作者：潘宪伟 来源：药研数据库

Pharmaceutical Technology; FEBRUARY 2011（2011年2月）

Common Deficiencies in Abbreviated New Drug Applications

Part 3: Control of the Drug Product and Stability

Aloka Srinivasan, Robert Iser, and Devinder S. Gill

仿制药申报常见缺陷信解读

第三部分：制剂的控制和稳定性

Chemistry reviewers in the US Food and Drug Administration’s Office of Generic Drugs provide Part 3 of an overview of common deficiencies 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）的化学审评员提供了第三部分的概述，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,* is a team leader, Devinder S. Gill, PhD, is a deputy director, and Robert Iser, M.S., is an acting director, 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，Devinder S. Gill 博士是副主任，医学硕士 Robert Iser 是代理主任。

所有的信件都可以寄给：[email protected]。

As part of the FDA’s Office of Generic Drugs’ (OGD) ongoing effort to streamline the review process and reduce the number of deficiencies cited for the applications, a series of articles are being published to provide transparency and clarity to applicants submitting applications in the Question-based Review (QbR) format. The articles highlight the need and significance of science based justification in establishing drug substance (DS) and drug product (DP) specifications, in-process controls for both DS/DP, choice of formulation, selection of a product design and selection of the manufacturing processes. Part 1 of this series, which dealt with the deficiencies cited in the drug substance section, was published in January 2010 (1). Part 2 of the series dealing with drug product composition and excipients was published in August 2010 (2).

作为美国食品和药物管理局（FDA）的一部分，仿制药办公室（OGD）正在努力简化审评流程和降低审评中缺陷的数量，目前正在发表一系列文章，为“以基于问题审查（QbR）格式”提交申请的申请人提供透明度和清晰度。在建立原料药（DS）和制剂（DP）质量标准、过程控制、处方选择、产品设计选择，和生产工艺选择中，这些文章强调了科学论证的必要性和重要性。ANDA申报常见缺陷系列第1部分发表于2010年1月，是关于原料药部分提到的缺陷；第2部分发表于2010年8月，是关于药品组成和辅料方面的缺陷。

本文的意图是阐明，以通用技术文件（CTD）和基于问题审查的质量总体概述（QbR-QOS）格式为指南，在递交简化新药/仿制药申请（ANDAs）中，引用的制剂（3.2.P.5）和稳定性（3.2.P.8）部分的，一些常见缺陷的意图和重要性。这不是一个包含所有关于药品质量标准和药品稳定性的评论和缺陷的列表，但包括了经常被引用的问题。

1. The specifications of the drug product provided in the QbR–QOS and the body of data do not match. Please clarify your proposed release and stability specifications for the drug product.QbR-QOS（基于问题的审核-质量综述）中所提供的制剂标准与主体数据中不一致。请阐明你提议的制剂放行和稳定性标准。
2. The limit for specified impurity X in the drug product is not acceptable as it is listed as a process impurity and should be controlled at no higher than that proposed in the drug substance. Please revise or justify.

   制剂中特定杂质X的限度不能接受，因为该杂质列为工艺杂质，不应该控制得高于原料药中所提议的限度，请修订或确认。

3. Impurity X is a known degradant of the drug product and its level is increasing during shelf life. Thus we request that you set tighter limit of this impurity in release to assure the meeting of regulatory criteria during shelf life.

   杂质X是制剂的已知降解产物且在货架期是增长的，那样我们要求你们在放行标准中设定较严格的限度以保证在货架期内符合监管标准。

4. The limit proposed for Impurity X in release and stability of the drug product is wider than that recommended by ICH Q3B (R2) qualification threshold. Please tighten the limit or justify the proposed limit based on analysis of several lots of RLD, close to expiration date.

   制剂的放行和稳定性中杂质X所提议的限度较Q3B（R2）所推荐的质控限度较宽，请严控限度或根据多批近效期的参比药物的分析来确认限度。

5. In view of the chiral nature of the active pharmaceutical ingredient in your drug product, we request you to include controls for the enantiomer and the relevant diastereomers. We also request you to include chiral identification as a routine release test.

   因为你的制剂中原料药的手性属性，我们要求你包含对映体和相关非对映体的控制，我们同样要求你们包含手性鉴别作为例行放行检测。

6. We request you to include a quantitative control for the color of your drug product with adequate justification.

   我们要求你们包含你的制剂颜色的定量控制，并提供充分理由。

7. Please establish a criterion for reconstitution time based on a comparison with the RLD product.

   请根据与参比药物的比较来建立重构/复溶时间的标准。

8. Your proposed disintegration time in release and stability is different from that proposed in the in-process control during the manufacturing of the drug product. Please revise or justify.

   你们所提议的放行和稳定性的崩解时限与制剂生产的工艺控制标准不一致，请修订或确认。

9. Based on the fact that your tablets are scored, please submit data demonstrating uniformity of dosage on each half of the tablet. Please also submit data to demonstrate that the score depth is suitably to evenly split the tablets.

   根据你们片子是刻痕的事实，请提交数据证实每半片的剂量均匀性，同时请提交数据证实刻痕深度适合于平均分割片剂。

10. Please justify the proposed water content criteria in the drug product release and stability specifications and the also provide the reason for relaxing the criterion for stability samples compared to release.

    请提供制剂放行和稳定性标准中所提议的水分标准的理由，并同时提供放宽相比于放行标准的稳定性样品的限度的原因。

11. The formulation for your drug product contains significant amounts of excipients which make it susceptible to microbial growth. Thus, we request that you include microbial controls for the release and stability of your product. Alternatively, you may conduct a one time test for water activity on stability samples of the drug product or demonstrate by a suitable method that your formulation does not support microbial growth.

    你的制剂处方含有大量的容易使微生物生长的辅料，因此，我们要求你们在你们产品的放行和稳定性中包含微生物控制，或者，你也可以对制剂的稳定性样品的水活性进行一次性检测或通过适宜方法来证实你们的处方不支持微生物生长。

12. Based on the formulation, please include a control for the osmolarity of the drug product based on comparison with the reference listed drug product.

    根据处方，请基于与参比制剂比较而包含制剂的渗透压控制。

13. Please include a control of p-hydroxybenzoic acid in the release and stability specifications of the drug product in view of the fact that methylparaben has been used as a preservative in the formulation.

    因为处方中使用了对羟基苯甲酸甲酯作为防腐剂，所以请在制剂的放行和稳定性标准中增加对羟基苯甲酸的控制。

14. Please include a justified control for viscosity and redispersibility of your oral suspension.

    请在你的口服混悬剂中包含粘度和再分散性的合理控制。

15. In view of the fact that the formulation of your oral suspension has shown a tendency of crystal growth on storage, we recommend a control of particle size during analysis of release and stability samples.

    因为你的口服混悬剂处方显示在贮藏中有晶体生长的趋势，我们建议在放行和稳定性样品的分析中对粒径进行控制。

16. Please add controls in the release and stability specifications of your multilayer tablet, to ensure the tablet integrity over shelf life.

    请在你们的多层片的放行和稳定性标准中增加控制以确保在货架期内片子的完整性。

17. Please provide results of analysis of all exhibit lots of the drug product.

    请提供制剂所有展示批的分析结果.

18. The label for the reference listed drug states that the patient may dissolve the drug product completely in one teaspoon of water in one minute and drink it. Please provide information to establish that your product meets this criterion. We recommend that a control be introduced in release and stability to ensure that the drug product is completely dissolved in water in one minute throughout the product shelf life.

    参比药物的标签表明病人可以将药物制剂在1分钟内完全溶于1汤匙水中饮用，请提供确定你们产品符合该标准的信息，我们建议在放行和稳定性中引入此项控制以保证产品在货架期内制剂可以在1分钟内完全溶于水。

19. Please provide information that the process impurities, possible in the drug substance, are separated from the parent peak and other degradants in your methods related to the drug product.

    请提交有关原料药中潜在的工艺杂质在你们制剂的方法中可以与主峰和其他降解产物分离的信息。

20. Based on Division of Bioequivalence recommendation regarding the dissolution specification, provide revised specification for drug product release and stability testing, a revised certificate of analysis and revised stability data sheets to reflect the recommended dissolution method and specifications. We also request you to test the third month accelerated stability samples to establish that your product meets the proposed dissolution specification.

    根据BE部门关于溶出度标准的建议，提供制剂放行和稳定性检测的修订标准，修订的检验报告书和修订的稳定性数据表以反映推荐的溶出度方法和标准。我们同样要求你们检测加速试验第3个月的样品以建立你们产品符合所提议的溶出度标准。

21. You have provided comparative assay and impurity profiles between your product and the reference listed drug under accelerated conditions to justify your drug product release and stability acceptance criteria. Since accelerated storage conditions are not the normal storage conditions for the drug product, it is recommended that comparative batch analysis data be conducted at controlled room temperature conditions to demonstrate similar behaviors between your drug product and the reference listed drug.

    你们已提供你们产品和参比药物在加速条件下的含量和杂质谱对比数据来确认你们制剂放行和稳定性可接受标准，因为加速贮藏条件并不是该制剂正规的贮藏条件，建议进行在控制室温条件的对比批分析数据来证实你们的制剂产品和参比药物具有相似行为。

22. Based on the fact that semi-permeable containers have been used in packaging of your drug product, please include a control for water loss in the stability specification.

    因为你们的制剂采用了半通透性容器作为包装材料，请在稳定性标准中包含水分流失的控制。

23. Indicate any special studies conducted to support stability specifications such as data for drug product after constitution, combination with admixtures and/or under other conditions that occur when the drug product is administered according to the labeling instructions.

    指明所进行的任何特定研究以支持稳定性标准，例如制剂在复溶后、与外加剂混合和/或在当制剂按照说明书指示服用时的其他条件下的研究数据。

24. Based on the intended use, please provide information regarding any cycling studies (freeze-thaw and heat-cool studies) and photostability studies that were conducted for your drug product.

    根据目的用途，请提供你们制剂的关于循环研究（冻-融和热-冷研究）和光照研究的信息。

25. Please be informed that based on trends observed in the accelerated stability data, the expiry date for this product will be based solely on the accumulated full long-term stability data.

    请了解基于加速试验数据观察的趋势，产品的有效期应完全基于累积的全面长期稳定性数据。

**Comments are usually not deficiencies and are found in section B of deficiency letters评论通常不是缺陷，见缺陷信的B章节项下

The P.5 sections of the QbR–QOS and the body of data, in submitted ANDAs, should include all the proposed controls for routine analysis of the drug product batches including the proposed specifications, analytical methods with associated validations, batch analysis data for exhibit batches, and justifications for all proposed criteria. Much of the information provided in this section is relevant to both release testing (P.5) and stability or shelf-life testing (P.8). We will address the stability section later in the article.

The QbR–QOS includes two sets of questions with respect to control of the drug product. The questions are as follows:

• What is the drug product specification? Does it include all the critical drug product attributes?
• For each test in the specification, is the analytical method(s) suitable for its intended use and, if necessary, validated? What is the justification for the acceptance criterion?

在递交ANDAs时，QbR-QOS（基于问题的审核-质量综述）的P.8部分和主体数据应包括对药品批次进行常规分析的所有拟议控制，包括拟定质量标准、相关验证的分析方法、展示批的批分析数据和所有拟定标准的制定依据。本节提供的大部分信息都与放行检验（P.5）和稳定性或货架期/有效期检验（P.8）相关。我们将在本文后面讨论稳定性部分。QbR-QOS包括两组关于药品控制的问题。问题如下：

• 制剂的质量标准是什么？该质量标准是否包含了制剂的所有CQAs（关键质量属性）？
• 对于质量标准中的每项测试，分析方法适用于预期的用途吗？如果必要，进行方法学验证？可接受标准的制定依据是什么？

The intent of the first set of questions is for the applicant to provide the specifications for routine release testing of the drug product; and to ensure that all critical drug product quality attributes are included in the specifications. The critical quality attributes (CQA) are linked to the intended use, function and performance of the product and are chosen based on the desired quality target product profile (QTPP). The CQAs may be based on compendial specifications and/or the attributes of the reference listed drug (RLD); and also information in the associated labeling. Development studies may be conducted by the ANDA holder to assure that the drug product meets the attributes of identity, purity, potency, assay, and quality. Examples of typical CQAs for solid oral and solution dosage forms are provided in ICH Q6A (3) and the QbR–FAQ (4).

第一组问题的目的是让申请人提供药品常规放行检测的规范，确保质量标准中包括药品所有关键质量属性。关键质量属性（CQA）与药品的预期用途、功能和性能相关联，并根据期望的产品目标质量概况（QTTP）进行选择。CQAs可能基于药典质量标准和/或参考上市药物（RLD）的属性，以及相关标签中的信息。ADNA持有人应进行开发研究工作，以确保药品满足鉴别、纯度、效能、含量和质量特性。口服固体和溶液剂型的典型CQAs的例子，见ICH Q6A和QbR-FAQ。

根据ICH Q6A，质量标准的定义为“由一系列的检测项目、有关分析方法和认可限度组成，这些认可限度以数值限度、范围或其他描述来表示。它建立了一套新原料药和制剂都必需遵循的、与其用途相适应的认可标准”。根据这个定义，其相关信息可通过图表形式或清单形式进行列举出来，包括检测项目、可接受标准、分析规程等。一个非常常见，应始终避免的缺陷是，QbR-QOS（CTD模块2.3）中列出的规范/质量标准与主体数据（CTD模块2.2）之间不一致。两套质量标准必须一致。如果不一致，审评专家将无法确定哪一个才是产品的最终拟定标准。质量概述（QOS）中提供的信息应该主体数据中详细信息/资料的总结。

其它评论和缺陷，适用于 与药品控制相关的具体类别，包括杂质和降解产物、特定剂型的特有控制，和分析方法

Impurities/Degradation products. 杂质和降解产物

There are a number of common deficiencies with respect to impurities and degradation products in the drug product. These include inappropriate criteria and unacceptable justifications.

关于成品中杂质/有关物质方面的缺陷比较常见，包括：不恰当的标准和不可接受的依据。

Poor justification for the proposed degradation product is another common area where deficiencies are being cited. There are a number of ways to justify specified degradation product criteria including the following, which are not reported in any specific order:

在成品质量标准的建立过程中，产品的工艺杂质往往易出现缺陷，通常情况下，建议按照ICH Q3B（R2）中的界定限（QT）对所有杂质设定可接受标准，该指南也适用于降解产物。但是，如果杂质仅仅是原料药合成路线中产生的（如合成工艺杂质），则不能遵循此法则；如果制剂产品中含有这方面的杂质，且为特定杂质，则其限度不能高于原料药的质量限度。

所提议的降解产物限度的制定依据不足是另一个被提及缺陷的常见领域。产品中降解杂质限度的合理性可通过以下几种方式来论证，未按任何特定顺序报告：

• Specified impurity limits are in-line with US Pharmacopeia (USP) monograph criteria for specified impurities.

  特定杂质限度可与USP对应的专论中的限度标准一致

• Acceptance criteria are in-line with the qualification threshold (QT) recommended in ICH Q3B(R2) and ANDA Guidance: Impurities in Drug Products (draft) (5, 6) as long as there are no safety concerns. The guidance for calculation of the QT using recommended percentage or total daily intake of specified impurities, whichever is lower, should be followed.

  可接受标准的质控线（QT）可参考ICH Q3B（R2）和ANDA关于制剂产品的杂质指南（草案）进行控制，但前提是无安全性问题或隐患。指南中关于QT的计算一般是采用百分比或最大日服用量来控制，取其中的最小值

• Qualification of the proposed criterion may be based on the following:

• Level of impurity observed in the reference listed drug (RLD). Data from multiple batches of the RLD at or near expiration date may be provided for qualification.
• Significant human metabolite of drug substance. Literature references should be provided to verify that the compound is a significant human metabolite.
• Scientific literature: as long as there are no safety concerns with respect to the intended use.

• 拟议标准的界定限度，可以参考以下几个方法建立：

• RLD中检测到的杂质水平。建立采用多批RLD进行综合考虑，也可检测临近效期的RLD杂质水平情况进行考虑

• 杂质是主成分的重要代谢产物，应有文献支持证明其为人类重要代谢产物

• 科学文献：关于它的使用范围应没有安全性的报道

• Impurities that are structural alerts for genotoxicity need to be controlled at the Threshold of Toxicological Concern (TTC) of 1.5 μg/day, as found in the European Medicines Agency (EMA) and draft FDA guidance (7, 8). However, a higher limit may be proposed based on safety studies demonstrating that the proposed limit does not pose a safety concern. These studies are typically consulted to reviewers in the Pharmacology–Toxicology division.

  对于具有基因警示结构的杂质，应控制在毒理学关注阈值（TTC）1.5μg/day以下，具体可参考EMA或FDA相关指南。但如果有安全性试验能证明高于1.5μg/day的限度也是安全的，则也可以采用这一限度。这些研究通常要提供给药理学-毒理学部门的审评员参考

对于非特定杂质（unspecified impurities），它们的限度应不高于ICH Q3B（R2）中的基于最大日服用量而建立的鉴定限（IT）。需注意的是，如果USP中有提到某个或某些非特定杂质（“any impurity”或“any other impurity”）的限度，那么建议采用ICH的鉴定限（IT）标准，而不是药典限度标准。

An additional area that may lead to a deficiency is the setting the same criteria in both the release and stability specifications for a degradation product, where there is an increasing trend during stability studies. If an upward trend is observed, it is recommended that the criteria in the release specifications are set tighter so as to provide better quality assurance that all manufactured batches meet the regulatory criteria throughout the product life cycle.

另一个可能导致缺陷的方面是，在稳定性研究过程中有增长趋势时，降解产物的放行标准和稳定性标准仍设置相同的限度。如果发现在稳定性研究的过程中降解产物有增长趋势，则产品的放行标准应该比稳定性标准更严格，从而提供更好的质量保证，确保所有生产批次在整个产品生命周期内符合法规标准。

Stereoisomeric drug products. 立体异构的药物产品

This is a class of drug products which has been gaining ground over the last two decades. With great strides made in the field of analytical separations and also chiral reagents, use of a specific enantiomer is becoming more of a norm in the field of pharmaceuticals. Insufficient information in the application may lead to deficiencies being cited.

这是一类在过去二十年里不断发展壮大的药品。随着分析分离和手性试剂领域的巨大进步，特定对映体的使用在医药领域正变得越来越普遍。申请资料中未提供充分的信息，可能会导致缺陷的产生。

There are two significant guidance documents which may be followed regarding chemistry and manufacturing controls for stereoisomeric drug products, Development of New Stereoisomeric Drugs (9) and ICH Q6A (3). Decision Tree 5 in ICH Q6A summarizes the requirements for the chiral drug substances and drug products.

关于立体异构体药物的化学和生产控制，有两个重要的指导文件可以遵循：新型立体异构药物的开发（9）和ICH Q6A（3）。ICH Q6A决策树5对手性原料药和药物产品的要求进行了总结。

Control of the chiral impurities. 手性杂质的控制

It is preferable to include controls for the enantiomer and also diastereomers in the drug product within the constraints of sensitivity of the analytical procedure, unless adequate pharmaceutical development studies demonstrate that racemization or epimerization is not a possibility during the manufacturing or storage of the drug product. The limits for the chiral impurities may be justified by comparison with the RLD product, published literature or safety studies.

最好将对映体和非对映体的控制纳入分析程序的灵敏度范围内，除非有充分的药物开发研究表明，在药品的生产或储存过程中不可能发生外消旋或差向异构化。通过与RLD产品比较、已发表的文献或安全性研究，论证手性杂质的限度的合理性。

Chiral assay. 手性含量

In cases where racemization is found to be insignificant or a very small amount of chiral impurities are expected to be present, a non-chiral assay may be considered sufficient as a control. However, if the active pharmaceutical ingredient (API) is prone to racemization or formation of other diastereomers during the manufacturing or storage of the drug product, a chiral assay is preferable.

如果发现外消旋作用不明显或预期会出现少量手性杂质，采用非手性含量控制即可。但是，如果活性药物成分（API）在药物产品的生产或储存过程中容易外消旋或形成其他非对映体，则首选手性含量方法。

Stereospecific identity. 立体定向鉴别

The agency’s guidance, Development of New Stereoisomeric Drugs (9), states that drug products which contain enantiomers should have a discriminatory identification test. This is especially important when the racemate of the API is present in an approved drug product. Under such circumstances, a stereospecific identification test is requested, as it clearly demarcates between the enantiospecific drug product and the one containing a racemate.Another scenario in which a stereospecific identification test is desirable is when the drug substance is prone to racemization under the proposed manufacturing process and storage conditions of the drug product.

指南“新型立体异构药物的开发（9）”指出，含有对映体的药品应进行有辨识力的鉴别试验。在已批准药品的原料药中，存在外消旋化时，这一点尤为重要。在这种情况下，需要进行立体特异性鉴别试验，因为它能清楚地将对映体特异性药物产品与含有外消旋体的药物产品区分开来。另一种需要进行立体特异性鉴别试验的情况是，在建议的药品生产工艺和储存条件下，原料药容易发生外消旋。

Additional issues with drug product controls and information. 药品控制和信息的附加问题

The following is a discussion of other common deficiencies that are related to inadequate controls or justifications and missing information with respect to the drug product.

以下是对其他常见缺陷的讨论，这些缺陷与药物产品的控制或理由不足以及信息缺失有关。

Identification.鉴别

Identity testing of the drug product is a required quality requirement, as well as, a cGMP requirement (10). Most products include a satisfactory test for identity; however, there are cases where deficiencies have been issued based on the fact that another identity test may be necessary, if the proposed identity test is non-specific. In some cases a specific identification test is required, especially when there is a possibility of conversion of the active ingredient into another form (e.g., another salt, polymorph, or stereoisomer) based on the process conditions or during typical storage.

根据cGMP要求（10），产品需要有适当的鉴别实验。事实上大部分产品的鉴别试验也比较符合要求；但是，在某些情况下，如果拟议的鉴别试验是非专属性的，这时会导致缺陷的产生，可能需要进行其它的鉴别试验。对于某些产品，如在生产过程中或常规储存过程中活性成分可能会转变成其它形式（盐型的变化、晶型的变化、立体异构的变化），这时候可能还需要额外的、更具有特异性的鉴定试验。

Color. 颜色

This control may be especially important for solutions. A quantitative control for color based on comparison with the innovator’s product is desirable. A quantitative control for color is often requested for oral solutions and injections, especially where degradation of the API may occur during storage; or where there is evidence that interactions of the API with the excipients, manufacturing equipment or interaction amongst excipients may cause a change in color of the drug product. Again, adequate pharmaceutical development studies demonstrating the absence of these interactions may justify not including a quantitative control for color for solutions.

颜色的控制对于溶液剂、注射剂更为重要，需基于原研药（RLD）的颜色进行定量控制，尤其是API在储存过程中易发生降解的产品。有时，API与辅料、API与生产设备、辅料与辅料之间也会发生相互作用而产生成品颜色的改变。此外，若充分的药物开发研究证明不存在相互作用，可以用于论证不包含溶液剂颜色定量控制。

Reconstitution time. 复溶时间

For products that are intended to be reconstituted, such as powders for injection, a meaningful criterion for reconstitution time should be proposed. In many ANDA submissions this test is either not proposed or the limit is unreasonable based on the observed data, the RLD, or the intended use (e.g. for emergency administration). Most importantly, the limit should be based on a comparison with the RLD product. Additionally, ICH Q6A (3) states that test for reconstitution time can also be omitted based on development studies, however, these studies should be clearly referenced in the appropriate P.5 section.

对于拟进行复溶的产品，如注射用粉剂，应拟定复溶时间的有实际意义的接受标准。在ANDA申请中，很多未规定复溶时间的接受标准；或依据观察到的数据、RLD 或根据拟定用途（如 紧急用药产品），设定的复溶时间限度不合理。最重要的是，应该基于与RLD产品的比较确定限度。此外，ICH Q6A（3）指出，根据开发研究工作，复溶时间的测试也可以省略，但是应在P.5章节的适当位置，说明已进行的研究。

Disintegration.崩解时限

Many submissions include disintegration limits that are not reasonable based on the data and also the intended use. In general, if disintegration testing is included in the drug product release specifications, the criteria should be based on data generated from analysis of the exhibit batches. Also the disintegration time in release and stability should be commensurate with that proposed in the in-process control during manufacturing of the drug product.

If the product is an Orally Disintegrating Tablet (ODT), it is recommended that, in most cases, a criterion of NMT 30 seconds is proposed based on the current guidance (11). However, a higher criterion may be allowed for disintegration time if justified based on comparison to the RLD.

根据申报资料中的数据和产品的实际用途，很多崩解时限要求设定的不合理。一般而言，如果崩解时限在产品的放行标准中，那么它的标准应是基于执行批记录中的数据而设定的。并且，在制剂生产过程中过程控制的崩解时限标准应与放行标准、稳定性标准保持一致。

而对于口崩片（ODT）而言，基于现行的法规（11）要求为不超过30秒，但对于其崩解时限应基于RLD的结果而适当设定更严的标准。

Scoring.刻痕

It is generally required that the scoring configuration of generic tablets be the “same as” that of the reference listed drug. For more information regarding scoring requirement, please refer to the CDER MAPP 5223.2, Scoring Configuration of Generic Drug Products (12). Other sources of information regarding scoring may be obtained in British Pharmacopeia (BP) (13) and a recent USP stimuli article (14).

通常要求仿制片剂的刻痕与参比药物“一样”。关于刻痕要求的更多信息，请参考CDER MAPP5223.2（CDER：Center for Drug Evaluation and Research医药评价和研究中心；MAPP：Manual of Policies and Procedures政策与程序手册） 仿制药制剂的刻痕构造。关于刻痕信息的其他来源可以参考BP和最近的USP stimuli 文章。

Applicants have frequently been asked questions based on the fact that the tablets are scored. In order to ensure the quality of the split tablets, information regarding uniformity of dosage based on content uniformity or weight variation on each half of the tablet is generally requested, based on drug load. Regarding the breakability of the drug product, applicants are often requested to provide the mass loss after splitting. In certain cases, where breakability is in question based on the shape and size of the tablet, the reviewer may also request the applicant to provide the score depth as a fraction of the tablet thickness. For modified release tablets with score, a one time demonstration of the comparability of the dissolution on whole vs. split tablets is recommended. The aforementioned studies on split tablets should be performed during product and process development. As the dosage form becomes more complex, the necessity of routine testing during drug product release and stability analysis is more critical to the overall control strategy.

申请人经常会被问到一些问题，而这些问题都是基于片剂刻痕这一事实。为了确保掰片的质量，每掰片部分的单位剂量均匀度（含量均匀度或片重差异）也应进行相应的检测。同时，为了保证产品的脆碎性，仿制药申请者也应提供掰片后的质量损失数据。有时基于片子的形状与大小，可能会要求申请者提供片子刻痕的深度数据。而对于缓释制剂而言，同时建议检测掰片部分vs整片的溶出相似性，以确保释放基质保持不变。在产品和工艺开发过程中应进行上述的掰片研究。随着药物剂型越来越多样化，在整个质量控制范围内，药物放行标准和稳定性标准的常规检测项目也应越来越重要。

Water content. 水分

In many cases a control for water content is either not proposed or is poorly justified. An appropriate limit for water content takes into consideration contributions from the formulation components, the manufacturing process (e.g., a wet or dry process) and the product stability. The proposed limit should be reasonable based on the observed data for the exhibit batch(es). The criticality of the limit is heightened for products that contain API or excipients that are sensitive to residual moisture, which may lead to degradation or product performance issues.

很多申报资料中没有对水分进行控制或者拟定限度标准不合理或不充分。产品中水分含量的控制应根据产品处方的成分组成、生产过程（如加湿或干燥）进行相应的控制。而控制限度的标准应基于执行批记录的数据而进行合理的设定。对于活性成分或含有引湿性辅料的产品，产品中水分的残留更应该进行控制，特别是对于易产生水降解杂质或因湿度而引起产品某些性能的改变的品种。

Microbiological controls–nonsterile products. 微生物控制-无菌产品

A common comment that may come from the Agency during the review is with respect to microbiological control for nonsterile products. Based on the formulation components (e.g., lactose, other sugars) and product’s water content, it may be prudent to include standard microbiological tests including aerobic microbial count, total yeasts and molds or specific pathogens. In some cases data on water activity of the product can be used to justify not performing microbial limits testing. The term‘water activity’ (aw) describes the (equilibrium) amount of water available for hydration of materials (15). Published literature shows that absolute limit of microbial growth is about aw = 0.6. Thus, pharmaceutical development studies showing the water activity of the formulation is below this level during typical storage may justify not including microbiological controls for non-sterile, solid oral dosage forms. Additional references for microbial testing for non-sterile products and water activity may be found in ICH Q6A and USP<1111>(3, 16); and USP<1112>(16), respectively.

在审查期间来自该机构的一个常见评论是关于非无菌产品的微生物控制。根据处方组成（如乳糖、其他糖）和产品的含水量，最好包括标准的微生物测试，包括需氧菌总数、霉菌和酵母菌总数或控制菌/特定病原体。在某些情况下，有关产品水活度的数据可以用来证明不进行微生物限度检测的合理性。术语“水活度”（aw）是描述可用于物质水合作用的（平衡）水量（15）。已发表的文献表明，微生物的绝对生长限度约为水活度（aw） = 0.6。因此，若药物开发研究表明，在储存期间，处方的水活度低于0.6，非无菌口服固体剂型可以不进行微生物控制。在ICH Q6A和USP <1111>（3,16），和USP <1112>（16）中可以找到关于非无菌产品和水活度的微生物检测的其他参考。

Osmolality/Osmolarity/Tonicity. 渗透压/渗透压浓度/张力

For injectables (especially intravenous products) comparison of osmolality/osmolarity to RLD should be provided. If the results differ, then justification may be needed. As buffer systems may be different based on 21 CFR 314.94(a)(9)(iii) (17), differences in the osmolality/osmolarity compared to the reference product may be observed. The applicant needs to address this difference, as noted in the CFR, which states that the difference in formulation should not affect the safety of the proposed product. If the acceptance criterion for osmolarity/osmolality is listed in the RLD labeling, it is recommended that it be included in the product specification.

对于注射剂（特别是静脉注射产品），应提供渗透压/渗透压浓度与RLD的比较。如果结果存在差异，需提供合理性依据。根据21 CFR 314.94 (a)(9)(iii)(17)，缓冲系统可以不同，因此可以观察到与参比制剂（RLD）相比，渗透压/渗透压浓度存在差异。按照CFR要求，申请人需说明不同之处，并声明配方上的差异不应影响产品的安全性。如果在RLD标签中列出了渗透压/渗透压浓度的接受标准，则建议将其定入产品的质量标准中。

Antimicrobial preservative and antioxidants. 抗菌防腐剂和抗氧化剂

Antimicrobial preservatives and antioxidants may be essential for establishing an acceptable shelf life of drug products. Antimicrobial preservatives by preventing microbial proliferation and antioxidant by preventing oxidation of the API, as well as, the excipients. In a parenteral formulations, based on 21 CFR 314.94(a)(9)(iii) (17) an applicant may choose to substitute or add antimicrobial preservative or anti-oxidant based on adequate justification. The key term here is “adequate justification”. On many occasions deficiencies are cited as the applicant may have failed to rationalize the proposed levels of the antimicrobial preservatives or antioxidants in the proposed drug product. Additionally, there have been instances where applicants have not provided substantial rationale for substituting or adding the antimicrobial preservative or antioxidant in a parenteral formulation, especially when the RLD product does not contain one or the other.

抗菌素防腐剂和抗氧化剂可能是建立可接受的药品货架期标准所必需的。抗菌防腐剂可以防止微生物的增殖，抗氧化剂可以防止原料药以及辅料的氧化。根据21 CFR 314.94(a)(9)(iii)，在非肠道制剂中，如果有充分的理由，申请人可以选择替换或添加抗菌防腐剂或抗氧化剂。这里的关键术语是“充分理由”。在许多情况下，申请人可能没有合理解释所建议的药物产品中所含的抗菌防腐剂或抗氧化剂的水平，从而导致缺陷的产生。此外，有些情况下，特别是当RLD产品不含上述任何一种时，申请者没有提供实质性的理由，在非肠道制剂中替代或添加抗菌防腐剂或抗氧化剂。

USP<51>, which deals with Antimicrobial Effectiveness Testing, clearly recommends the minimization and justification of the range and/or criteria proposed of antimicrobial preservatives (16). Similarly, the applicants need to justify the chosen level of antioxidant in the formulation. The level of antioxidants is preferably justified based on pharmaceutical development studies demonstrating the minimum level at which the required activity is achieved and supported by the stability data provided in the application. The finished product release and stability specification should include limits for any antioxidant or antimicrobial preservative present in the formulation. The controls should comply with the requirements in ICH Q6A (3).

USP<51>抗菌有效性测试，明确建议将抗菌防腐剂的范围和/或标准最小化和合理化（16）。同样，申请人需提供处方中抗氧剂水平选择的理由。最好是基于药物开发研究，论证抗氧剂所需的最低水平，并在申请中提供支持的稳定性数据。终产品的放行标准和稳定性标准中，应包括处方中抗氧剂或抗菌防腐剂的限度，并满足ICH Q6A的要求（3）。

In some cases, the applicants are also requested to control plausible degradants in the antimicrobial preservatives and antioxidants. Some well known examples of degradants are benzaldehyde and benzoic acid in benzyl alcohol and p-hydroxybenzoic acid in methylparaben and propylparaben. The applicants may be asked to monitor these during routine drug product release and stability analysis. The justification of the criteria for these degradants, in most cases, is consistent with the justifications used for drug product impurities, noted previously.

在某些情况下，申请人还被要求控制抗菌防腐剂和抗氧化剂中可能的降解物。一些众所周知的降解物的例子，如使用了苄醇，应控制苯甲醛和苯甲酸；如使用了对羟基苯甲酸甲酯和对羟基苯甲酸丙酯，应控制对羟基苯甲酸。申请人可能被要求，在药品的放行检验和稳定性检验中进行监控。在大多数情况下，这些降解物的接受标准与样品中杂质的接受标准一致。

Rheological properties, redispersibility and particle-size distribution of oral suspensions. 口服混悬液的流变性、再分散性和颗粒分布

There are often questions regarding the above attributes, especially in case of oral and injectable suspensions. The viscosity of a suspension is considered an important attribute, as it is reflective of the settling tendency of the particulate matters in the suspension. It is also an indicator of the ease of pouring a suspension from a bottle or injecting it through a needle (18). The controls should be based on studies that demonstrate that the tendency to segregate during the manufacturing and storage has been minimized and/or controlled. Suitable tests should be included based on comparison with the innovator’s product or pharmaceutical development studies.

通常会有关于上述属性的问题，特别是口服和注射用混悬液。黏度是混悬液的一个重要属性，因为它可以反映混悬液中颗粒物的沉降趋势。它也是从瓶子里倒出混悬液或通过针注射混悬液容易程度的指标。这些控制应该基于研究，以证明在生产和储存过程中隔离segregate的倾向已经被最小化和/或控制。在与RLD或药物开发研究进行比较的基础上，应包括适当的测试。

Suspension stability and particle size. 悬浮稳定性和粒度

Redispersibility is critical for oral and injectable suspensions if sedimentation occurs during the storage of the suspension. The acceptance criteria should be set based on an appropriate and reproducible method. The time taken for re-suspension should be defined, based on pharmaceutical development studies and have minimal intra and inter-lot variability.

如果混悬液在储存过程中发生沉降，那么再分散性对于口服和注射用混悬液来说是至关重要的。接受标准应根据适当和可重复的方法制定。重新悬液的时间应根据药物开发研究确定，应具有最小的批内和批间差异。

有时，在药物悬浮液中的晶体生长会导致粒径大小分布的剧烈变化，这反过来又会影响悬浮液的物理稳定性，有时还会影响生物利用度。因此，粒径分布可能是一些悬浮液的关键质量属性，需要在放行标准和整个货架期内进行监控。其它信息，参见ICH Q6A和QbR-FAQ。

Multilayer tablets. 多层片

With respect to multilayer tablets, it is incumbent on the applicant to provide development studies and/or suitable controls to ensure tablet integrity. If controls or development studies are not provided, it is likely that applicants will receive a deficiency. It is recommended that when an applicant develops a multilayer tablet, they should provide data on layer integrity (e.g., radial crushing test). Additionally, during development or through a control strategy the applicant should provided assurance that tablets, throughout the product lifetime, exhibit consistent cohesion. In some cases a routine friability test performed on stability samples may be sufficient.

对于多层片，片子的完整性控制和研究是非常重要的。如果没有提供控制或开发研究数据，申请人很可能会得到一个缺陷。在研发多层片的过程中，申请者应提供每层完整性的数据（如硬度检测）。在药物研发或整个质量控制战略中，申请者应保证在产品的整个生命周期里，层与层之间的凝聚力是一致的。在某些情况下，稳定性样品也应进行脆碎度检测。

片层的完整性与所用的辅料属性密切相关，因此，如果产品的后期变更中涉及到辅料供应商的变更或辅料级别的变更，申请者应证明在多层片的生产过程中，产品的质量与性能与变更前保持一致；生产设备的变更和生产工艺的变更也应如此。申请人可能被要求提供数据，以证明生产的多层片的质量和性能相当。在最近一篇关于多层片的文章中可以找到更多的注意事项。

Transdermal delivery systems and locally acting patches. 透皮给药系统和局部作用贴片

Although transdermal delivery systems (TDDS) and other patches are not currently common dosage forms, as these products become more popular deficiencies would be cited with respect to specific critical quality attributes (CQAs) if they are not addressed in the submission.

尽管透皮给药系统（TDDS）和其它贴片不是常规剂型，随着这些产品变得越来越受欢迎，如果提交的报告中没有涉及到特定的关键质量属性（CQAs），就会导致缺陷的产生。

粘附是申请中应该说明的最关键的质量属性。产品粘附是一个关键质量属性（CQA），因其不仅关系到产品的质量和性能，而且关系到产品的安全。申请人应通过适当的、合理的方法，测试所提议的产品中的附着力，并能够证明所提议的系统在附着力方面显示了一致的产品质量、性能和安全性。最近的一篇综述文章对透皮给药系统（TDDS）粘着的关键性有很好的参考价值（20）。关于透皮给药系统（TDDS）和贴片的关键属性，也可参考其他的文献和指南（21,22）。

General drug product information. 仿制药的产品信息

There are a few pieces of general information that if not provided will lead to deficiencies. As stated previously, this is not intended to be an all inclusive list. Common information not provided in the ANDAs that has lead to deficiencies includes the following:

• Results for all strengths are not included.
• Quantitative results are not presented for numerical tests, but general terms such as “complies” or “meets limit” are reported.
• A USP<467>compliance statement along with option used is not included in the drug product specifications.
• In case of the drug product label having specific information regarding how the patient may use a drug product, additional controls may be requested in release and stability. For example, if the label of a chewable, dispersible tablet claims that it may be dissolved in water or juice completely before taking, a test may be needed to establish that the generic meets the same criteria.

仿制药申请过程中有时会遗漏部分信息而造成缺陷。如前所述，这并不是一个包含所有内容的列表。ANDAs中没有提供的导致缺陷的常见信息包括以下内容：

• 未提供所有规格的结果
• 对于需要进行定量研究的检测项，检测结果没有写清具体数据，而只是写了符合要求“complies”或符合限度要求“meets limit”
• USP<< span=””>467>残留溶剂的相关申明没有包含在产品的质量标准中
• 产品说明书中如果涉及到关于病人服用的特殊信息，在产品放行和稳定性考察时，可能还需要做额外的检测控制。如：如果说明书中已说明能在水中或橘子汁中完全溶解的口崩片或分散片，那么在产品放行和稳定性研究时应考察该项目

Methods and validations. 方法和验证

There are a variety of common deficiencies regarding the analytical methods used for the drug product analysis, as well as, the associated method validation studies. One common question cited to applicants is related to insufficient method information being provided in the QbR-QOS, especially for non-compendial methods. The applicant should provide a brief summary of each non-USP method. This can be in a tabular or descriptive form and the information should include the critical parameters for the method and system suitability criteria, if applicable. Specifically for impurity methods, it should be clear that impurities (degradation products) are quantified using impurity standards or by the use of relative response factors (RRF).

在用于药品分析的分析方法以及相关的方法验证研究方面，通常会产生一些缺陷。其中常见的缺陷之一是基于QbR-QOS提供的分析方法信息不足，特别是那些非药典方法。对于每一个非USP方法，申请者应当为其分别建立一个简要概括，可以是图表形式或是语言描述形式，信息中应含有方法中关键的参数信息和系统适应性标准。对于杂质方法，应明确写明杂质（降解产物）的定量是通过杂质标准品的还是通过相对响应因子（RRF）定量的。

在一些提交的ANDAs中，没有提供足够的方法验证信息。对于内控方法，方法验证方案应涵盖USP<1225>方法验证中的所有相关项目，包括方法的稳健性/耐用性（16）。对于HPLC方法的耐用性测试可包括改变色谱条件、色谱系统、流动相配制方法等。如果分析方法需要转移，则应对中间精密度（耐用性）、检测限（LOD）、定量限（LOQ）等进行确认。应对药典方法进行确认，以验证实验室执行方法的能力。USP<1226>为方法确认提供了很好的参考。

提交的方法验证报告缺少具体的研究信息，包括线性研究未包括拟定的限度或LOQ；验证方案中不充分或不相关的接受标准，和缺少加标研究，无法评估方法检测随时间具有增长趋势的特定降解产物的适用性。另外，强制降解试验研究不充分，降解样品中并未发现降解杂质，无法评估方法稳定性指针的能力，一般推荐主成分降解10%-30%；而对于比较难降解的小分子，则也应该汇总在强制降解中并作相关说明（如降解条件已显著超过常规条件但仍未发生降解），也可采用其它合理的方法证明。

2.3.P.8 Stability 稳定性

The P.8 sections of the QbR–QOS and the body of data in submitted ANDAs include information with respect to stability studies used to determine the shelf-life of the product. As stated previously, much of the information provided in the P.5 section is relevant to both release testing (P.5) and stability testing (P.8).There are three QbR–QOS questions noted in P.8. These are as follows:

• What are the specifications for stability studies, including justification of acceptance criteria that differ from the drug product release specification?
• What drug product stability studies support the proposed shelf life and storage conditions?
• What is the post-approval stability protocol?

This article will focus on the first two questions with respect to common deficiencies and comments cited in ANDA submissions.

在递交的ANDA申请中，QbR-QOS（基于问题的审核-质量综述）的P.8部分和主体数据，包括用于确定产品货架期的稳定性研究的信息。如前所述，P.5中提供的大部分信息都与放行检验（P.5）和稳定性测试（P.8）相关。在P.8中，有三个QbR-QOS问题，如下所述：

• 稳定性的可接受标准是什么？是如何确认与放行标准不同的可接受标准的合理性的？
• 支持药品有效期/货架期及贮存条件的稳定性数据是什么？
• 批准后稳定性方案是什么？

本文将集中在前两个问题上，涉及到ANDA提交的常见缺陷和评论

Stability specifications.稳定性标准

Based on ICH Q1A(R2) (23) stability studies should include testing of attributes of the drug product that are susceptible to change during storage and may influence quality, safety, and/or efficacy of the drug product. The testing should cover the physical, chemical, biological, and microbiological attributes, preservative content (e.g., antioxidant, antimicrobial preservative), and functionality tests (e.g., for a dose delivery system). Analytical procedures should be fully validated and stability indicating.

基于ICH Q1A（R2）稳定性研究指南，产品稳定性研究的检测内容应该涵盖那些在贮藏期间易变化的、可能影响质量、安全性和/或有效性的项目。检验项目应包括产品的物理属性、化学属性、生物属性、微生物学特性、防腐剂含量（如抗氧剂、抑菌剂）和功能性测试（如定量给药系统），并且应采用已经过验证的、能指示稳定性的分析方法。

Modification of limits for stability. 稳定性限度修订

In some cases, the relaxation of the limits of certain quality attributes in stability is necessary based on the nature of the drug product. Applicants should take great care in using realistic, as well as, scientific and regulatory approaches to setting acceptance criteria for the stability studies.

在某些情况下，根据药品的性质，如果有必要的话，可以为稳定性研究设定一个相对宽泛的可接受标准。申请人应谨慎使用现实的、科学的和监管的方法来为稳定性研究设定接受标准。

如，固体制剂处方中的API或者某一辅料具有引湿性，那么成品在储存过程中水分含量可能会有所上升，因此可为水分含量设定一个相对宽的可接受标准。同样，如果与原料药相关的水解降解途径在文献中有充分的记录，在稳定性研究中，合成的降解物可控制在较高的水平。由原料药与剂型中的一种或多种辅料发生反应产生的杂质，也是如此。然而，当对设定的相对宽的可接受标准，未提供合理的说明时，则会被提供缺陷。

对于水含量，在上面提到的例子中，需要证明拟议的较宽的水分接受标准，不会影响到产品的质量，包括产品的外观变化、理化属性变化和杂质水平。对于降解产物，拟定的可接受标准应符合ICH Q3B（R2）界定限（QT）的基本要求，同时不能是具有基因毒性结构的杂质。但如果杂质限度超过了界定限，则需要通过检测多批（最好是临近效期或已过期）的RLD来证明杂质限度的合理性。但是，如果API与辅料相互作用产生某杂质，该杂质的限度水平也应该遵从ICH Q3B（R2）的要求，否则应提供安全性数据以证明其合理性。

Accelerated stability data on RLD samples. RLD样品的加速稳定性数据

Deficiencies are often cited when the relaxation of specifications of impurities in stability is justified by comparison with RLD, which has been subjected to degradation under accelerated stability conditions. Since accelerated storage conditions are not the normal storage condition of the drug product, it is recommended that the comparative batch analysis is conducted at controlled room temperature conditions to demonstrate similarity of behavior between the RLD and the generic.

将仿制药与RLD同时进行加速稳定性研究并作对比时，如果某一个或多个杂质增加而将其可接受标准进行放宽，这种理由是不充分的，还需增加仿制药与RLD在控制室温条件下的稳定性考察，以证明两者具有真正的相似行为，因为加速条件并非产品最终真正的储存条件。

Specific studies or tests on stability samples.稳定性样品的特定研究和检测

Water loss. 失水性检测

Per ICH Q1A(R2) (23), it is recommended that aqueousbased products packaged in semi-permeable containers should be evaluated for potential water loss during stability studies. Deficiencies have been cited with respect to applicants using semipermeable containers with no evaluation of potential water loss. It is recommended that the ICH Q1A guidance approach be used with respect to performing studies under low relative humidity conditions. Alternative approaches to determine water loss based on differing stability conditions can also be used, per the guidance.

根据ICHQ1A（R2）中的相关描述，包装在半渗透容器中的水溶液制剂在进行稳定性研究时，应考察潜在的失水性。申请者若使用了半渗透容器但没有进行失水性研究，则是一个缺陷。关于失水性的检测，可参考ICH Q1A中的推荐方式，在相对湿度偏低的条件下进行。根据该指南，还可以根据不同的稳定性条件采用不同的方法来确定失水性。

Dissolution. 溶出

The responsibility of reviewing the adequacy of the dissolution specification rests with the Division of Bioequivalence (DBE). However, a frequent deficiency provided to the applicants is to update the drug product release and stability specification based on DBE recommendations. It is also imperative that the applicants conduct the dissolution test by using the DBE recommended method on retained 3rd month accelerated stability samples for all packaging configurations and ensure that the exhibit batch meets the proposed specification. If accelerated stability samples are not available, testing should be conducted on samples placed in controlled room temperature. In this case, typically, the age of the samples at the time of testing will be the tentative expiration dating period that OGD will grant to the drug product. As such, updated stability protocols should be provided reflecting the reduced tentative expiration date. To avoid the reduction of shelf life, it is recommended that samples, which have already been taken out from the accelerated stability study chamber be retained until approval of the ANDA.

产品溶出标准的合理性一般是由BE部门（Division of Bioequivalence，DBE）负责复核。常见的缺陷是建议申请者根据BE部门的建议对产品的放行标准和稳定性标准进行更新。应当根据DBE推荐的溶出方法，将所有的包装规格样品进行加速稳定性3个月后检测溶出，以确保展示批符合所提议的溶出标准；如果没有加速稳定性样品，则应该将样品于控制室温下进行检测，可一直维持至仿制药办公室（OGD）即将批准该产品为止。这种情况下，仿制药申请者应当提交更新的稳定性研究方案，以此反应出暂定有效期的缩短。同时，为了避免产品货架期的缩短，建议将已从加速稳定性箱中取出的样品保留至ANDA的最终获批。

Photostability studies. 光稳定性研究

The information regarding photostability studies for the drug product is often absent from the application. As ICH Q1B (24) states, the studies on the photostability of drug product need to be done in a sequential manner, starting with the fully exposed product and proceeding, if necessary to the immediate pack and then to the marketing pack, until results demonstrate that the drug product is adequately protected from exposure to light. In some cases, the ANDA holder justifies not performing photostability studies for the drug product based on the fact that the drug substance did not show photo-degradation during the forced degradation studies. However, this is may not be acceptable, in some cases, since the excipients or impurities there in, may catalyze photo-degradation of the API in the drug product. In these cases the applicant will need to scientifically justify why photostability studies are not necessary.

Alternatively, if the applicant demonstrates that the generic product packaging provides a comparable level of protection to the RLD packaging, photostability studies may be exempted.

仿制药申请者往往容易忽略掉对产品进行光稳定性研究。正如ICH Q1B（24）所述，对药物产品光稳定性的研究需要循序渐进：第①步，去除内包装（将样品直接暴露于光照下）的制剂试验；第②步，去除外包装（带内包装）的制剂试验；第③步，市售包装的制剂试验；直到试验考察能证明产品能有效的避光。之所以仿制药申请者容易忽略成品的光稳定性研究，是因为他们认为，他们的原料药在强制降解试验中，并没有光降解杂质的产生；但是，有时因辅料和杂质存在会催化制剂成品中API的光降解的发生。综上所述，ANDA申请者应当基于科学的角度来证明为什么光稳定性研究可不必做。

或者，如果申请人证明仿制产品的包装提供了与RLD包装相当程度的保护，则可免除光稳定性研究。

Thermal cycling. 热循环检测

Thermal cycling studies or freeze-thaw cycling studies are recommended for certain dosage forms such as solutions, suspensions and emulsions to ascertain the effect of extreme temperature fluctuations during shipping through various climatic zones, seasonal fluctuation in temperature and mode of transport on the physical stability of the drug products. These studies are generally desirable for those drug products which may undergo phase separation, loss of viscosity, precipitation, and change in particle size distribution. However, we frequently see deficiencies cited in the ANDA due to lack of thermal cycling studies. It is desirable that the ANDA holders carry out thermal cycling studies during product development to assure a robust formulation. Also, a one time thermal cycling stability study needs to be conducted on the exhibit lot of the drug product to verify its physical stability, when applicable.

对于部分制剂剂型，如溶液剂、混悬剂和乳剂，有必要进行热循环研究或者冻-融循环研究，以确保这些剂型因在运输过程中经历不同气候带或是因季节波动等一些极端的温度波动下，或是不同的运输方式下，产品的物理稳定性仍能保持不变。对于那些容易发生相分离、黏性降低、沉淀或粒径分布的改变的产品，热循环研究或者冻-融循环研究是有必要的。但是，ANDA申请者通常缺少对产品热循环的相关研究。ANDA申请者可在药物研发阶段进行此项研究，以确定一个初步的处方；但是，展示批应当有一个时间点的热循环研究内容，以确保产品具有物理稳定性。

Diluent studies. 稀释研究

Stability testing of the pharmaceutical product after constitution or dilution, where applicable, should be conducted based on the information in the labeling of the RLD. This testing should be performed on the constituted or diluted product through the proposed in-use period on exhibit batches as part of the ANDA submission.

必要时，应参考RLD标签上的信息，对配制或稀释后使用的制剂药物进行相关稳定性研究。作为ANDA申报信息中的一部分内容，将展示批配制或稀释后，在建议的使用期限进行相关研究，以提供依据。

Accumulated data/studies. 累积数据或研究

Usually, satisfactory results of three months accelerated studies justify a tentative expiration date of 24 months. However, based on trends observed in the accelerated stability data, the expiry date for some products may be based solely on the accumulated full long-term stability data. There are drug products, due to their inherent nature show a significant change during the accelerated stability studies. In these cases, the expiration date is based on the long term stability data, though the ANDA holder may demonstrate that the RLD exhibits similar behavior under accelerated stability conditions. In cases were significant changes occur in accelerated conditions, applicants may also need to demonstrate (e.g., intermediate storage conditions) that excursions in temperature during routine shipping and storage have no detrimental impact on the product quality.

通常，3个月的加速稳定性数据能证明产品暂定有效期为24个月，但是，根据加速稳定性数据的变化趋势，有些产品因其自身的特点，在加速条件下能发生显著变化，因此它的货架期的制定仅能根据累积的全面长期稳定性数据而制定。但是，对于这种依靠长期稳定性数据而制定货架期的情况，ANDA申请者也应当证明在加速稳定性条件下，RLD与其具有相似的变化行为。当加速试验结果产生了显著变化，ANDA申请者也应证明（如中间条件稳定性考察）常规的运输途径或储存条件发生暂时性的温度变化对产品不会有质量影响。

Conclusion 结论

This concludes our discussion on the commonly cited deficiencies for control of the drug product (3.2.P.5) and stability (3.2.P.8). This is by far the most active area when it comes to deficiencies and comments cited to ANDA applicants. The prevalence of deficiencies speaks to the criticality of the information with respect to controls proposed for routine release and stability analysis of the drug product. Applicants should endeavor to provide sound scientific and regulatory justification for all specifications (tests, methods, and criteria) that are proposed.

该部分总结我们对制剂的控制（3.2.P.5）和稳定性（3.2.P.8）中常见缺陷信的讨论。当谈到ANDA申请中的缺陷和评论时，这是目前最活跃的领域。缺陷的普遍性说明了，对于药品的放行检验和稳定性分析来说，提供适当控制信息的重要性。申请人应努力为所提出的所有规范（测试、方法和标准）提供合理的、科学的法规依据。

As stated in the beginning of the paper, this is not an exhaustive list of deficiencies in the drug product release and stability sections. However, the authors have attempted to provide the underlying reasons for common deficiencies related to the control of the drug product during release and stability testing. Our goal is to shed light on the rationale for citing these deficiencies and demonstrating how pharmaceutical development studies, performed during the initial development of the product, may reduce the instances of these deficiencies being cited.

如文章开始所述，本文不是药品放行和稳定性检验中缺陷的详细清单。然而，作者试图提供与药物放行和稳定性测试中控制相关的常见缺陷的潜在原因。我们的目的是，阐述引起这些缺陷的原因，并说明在药物开发早期，如何进行药物开发研究，以降低这些缺陷的产生。

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 Chemistry, for his encouragement and invaluable insight.

感谢仿制药办公室（OGD）科学和化学副主任Lawrence Yu博士的鼓励和宝贵建议

Disclaimer 免责声明

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