果批准后生产地址有可能变化，这个信息的变更应该包括在ANDA申报者的法规策略中。

2.3.S.3 Characterization 特性

For drug-substance characterization information, the ANDA sponsor typically refers to the applicable portions of the referenced DMF. This section, however, also provides the introduction to potential impurities that may or may not be adequately controlled by the DMF holder. A summary of the potential impurities (organic and inorganic), related substances, residual solvents, and residual reagents should be included in this section (see section 2.3.S.4 below for a discussion of criteria for the impurities). Many times. the information with respect to International Union of Pure and Applied Chemistry (IUPAC) names, structures, and classification as process related and/or degradation impurities is missing from the ANDA. This type of information is part of a complete response to the QbR question found in section 2.3.S.3. Additionally, justification should be provided for any potential impurities including, in some cases compendial impurities (e.g. USP monograph specified impurities), that are process specific and are not specified in the drug·substance specifications.

对于原料药特性的信息，ANDA申报者一般引用所涉及的DMF的公开部分。但是，这一部分也提供了潜在的杂质的介绍，DMF持有者可能控制得很好也可能控制得不够好。潜在杂质（有机杂质和无机杂质）、有关物质、残留溶剂以及残留试剂的概述应包括在这部分中（参见下面的2.3.S.4部分对杂质的标准讨论）。很多时候，ANDA中缺少IUPAC名称、结构，以及按工艺相关和/或降解产物的杂质分类这些信息。这种类型的信息是在2.3.S.3中发现的对QbR问题完整回复的一部分。另外，对任何潜在的杂质应该提供说明，包括在一些例子中出现的药典杂质（如USP中的特定杂质），这些杂质在原料药标准中是工艺特定杂质和非特定杂质。

2.3.S.4 Control of Drug Substance 原料药的控制

Common questions with respect the control of the drug substance can be grouped into four major categories. These categories include: control of impurities (i.e. organic. inorganic. residual solvents, and residual reagents), drug substance identity, physical characteristic controls, and analytical methodology. Each category will be expounded upon with respect to common questions asked after the reviewer assesses sections 2.3.S.4 and 3.2.S.4.

关于原料药控制的常见问题可分为四大类。这些类别包括：杂质的控制（即有机杂质、无机杂质、残留溶剂和残留试剂）、原料药鉴别、物理特性控制以及分析方法学。审核者评估2.3.S.4 和 3.2.S.4后，针对每一大类会涉及到的常见问题进行论述。

Control of impurities 杂质控制

The authors noted above that two common question topics regarding the drug substance are polymorphism and DMF inadequacy. Other than these two, the most commonly asked question regards control of impurities. Impurity controls are critical for ensuring the quality of the drug substance. The control of impurities is directly linked to the route of synthesis, choice of solvents, and other reagents used in the synthesis. This control is also essential to developing a good understanding of the drug substance manufacturing process.

上面已经指出，关于原料药两种常见的问题是多晶型现象和DMF的缺陷。除了这两个之外，最常问到的问题就是杂质的控制。杂质控制对于确保原料药的质量非常关键。杂质的控制直接关系到合成路径、溶剂的选择以及在合成中用到的其它的试剂。这种控制对于开发出一种好的原料药的生产工艺也很有必要。

Generally, organic impurities should be in line with the DMF holder’s criteria; however, compliance with United States Pharmacopeia (USP) monographs and the ICH Q3A(R2) guideline on impurities in new drug substances is crucial in providing justification (4). For details, the sponsor is referred to the OGD guidance on impurities in drug substances (5). For non-USP articles, other compendia (e.g., European Pharmacopoeia (EP) or Japanese Pharmacopoeia (JP)), comparison to the reference listed drug (RLD), or safety studies may be used to justify limits for impurities. For highly toxic impurities (e.g., genotoxic, carcinogens). Additional considerations such as those found in the draft CDER guidance on genotoxic impurities are necessary in providing justification (6). It is advocated that the unidentified and unspecified impurities be controlled at the recommended ICH Q3A (R2) threshold (5). It is also recommended that documentation be provided to demonstrate efforts made toward identifying the impurities based on the synthetic process before classifying them as unidentified or unspecified impurities.

一般来说，有机杂质应符合DMF持有者的标准。然而符合USP和ICH Q3A（R2）关于新原料药杂质的指南对提供合理说明是至关重要的。具体的情况，申报者可参考仿制药办公室（OGD）关于原料药杂质的指南。对于非USP的品种，与其它的药典（如EP或JP）、参比制剂或安全性研究相比较，也可用于证明杂质的限度。对于毒性高的杂质（如基因毒性、致癌物），必需另外考虑CDER（医药审评和研究中心）指南中关于基因毒性杂质的草案，来提供有利的证明。提倡按照ICHQ3A推荐的限度对未鉴定的和非特定杂质进行控制。还推荐提供文件来证明，在将这些杂质归为未鉴定的和非特定杂质之前，根据合成工艺识别这些杂质做出的努力工作。

Residual solvents are directly linked to the synthetic process and, as such, should be controlled based on the criteria in ICH Q3C (impurities in residual solvents) and USP<467>(7,8). However it is recommended that the DMF holder and the sponsor have a complete understanding of the effect of the residual limits on product quality rather than accepting the limits recommended in ICH Q3C and USP < 467>. If the sponsor wishes to set a less stringent limit, they need to justify it adequately. Additional guidance for CMC reviewers and industry is also found in the OGD questions and answers on residual solvents in ANDAs document and the CDER guidance on residual solvents (9, 10).

残留溶剂直接关系到合成工艺，而且应该按照ICHQ3C（残留溶剂杂质）和USP<467>的标准控制。然而，建议DMF持有者和申报者对残留限度对产品质量的影响有一全面的了解，而不是接受ICHQ3C和USP<467>中推荐的限度。如果申报者希望设定一个宽松的限度，他们需要有足够的理由来证明。对于CMC（Chemistry, Manufacturing, and Controls 化学、制造和控制）部分审核者和企业来说，其它的指南也可在仿制药办公室（OGD）的关于ANDA文件中残留溶剂问答和CDER（医药审评和研究中心）关于残留溶剂的指南中找到。

Specific questions are often asked with regard to residual metals from the synthetic process. The current USP < 231> test and criteria are not comprehensive and do not cover all potential metal impurities that may be present in the drug substance. It is thus recommended that sponsors follow the European Medicines Agency (EMEA) guidance for metal catalysts or the Stimuli article, General Chapter on Inorganic Impurities: Heavy Metals, published in the Pharmacopeial Forum (5) in establishing the specifications (11, 12). Similar to the case for residual solvents, the intended use of the product should be taken into account when proposing a criterion.

经常会问到关于合成工艺中的残留金属这样的具体的问题。现行的USP<231>，测试和标准不太全面，没有涵盖所有可能出现在原料药中的潜在金属杂质。因此建议申报者按照EMEA关于金属催化剂的指南或发表在药典论坛上的引发文章（关于无机杂质的通则：重金属）来建立标准。残留溶剂也是同样的情况，当建议标准时应考虑到产品的既定用途。

In addition. other inorganic impurities (e.g., cyanide or thiocyante) and reagents (e.g., triethylamine, alkyl halides, etc.) may need to be controlled in the drug substance, and established limits must be justified based on good science. Guidance for setting meaningful criteria may be found in many of the same guidance documents noted throughout this article.

另外，其它的无机杂质（如氰化物或硫代物）和一些试剂（如三乙胺、卤代烷等）在原料药中可能需要控制，而且制定的限度必须依据科学证实合理可行。关于设定有意义的标准的指南可能在本文中提到的指南文件中找到。

Drug substance identity 原料药鉴别

Common questions that arise during ANDA reviews regarding drug substance identity include control of counter ions, stereospecific identity or assay tests. and compliance with USP identity tests.

ANDA审核过程中，出现的关于原料药鉴别的常见问题包括对应离子的控制，立体定向的鉴别或含量测定以及与USP鉴别试验的一致性。

Control of counter ions: In ICH Q6A, test procedures and acceptance criteria for new drug substances and new products. it is recommended that, for drug substances that are salts, the ” … identification testing should be specific for the individual ions. An identification test that is specific for the salt itself should suffice” (13). However, there are cases where quantitative control of counter ions is requested by FDA. This request may be due to the information available regarding the route of synthesis for drug substance based on the DMF. For example, in some cases, an intermediate with a specific counter ion is converted to the final drug with another counter ion. Thus, the chemist may request a quantitative control of the counter ion to establish the completeness and reproducibility of the manufacturing process. The above approach is consistent with our current effort to establish critical control points based on process understanding.

对应离子的控制：在ICHQ6A中，对于新原料和新制剂的测试程序和可接受标准的指南中建议是：对于盐类的原料药，每个离子应有专属的鉴别试验，对于盐本身来说有一专属的鉴别试验应该就足够了。但是在一些情况下，FDA要求对对应离子进行定量控制。这一要求可能是由于根据DMF中原料药的合成路径而定的。例如，在一些案例中，带有特定对应离子的中间体与另一相反的离子转化为最终的药品。因此，为了建立一套完全的重现性好的生产工艺，化学合成人员可能要求对对应离子进行定量控制。以上的方法与我们目前的根据工艺理解建立关键控制点是一致的。

Control of chirality: With respect to identity of chiral compounds, the authors recommend that both ICH Q6A and the CDER guidance on the development of new stereoisomeric drugs be consulted (13,14). ICH Q6A recommends that “drug substances that are optically active may also need specific identification testing or performance of a chiral assay.” In the referenced CDER guidance for stereoisomeric drugs, it is recommended that “applications for enantiomeric and racemic drug substances should include a stereochemically specific identity test and/or a stereochemically selective assay method. The choice of the controls should be based upon the substance’s method of manufacture and stability characteristics” (14).

手性控制：关于手性化合物的识别，建议查阅ICHQ6A和CEDR关于新立体异构体药物开发的指南。ICH Q6A建议：对于具有光学活性的原料药也可能需要专属鉴别试验或手性含量性能测试。参考CDER关于立体异构体药物的指南，其中建议：对映异构体和外消旋体原料药的申请应包括立体化学特异性鉴别试验和/或一种立体化学的选择性分析方法。选择用哪种进行控制应根据原料药的生产方法和稳定性特性。

In many ANDA submissions, suitable tests are not proposed for control of stereoisomeric drug substances, and ‘deficiencies are often cited. A chiral identification is highly recommended for chiral drug substances in addition to the control of chiral impurities. However, if the amount of chiral impurities is significantly high and the drug substance is prone to racemization over shelf life, a chiral assay method may be desirable in addition to identification.

在许多递交的ANDA中，没有提到用合适的测试来控制立体异构体原料药，因此经常会被提出缺陷。强烈建议手性原料药在控制手性杂质时加入手性鉴定。但是，如果手性杂质的量明显的高而且原料药在有效期内倾向于外消旋化，除了鉴别以外，加上手性含量方法应是可取的。

Identity Tests for USP Artides: Often, alternate identity tests are proposed for drug substances that are official USP articles. We reference the USP General notices, section 5.40 Identification Test, specifically noting that the “failure of an article to meet the requirements of a prescribed Identification test may indicate that the article is mislabeled” (7). It is recommended that the USP identity tests are part of the proposed drug substance specifications.

USP物质的鉴别测试：通常，对于正式USP中的原料药，建议选择其中一个鉴别测试。我们参考USP通则5.40鉴别试验部分，明确指出：如果一种物质不符合法定的鉴别测试要求，可能表明不是该物质。建议将USP鉴别试验做为原料药标准的一部分。

Physical attributes of the drug substance 原料药的物理属性

Partide size: Reviewers may ask questions regarding control of particle size when particle size of the active pharmaceutical ingredient (API) has a significant effect on the manufacturability of the drug product and its performance. There are also APIs that are prone to agglomeration, thus requiring particle-size control. It is recommended that the firms report the distribution and ranges, if possible. A soon-to-be published paper will provide regulatory perspectives on particle size specifications (15).

Polymorph: See above.

粒径：当API的粒径大小对制剂的可制造性以及性能有显著的影响时，审核者会就粒径控制提出问题。也有的API易于结块，因此也需要控制粒径大小。建议公司如有可能要报告出粒径分布及其范围。即将发表的一篇论文将提供有关粒度规范的监管观点（15）。

多晶型问题：参见上面所论述的要求。

Water content: Based on the nature of the drug substance, water content may or may not be a CMA. However, the ANDA sponsor needs to justify the proposed control. Water content becomes a critical control for drug substances, which may be present in any of a variety of forms: anhydrous or one of several hydrated forms, and a specific hydrate is used. In such cases, a range may be proposed. For hygroscopic drugs, the water content may be critical in determining the impact on the manufacturability of the product.

水分：根据原料药的特性，水分可能是，也可能不是关键物料属性（CMA: critical material attributes）。然而，ANDA申报者需要对建议的控制给出正当的理由。水分成为原料药的一项关键控制项目，这可能出现在多种形式下的任何一种：所用的是无水的或一个到几个水合的形式以及是具体几水合物。在这种情况下，可能建议有一个范围。对于具有吸湿性的药物，水分可能在确定对制剂的可制造性的影响方面很关键。

Analytical methods related to the drug substance 关于原料药的分析方法

Verification of compendial methods: If a compendial analytical method is used, the ANDA sponsor is not required to provide complete validation. However, documentation of suitability of use needs to be established based on 21 CFR 211.194(a)(2) of the current good manufacturing practice (CGMP) regulations, which states that “the suitability of all testing methods used shall be verified under actual conditions of use” (16). ANDA sponsors are requested to refer to USP<1226>for verification of compendial methods (8).

药典方法的确认：如果使用药典的分析方法，那么不要求ANDA的申报者提供完整的验证。但是，需要根据美国联邦法规21 CFR 211.194(a)(2)中CGMP法规的要求应建立使用适用性文件，法规中指出“所有的测试方法适用性应在实际使用的条件下得到确认”。要求ANDA申报者参照USP<1226>对药典方法进行确认。

USP methods versus in-house methods: In cases where there is an USP monograph for the drug substance and the sponsor decides to use an in-house method, a comparison to demonstrate the equivalence of the methods is considered valuable. Again, the impurity profile of the API used by the sponsor may be significantly different from the source of the USP monograph, based on the synthetic route. Thus, it is important to demonstrate that the USP method is capable of separating all the possible process impurities and degradants since in the event of any dispute the USP method is considered the method of resolution.

USP方法与内控方法的比较：如果USP中有原料药的方法，而申报者决定采用内控的方法，要进行对比以证明方法的等效性。另外，根据合成的路径，申报者使用的杂质谱可能与USP方法中的有明显差异。因此，重要的是要证明USP方法可分开所有可能的工艺杂质和降解物，因为遇到任何争议时，USP方法是认为解决问题的方法。

Adoption of DMF holder’s method: ANDA sponsors frequently state that they have adopted the DMF holder’s methods for analysis of the drug substance and refrain from providing the details of validation. It is acceptable to adopt the DMF holder’s methods for analysis of the API. However, because the ANDA is a standalone document, the information regarding validation of the method needs to be complete. The sponsor may provide details of the validation from the DMF holder with additional information regarding its own verification of the method.

采用DMF持有者的方法：ANDA申报者常常声明他们采用DMF持有者的方法来分析原料药并且不提供验证的细节。采用DMF持有者的方法来分析API是可以接受的，但是，因为ANDA是一个独立的文件，关于方法验证的信息应该是完整的。申报者可以从DMF持有者处提供验证的细节并且附加自己对方法的确认的信息。

HPLC method versus titration for assay of the active pharmaceutical ingredient: It is generally recommended that a specific, stability indicating procedure is included for assay of the API. In many cases it is possible to employ the same procedure (e.g., high-performance liquid chromatography) for both assay of the API and quantification of impurities.

In some cases where use of a nonspecific assay is justified, other supporting analytical procedures should be used to achieve overall specificity. For example, where titration is adopted to assay the drug substance, the combination of the assay and a suitable impurities test could be used. However, there may be occasions, when a non-specific titration assay is not preferred due to the inherent nature of the API and the impurities. For example, when the API is basic in nature and so are most of the impurities, a perchloric acid titration may yield to a “false-high” assay result due to non-specific titration of the API and the major impurities. In these cases, the ANDA sponsors may be requested to revert to a specific assay method.

API的含量测量：HPLC方法与滴定方法的比较

API的含量测定通常推荐用专属的、具有稳定性指示性的方法。很多情况下，有可能API的含量测定与杂质的定量采用相同的程序（如高效液相色谱法）。

在一些情况下，使用一种非特异性的检测是合理的，应用上其它配套的分析程序以实现整体的特异性。例如，采用滴定法来测定原料药，可以结合使用含量和适当的杂质检测方法。但是，有时候由于API和杂质固有的特性，非特定性的滴定分析不是首选。例如，API和大多数的杂质性质类似，由于API和主要杂质的非特异性滴定，高氯酸滴定液可能产生一个“假高”的分析结果，在这样的情况下，可能要求ANDA申报者改成使用一种特异的分析方法。

Reporting results: ANDA sponsors frequently report results of analysis as “conforms” versus providing the quantitative figures. This may only be acceptable in case of limit tests. In all quantitative analysis, results above limit of quantitation need to be reported accurately.

Occasionally, sponsors provide quantitative values that are below the limit of quantitation (LOQ). We recommend that sponsors in these cases not report numerical values below the LOQ, as they have minimal significance. Additionally, the limit of detection (LOD) and limit of quantitation (LOQ) should be provided for all methods used to control impurities and residual solvents in the API.

结果报告：ANDA报告分析结果时通常会使用“符合规定”，而不是提供确切的数值。这可能仅仅在限度测试时是可以接受的。在所有的定量分析中，定量限之上的结果需要准确的报告。

少数情况下，申报者要提供定量限以下的数值。我们建议申报者在这些情况下不必报告定量限之下的数据，因为他们没有什么意义。另外，应提供API中用于控制杂质和残留溶剂的所有方法的检测限和定量限。

2.3.S.5 Reference Standards 标准品

Most ANDA sponsors provide satisfactory information when it comes to API reference standards. However, one common deficiency is cited with respect to the impurity reference standard used in the proposed methods and/or the standards used during method validation. The sponsor should provide at a minimum the source, lot number, and purity of the impurity standards. This information is often found in the method validation report. and if this is the case, a reference to the relevant section or report can be provided in section 2.3.S.5.

提到API的标准品，大多数的ANDA申报者都能提供符合要求的信息。然而，谈到用于建议方法中的杂质标准品和/或在方法验证中用到的标准品，一个常见的缺陷经常被提及。申报者至少应提供来源、批号、杂质标准品的纯度。这些信息经常可以在方法验证报告中找到。如属这种情况，有关章节或报告可参阅2.3.S.5部分。

Two other common questions from the reviewers’ regard standard spectra and revision of secondary or qualified standard specifications. Representative spectra and chromatograms should be provided for reference standards used. With respect to revision of secondary or qualified standards, any applicable changes to the drug substance specifications should be made to the specifications of the reference standard. An additional recommendation is that reference standards meet all relevant acceptance criteria.

审核者提到的其它的两个常见问题是关于标准光谱和二级或确认标准品规范的修订。应提供所用的标准品的代表性的光谱和色谱图。对于二级标准品或确认标准品规范，如果与原料药规范不同，应制定相应的标准品规范。另外，标准品应满足所有相关的接受标准。

2.3.S.6 Container Oosure System and 2.3.S.7 Stability

2.3.S.6容器密闭系统和2.3.S.7稳定性

With respect to the last two sections of 2.3.S, questions are not routinely asked as these portions usually reference the associated DMF(s). Questions that do arise regarding the drug substance container closure systems (section 2.3.S.6) are often prompted by “repackaging” of the drug substance by the ANDA sponsor. This action shifts the responsibility of storage and stability of the drug substance from the DMF holder to the ANDA sponsor, and the sponsor may have to provide detailed information and justification for the proposed container closure system and its effect on the drug substance’s stability. Stability studies used to support the container closure system should be included in sections 2.3.5.7 and 3.2.5.7 of the ANDA. Additionally, if storage conditions differ from what is recommended (e.g. temperature, inert atmosphere, etc.) and/or justified by the DMF holder, drug substance stability data are recommended to support the conditions.

关于2.3.S的最后的两个部分，问到的问题并不象这些部分中惯常地那样是涉及相关的DMF。关于原料药容器密闭系统2.3.S.6部分，确实出现的问题通常由ANDA申报者对原料药的重新包装引起。这一行为改变了由DMF持有者提供给ANDA申报者的原料药的储存条件和稳定性，而且申报者可能得需要对建议的容器密闭系统以及它对原料药稳定性的影响提供详细的信息和正当的理由。用于支持容器密闭系统的稳定性研究应包括在ANDA的2.3.S.7部分和3.2.S.7部分。另外，如果储存条件与所推荐和/或由DMF持有者证实的有所区别（如温度，惰性气体等等），建议用原药料的稳定性数据来支持这些条件。

An additional question that arises in section 2.3.S.7 asks the ANDA sponsor to provide the justification for the retest or expiry date if these are not supported by the DMF holder information provided. For example, if the DMF holder certificate of analysis reports a 2-year expiry date and the ANDA sponsor lists a 5-year retest date, the discrepanc will need to be clarified and justified. Sometimes, based on DMF review, the chemist is aware that the expiration date proposed by the DMF holder is not justified by the information submitted in the DMF. In these cases, the deficiency cited to the ANDA sponsor may be commensurate to that cited by the DMF holder.

出现在2.3.S.7部分的另一个问题是，如果DMF持有者的信息没有提供复验或有效期的这些支持，要求ANDA申报者对其提供正当的理由。例如，如果DMF持有者检验报告上是2年的有效期而ANDA申报者列出的是5年的复验日期，则需要澄清该差异并且要提供合理性依据。有时，根据DMF的审核结果，化学家了解到DMF持有者建议的有效期从提交的DMF中的信息中不能证明。在这种情况下，对ANDA申报者提出的缺陷可能与DMF持有者的相称。

Condusion 结论

It is well known that successful development of a drug product begins by understanding the drug substance’s physico-chemical characteristics as well as adequate control of the properties. which are critical to the drug product’s quality, efficacy, and safety. The authors hope that the information provided in this article will shed some light on the common deficiencies cited during the review of ANDAs. The information provided herein is intended to assist ANDA sponsors in building quality into their submissions so that they may convey meaningful drug-substance information to FDA, with the goal of reducing instances of these common deficiencies from being cited.

众所周知，成功的开发一种制剂源于深刻的了解原料药的物理化学特性以及充分控制那些对制剂的质量、有效性和安全性都至关重要的属性。希望本文中提供的一些信息可以让大家看到ANDA审核过程出现的常见缺陷。这些信息旨在帮助ANDA申报者提高其申报的质量，这样他们将把有意义的原料药信息传达到FDA，起到减少这些常见缺陷的目的。

Numbering in section heads correspond to those in the Common Technical Document (CTD).

分段编号与通用技术文件（CTD）中的编号相对应

Acknowledgment 致谢

The authors wish to acknowledge Lawrence Yu, PhD, OGD Deputy Director for Science, and Vilayat A. Sayeed, PhD, Director Division III, OGD, for their encouragement and invaluable insight.

感谢仿制药办公室（OGD）科学副主任Lawrence Yu博士和 仿制药办公室第三部门主任Vilayat A. Sayeed博士的鼓励和宝贵建议

Disdaimer 免责声明

The views and opinions expressed in this article are only those of the authors and do not necessarily reflect the views or policies of FDA.

本文所表达的观点仅代表作者个人观点，并不代表FDA的观点或政策

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10.FDA, Guidance jor Industry, Residual Solvents in Drug Products Marketed in the United States (Rockville, MD, November 2009).

11.EMEA, Guideline atJ the Specification Limits for Residues of Metal Catalysts or Metal Reagents, Committee for Medicinal Products for human Use (CHMP), European MedicirlCs Agency (Doc. Ref. EMEA/CHMP/SWP/4446/2000), Feb. 21, 2008.

12.USP Ad Hoc AdVisory Panel on Inorganic Impurities and Heavy Metals and USP Staff. “Stimuli to the Revision Process: General Chapter on Inorganic Impurities: Heavy Metals,” Pharmacop. Forum 34 (5). (September-October, 2008).

13.ICH, Q6A, Federal Register: 65(251) (Dec. 29, 2000).

14.FDA. Guidance for Industry, Development oj New Stereoisomeric Drugs (Rockville, MD, May 1992).

15.S. Zhigang et at. Amer. Pharma. Rev., in press.

16.FDA, “21 CFR 211 Current Good Manufacturing Practices for Finished Pharmaceuticals, Subpart J,” [Records and Reports, Sec.211.194 (a) (2) .

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