FDA行业指南 ANDA申报---拒绝接受缺乏杂质限度论证的申报

ANDA Submissions – Refuse to Receive for Lack of Justification of Impurity Limits Guidance for Industry

ANDA申报---拒绝接受缺乏杂质限度论证的申报

行业指南

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

August 2016

Generics

ANDA Submissions –Refuse to Receive for Lack of Justification of Impurity Limits Guidance for Industry

Additional copies are available from:

Office of Communications

Division of Drug Information, WO51, Room 2201

Center for Drug Evaluation and Research

Food and Drug Administration

10903 New Hampshire Ave., Silver Spring, MD 20993-0002

Phone: 301-796-3400; Fax: 301-847-8714

druginfo@fda.hhs.gov

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

August 2016

Generics

TABLE OF CONTENTS 目录

I. INTRODUCTION	前言
II. BACKGROUND	背景
III. JUSTIFYING IMPURITY LIMITS IN DRUG SUBSTANCES AND PRODUCTS	原料药和制剂中杂质限度的论证
A. Refusal to Receive for Lack of Impurities Information	拒收缺乏杂质信息的资料
B. Providing Justification for Impurity Limits	提供杂质限度论证

ANDA Submissions – Refuse to Receive for Lack of Justification of Impurity Limits

ANDA申报---拒收缺乏杂质限度论证的资料

Guidance for Industry[1]

行业指南

This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the title page. 本指南代表FDA当前对此主题的相当。它并不赋予任何人任何权力，对FDA和公众亦不形成强制。在满足本适用法律法规的要求时可以使用替代的方法。关于替代方法的讨论，请联系FDA办公室负责此本指南的人员，联系方式在标题页给出。

I. INTRODUCTION 前言

This guidance is intended to assist applicants preparing to submit to the Food and Drug Administration (FDA) original abbreviated new drug applications (ANDAs) and prior approval supplements (PASs) to ANDAs for which the applicant is seeking approval of a new strength of the drug product[2]. The guidance highlights deficiencies in relation to information about impurities that may cause FDA to refuse to receive (RTR) an ANDA[3].[4] An RTR decision indicates that FDA determined that an ANDA is not sufficiently complete to permit a substantive review[5].

本指南意在帮助申报者准备向FDA提交的ANDA和ANDA的PAS，从而获得新剂量制剂的批准。本指南重点说明了与杂质资料相关的缺陷，它可能会导致FDA拒收（RTR）ANDA。RTR决定表示FDA认为该ANDA不完全满足实质审评的在资料完整方面的要求。

Typical deficiencies leading to an RTR decision include: (1) failing to provide justification for proposed limits in drug substances and drug products for specified identified impurities that are above qualification thresholds; (2) failing to provide justification for proposed limits forspecified unidentified impurities that are above identification thresholds; and (3) proposing limits for unspecified impurities (e.g., any unknown impurity) that are above identification thresholds.

一般来说，导致RTR决定的缺陷包括：（1）未能提供原料药和制剂中对特定已鉴别杂质拟定的高于确认阈值限度的论证；（2）未能提供特定但未鉴别杂质所拟定的超出鉴别阈值限度的论证；（3）拟定非特定杂质（例如，任何未知杂质）的限度超出鉴别阈值。

This guidance is not meant to be a comprehensive list of deficiencies in relation to impurity information that may or will lead FDA to make an RTR determination. Rather, this guidance clarifies that a failure to provide justification for proposed impurity limits may lead FDA to RTR an ANDA. It also makes recommendations to ensure that applicants include appropriate justification for impurities in their ANDA submissions.

本指南无意成为一份与杂质资料有关缺陷的完全清单，或者是引导FDA做出RTR决定。本指南只是澄清未能为所拟杂质限度所交论证可能会导致FDA对ANDA做出RTR决定。它还建议确保申报中包括ANDA申报中杂质的适当论证资料。

In general, FDA’s guidance documents do not establish legally enforceable responsibilities. Instead, guidances describe FDA’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the wordshould in Agency guidances means that something is suggested or recommended, but not required[6].

一般来说，FDA的指南文件并不建立法律强制义务。指南所描述的只是FDA当前对某个主题的观点，应仅被作为是建议来看待，只有所引用的特定法规或法律要求除外。当局指南中使用SHOULD一词时，表示建议或推荐某事，但并不是强制要求。

II. BACKGROUND 背景

Pursuant to the enactment of the Generic Drug User Fee Amendments of 2012 (GDUFA)[7], the Office of Generic Drugs (OGD) is tasked with a number of activities, including the development of “enhanced refusal to receive standards for ANDAs and other related submissions by the end of year 1 of the program….”[8] Enhanced RTR standards are important because the practice of submitting an ANDA that is not sufficiently complete to permit a substantive review, which then is “repaired” via several cycles of applicant resubmission and FDA response, is inherently inefficient and wasteful of resources.

随着2012年GDUFA的实施，OGD办公室承担了大量活动任务，包括 “在计划的一年内制订ANDA和其它相关申报资料的拒收标准”。如果AND申报不够完整，则无法完成实质审核，从而会导致申报者要再次提交多次“发补”，而FDA则要多次回复，这样会使得效率降低，浪费资源，因此建立RTR标准是很重要的。

FDA evaluates each submitted ANDA individually to determine whether it can be received for Agency review. FDA’s receipt of an ANDA means the Agency has made a threshold determination that the ANDA is sufficiently complete to permit a substantive review[9]. FDA’s regulations at 21 CFR 314.101 provide the regulatory authority by which FDA may in certain cases, and will in others, RTR an ANDA[10].

FDA将单独评估每个提交的ANDA来决定是否可以接受用于当局审评。FDA接受一份ANDA表示当局做出了阈值决策，判定了ADNA足够完整可以进行实质审评。FDA在21CFR314.101中的规定为FDA提供了权力在特定情形下可以RTR一份ANDA。

Generally, FDA will not receive an ANDA for substantive review unless it contains the information required under Section 505(j) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) and in 21 CFR 314.101 and other regulations, for example[11]:

一般来说，FDA只有在ANDA中包括FDCA第505(j)部分和21CFR 314.101和其它法规所要求的信息时才能接受进行实质性审评。这些信息包括例如：

? 21 CFR 314.50

? 21 CFR 314.94

? 21 CFR 320.21

? 21 CFR 320.22

This guidance focuses on when FDA expects to RTR an ANDA because it lacks justification for proposed impurity limits[12].

本指南聚集于FDA什么时候会由于缺乏对所拟杂质限度缺乏论证时做出RTR决定。

III. JUSTIFYING IMPURITY LIMITS IN DRUG SUBSTANCES AND PRODUCTS 原料药和制剂中杂质限度的论证

All ANDAs must contain a description of the composition, manufacture, and specifications of the drug substance and the drug product (see 21 CFR 314.94(a)(9) and 314.50(d)(1)). Applicants are required to submit a full description of the drug substance including, but not limited to: its method of synthesis (or isolation) and purification of the drug substance; the process controls used during manufacture and packaging; and the specifications necessary to ensure the identity, strength, quality, and purity of the drug substance (§314.50(d)(1)(i)). Applicants are also required to submit a list of all components used in the manufacture of the drug product[13] (regardless of whether they appear in the drug product) and a statement of the specifications for each component and the specifications necessary to ensure the identity, strength, quality, purity, potency, and bioavailability of the drug product (§314.50(d)(1)(ii)(a)). To ensure purity, applicants should propose and justify appropriate limits on the impurities in their drug substances and drug product.

所有ANDA必须包括对原料药和制剂成份、生产工艺和质量标准的描述（参见21 CFR 314.94(a)(9) 和314.50(d)(1)）。申报者需要提交一份药品的全面描述，包括但不仅限于：原料药合成（或分离）方法和精制方法、在生产和包装中所用的工艺控制，以及保证原料药鉴别、剂量、质量和纯度所需的质量标准(§314.50(d)(1)(i))。申报者还需要提交一份制剂生产中所用的所有成份的清单（无论是否出现在制剂中），以及每种成份的质量标准，这些质量标准需要确保制剂的鉴别、剂量、质量、纯度、效价和生物等效性(§314.50(d)(1)(ii)(a))。为了确保纯度，申报者应拟定并论证其原料药和制剂中杂质的适当限度。

A. Refusal to Receive for Lack of Impurities Information 拒收缺乏杂质信息的资料

FDA may RTR an ANDA that is not sufficiently complete because it does not on its face contain information required under §314.94, which includes a demonstration of the purity of the drug substance and drug product and information on impurities and residues (§§314.101(d)(3), 314.94(a)(9) (requiring ANDA to contain the information required under § 314.50(d)(1)) (see also Final Rule on Abbreviated New Drug Applications, 57 FR 17950 at 17959 (Apr. 28, 1992))[14].

FDA可能会RTR不够完整的ANDA申报，因为其表面即未包括§314.94所要求的信息，包括对原料药和制剂纯度的证明，以及杂质和残留的信息(§§314.101(d)(3), 314.94(a)(9) (要求ANDA包括§ 314.50(d)(1)部分所要求的信息) (也请参考“ANDA最终规定”, 57 FR 17950 at 17959 (1992年4月28日))。

Accordingly, FDA may RTR an ANDA for: (1) failing to provide justification for proposed limits in drug substances and drug products forspecified identified impurities that are above qualification thresholds; (2) failing to provide justification for proposed limits for specified unidentified impurities that are above identification thresholds; and (3) proposing limits for unspecified impurities (e.g., any unknown impurity) above identification thresholds. FDA expects applicants to develop and use appropriate analytical methods to detect all observed impurities. Applicants are encouraged to review the draft guidance for industry ANDA Submissions – Content and Format of Abbreviated New Drug Applications for more information on the characterization of impurities for drug substances and drug products.

相应地，FDA可能会RTR以下ANDA：（1）未能提供原料药和制剂中对特定已鉴别杂质拟定的高于确认阈值限度的论证；（2）未能提供特定但未鉴别杂质所拟定的超出鉴别阈值限度的论证；（3）拟定非特定杂质（例如，任何未知杂质）的限度超出鉴别阈值。FDA期望申报者制订和使用适当的分析方法来检出所有观察到的杂质。鼓励申报者参考行业指南“ANDA申报---ANDA内容和格式”草案获得更多关于原料药和制剂中杂质鉴定的信息。

B. Providing Justification for Impurity Limits 提供杂质限度的论证

As stated in Section II, to help applicants ensure the appropriate purity of their drug substance (§314.50(d)(1)(i)) and drug product (§314.50(d)(1)(ii)(a)), FDA has published two guidances for industry: ANDAs: Impurities in Drug Substances and ANDAs: Impurities in Drug Products. These guidances provide recommendations on what CMC information applicants should include regarding the reporting, identification, and qualification of impurities in drug substances and impurities that are classified as degradation products in drug products. These guidances provide recommendations for justifying appropriate impurity limits[15] in a drug substance or drug product[16].

正如第II部分所述，为帮助申报人确保其原料药和制剂具备适当的纯度，FDA已公布了2份行业指南：“ANDA：原料药中的杂质”和“ANDA：制剂中的杂质”。这些指南提供了申报者应包括的关于原料药中杂质报告、鉴别和定性的信息，以及制剂中降解产物杂质的信息。这些指南提供了原料药和制剂中对适当杂质限度进行论证的建议。

If a generic product contains specified identified impurities that exceed the qualification thresholds[17] or specified unidentified impurities[18] that exceed identification thresholds[19],[20],[21], the ANDA should propose impurity limits and include supporting data to demonstrate that:

如果仿制药中包括特定的经过鉴定的杂质，超出其定性阈值，或者是特定的未经鉴定的杂质，超出其鉴别阈值，则ANDA中应拟定杂质限度，并包括支持性数据来证明：

(1) the observed impurity levels and proposed impurity limits do not exceed the level observed in the reference listed drug (RLD) product[22];

所检测到的杂质水平，所拟定的杂质限度不得超过在参比(RLD)制剂中所检出的水平；

(2) the impurity is a significant metabolite of the drug substance[23];

杂质是原料药的重要代谢物；

(3) the observed impurity levels and proposed impurity limits are adequately justified by the scientific literature[24];

所检出的杂质水平和所拟定的杂质限度经过科学文献的充分论证；

or 或者

(4) the observed impurity levels and proposed impurity limits do not exceed the level that has been adequately evaluated in toxicity studies[25].

所检出的杂质水平和所拟定的杂质限度不超过毒性研究中经过充分评估的水平。

FDA will RTR an ANDA under §314.101(d)(3) if the ANDA lacks supporting data or information to justify the proposed limits for specified identified and/or specified unidentified impurities that exceed qualification thresholds and/or identification thresholds, respectively, as described above. Also, FDA will RTR an ANDA under §314.101(d)(3) with proposed limits for unspecified impurities that exceed identification thresholds.

如果一份ANDA缺乏支持性数据或者信息来论证为特定经过鉴别的杂质和/或特定的未经鉴别的杂质所拟定的超出定性阈值和/或鉴别阈值的限度，如上所述，FDA将根据§314.101(d)(3)RTR该ANDA。FDA也会根据§314.101(d)(3)RTR所拟定的非特定杂质超出鉴别阈值的ANDA。

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[1] This guidance has been prepared by the Office of Generic Drugs in the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration.

本指南由FDA的CDER的OGD办公室起草。

[2] For purposes of this guidance, the use of the term ANDA will mean ANDAs and new-strength PAS submissions.

在本指南中，术语ANDA指ANDA以及新剂量PAS申报。

[3]This should not be confused with a refuse-to-approve determination.

这里不应与“拒绝批准决定”相混淆。

[4] The following types of products are currently excluded from this guidance: (1) biological/biotechnologicals; (2) peptides; (3) oligonucleotides; (4) radiopharmaceuticals; (5) fermentation products; (6) semisynthetic products derived from fermentation products; (7) herbal products; (8) crude products of animal or plant origin; and (9) enantiomeric impurities. For additional information on the applicability to ANDAs, see guidances for industry ANDAs: Impurities in Drug Substances; ANDAs: Impurities in Drug Products; See also, guidances for industry Q3A(R) Impurities in New Drug Substances (Q3A(R)); andQ3B(R2) Impurities in New Drug Products (Q3B(R2)).

以下药品类型目前不在本指南范围内：（1）生物/生物技术药品；（2）肽类；（3）寡核苷酸； （4）放射性药品；（5）发酵产品；（6）发酵产品衍生的半合成药品；（7）草药制品；（8）动物或植物来源的粗品；（9）对映体杂质。关于ANDA适用性的更多信息，参见行业指南“ANDA：原料药中的杂质”；“ANDA：制剂中的杂质”；以及行业指南Q3A（R）新原料药中的杂质（Q3A(R)）和Q3B(R2)新制剂中的杂质（Q3B(R2)）。

[5] 21 CFR 314.101(b)(1).

[6] At various points this guidance notes that when FDA sees a particular type of deficiency in an ANDA it will RTR the ANDA. It is important to understand that such statements do not impose legal obligations on applicants or on FDA, but are included for purposes of transparency. This means that FDA, in the normal course, will RTR an ANDA on the grounds described in this guidance. This guidance does not preclude the possibility that an ANDA applicant may be able to demonstrate, in particular circumstances, that the regulatory requirements for receiving an ANDA have been met even when, as described in this guidance, FDA would in the normal course find the application not sufficiently complete and RTR it.

在本指南的好几个地方都注明了FDA如果在ANDA中发现一个特别类型的缺陷也可能会RTR该ANDA。很重要的一点是要发解这样的说明并不会强加给申报人或FDA以法律义务，而只是为了使得流程透明。这表示FDA在一般情形下会依据本指南所述的情形下RTR一份ANDA，而即使ANDA符合本指南中所述的要求，FDA在常规流程中也可能发现申报资料不够完善而RTR该ANDA。

[7]  Generic Drug User Fee Amendments of 2012 (GDUFA), Public Law 112-144, Title III.

仿制药用户付费修正案2012（GDUFA），公共法112-144，标题III。

[8] See Generic Drug User Fee Act Program Performance Goals and Procedures (the Commitment Letter):http://www.fda.gov/downloads/ForIndustry/UserFees/GenericDrugUserFees/UCM282505.pdf.

参见仿制药付费法案计划绩效目标和流程（承诺函）。

[9] See 21 CFR 314.101(b)(1).

[10] See 21 CFR 314.101(d) -(e).

[11] In certain cases, other statutes or regulations may apply.

在特定情形下，可能适用其它法律法规。

[12] At the time of filing, FDA reviews the content of an ANDA to determine, among other things, whether the ANDA applicant has provided a complete justification for proposed impurity limits. FDA does not conduct a thorough review of the justification of the proposed impurity limits until after filing, during technical review of the ANDA. To help applicants ensure the appropriate purity of their drug substance (§314.50(d)(1)(i)) and drug product (§314.50(d)(1)(ii)(a)), FDA has published the following guidances for industry: ANDAs: Impurities in Drug Substances; ANDAs: Impurities in Drug Products; and M7 Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk .

在提交文件时，FDA审核ANDA的内容先决定是否ANDA申报者提交了完整的所拟的杂质限度的论证。在收档之前，FDA并不对所拟定杂质限度的论证进行全面审核。只有收档后，对ANDA进行技术审核时才会进行全面审核。为了帮助申报者确保其原料药和制剂具备适当的纯度，FDA已公布了以下行业指南“ANDA：原料药中的杂质”、“ANDA：制剂中的杂质”和“M7：药物中DNA活性（诱变）杂质的评估和控制以限制潜在致癌风险”。

[13]  Impurities that are monitored in the drug product are classified as degradation products. Process impurities from the drug substance synthesis are normally controlled during drug substance testing, and therefore are not generally included in drug product specifications, unless they are also degradation products.

在制剂中监测的杂质被归类为降解产物。原料药合成中产生的工艺杂质一般在原料药检测中进行控制，因此一般不包括在制剂的质量标准中，同时也是降解产物的除外。

[14] “As for possible impurities or residues in the ANDA product, ANDA applicants would be required to provide information on the drug substance and the drug product as part of the chemistry, manufacturing, and controls section of the application. This would include information on impurities and residues.” 57 FR 17950 at 17959.

“对于ANDA药品中可能的杂质或残留，ANDA申报者应提交原料药和制剂的信息，作为CMC部分的一部分。这些资料包括杂质和残留的信息”。57 FR 17950 at 17959

[15] The terms “impurity limit” as used in this guidance and “acceptance criterion” as used in the FDA guidances referenced above in this paragraph and in note 4 are synonymous.

本指南所用的术语“杂质限度”，和上述本段落中所引和注释4中所引FDA指南中所用的“可接受标准”是同义词。

[16] The referenced guidances apply to drug substances and drug products, generally. However, if FDA has issued a product-specific guidance, the most stringent impurity identification or qualification threshold would apply. For example, the guidance for industry Nasal Spray and Inhalation Solution Suspension, and Spray Drug Products – Chemistry, Manufacturing, and Controls Documentation states that unspecified impurities (degradation products) at levels of 0.1% or greater should be specified. Therefore, for these specific products, the limits for unspecified impurities (degradation products) should not exceed 0.1%.

一般来说，所引用的指南适用于原料药和制剂。但是，如果FDA已经发布了产品特定的指南，则适用最严格的杂质鉴别和定性阈值。例如，行业指南“鼻喷剂和吸入混悬液，和喷雾药品---研发、生产和检测文件”说0.1%或更高水平的非特定杂质（降解产物）应指定。因此，对于这些特定药品，非特定杂质的限度（降解产物）应不得过0.1%。

[17] See guidances for industry Q3A(R) and Q3B(R2). Identification and qualification thresholds should be based on the maximum daily dose (MDD) of the drug and total daily intake of impurities, which refers to the publicly available drug product dosage labeling. These thresholds should be reported as a percentage, and percentages should be based on lowest total daily intake (TDI) of impurities per ICH guidance tables for all impurities.

参见行业指南Q3A（R）和Q3B(R2)。鉴别和定性阈值应依据药品最大日服用剂量（MDD），和杂质的日总摄入量，这通常是指公众可以获得的制剂剂型标签。这些阈值应报告为百分比，百分比应依据ICH指南中所有杂质表里杂质最低的日总摄入量（TDI）。

[18] See supra, note 16. When specified unidentified impurities are listed in the specification, FDA recommends that applicants describe the identification efforts attempted and clearly identify the procedure used and assumptions made in establishing the level of the impurity. It is important that specified unidentified impurities are referred to by an appropriate qualitative analytical descriptive label (e.g., unidentified A, unidentified with relative retention of 0.9).

参见前注16.当特定未鉴别杂质列在质量标准中时，FDA建议申报者描述所做的鉴定工作，并清楚识别出所用的程序，以及在建立杂质水平时所做的假设。很重要的一点是特定的未鉴别杂质是通过适当的定性分析来描述的（例如，未鉴别杂质A，未鉴别杂质RRT0.9）。

[19]See supra, note 16. In some cases, it may be appropriate to decrease the threshold for qualifying impurities. For example, if there is evidence that an impurity in certain drug classes or therapeutic classes has previously been associated with adverse reactions in patients, it may be important to establish a lower qualification threshold. When such circumstances arise, and when these circumstances have not already been contemplated in a product-specific guidance, these changes will not be evaluated during the filing review but will be addressed during the technical review of the ANDA.

参见前注16。在有些情形下，降低定性杂质的阈值可能是恰当的。例如，如果有证据证明在特定药品类别或治疗类别中一个杂质之前已与患者不良反应有关系，则很重要的一点是要建立一个更低的定性阈值。如果有此情形，并且这种情形并未包括在产品特定指南中，则此变更在收档审核时并不会进行评估，但会在对ANDA进行技术审评时进行说明。

[20] See guidances for industry Q3A(R) and Q3B(R2) for definitions of an identified impurity, identification threshold, qualification, and qualification threshold.

参见行业指南Q3A?和Q3B(R2)中已鉴定杂质、鉴别阈、定性和定性阈值的定义。

[21] Acceptance criteria for unspecified impurities should not exceed the identification threshold in the guidances for industry Q3A(R) and Q3B(R2), even in the case when higher acceptance criteria for unspecified (other) impurities are listed in the U.S. Pharmacopeia (USP) monograph. If the acceptance criteria for unspecified (other) impurities in the USP monograph are lower than the identification threshold in Q3A(R) and Q3B(R2), the acceptance criteria for unspecified impurities should be set to the USP level.

非特定杂质的可接受标准应不得超过行业指南Q3A?和Q3B(R2)中的鉴定阈值，即使在USP各论中给出的非特定（其它）杂质可接受标准更高。如果在USP各论中非特定（其它）杂质的可接受标准低于Q3A(R)和Q3B(R2)中的鉴定阈值，则应将非特定杂质的可接受标准设定到USP水平。

[22] In the event that the RLD is no longer marketed, thereby preventing the ANDA applicant from obtaining samples to conduct a comparative analysis, an applicant is required to provide a justification of the proposed impurity limits based on other criteria delineated in this guidance (e.g., metabolite, scientific literature, or toxicity studies) in order for that ANDA to be received. An applicant that wishes to use an alternative approach is encouraged to submit a controlled correspondence to determine the acceptability of the approach prior to ANDA submission.

如果RLD不再销售了，因而ANDA申报者无法获得样品来实施对比分析，则申报者应根据本指南中阐明的其它标准（例如，代谢物、科学文献或毒性研究）来论证拟定的杂质限度，作为资料提交。鼓励期望使用替代方法的申报者在提交申报之前提交受控通信来决定方法的可接受度。

[23] The guidances for industry ANDAs: Impurities in Drug Substances and ANDAs: Impurities in Drug Products state that a significant metabolite of the drug substance is considered qualified. However, if the level of the significant metabolite impurity is too high, other quality attributes, such as potency, could be significantly affected. In this case, FDA recommends that the acceptance criterion be set lower than the qualified level.

行业指南“ANDA：原料药中的杂质”、“ANDA：制剂中的杂质”说原料药的重要代谢物被认为是经过确认的。但是，如果重大代谢杂质的水平太高，其它质量属性如效价也可能会受到显著影响。在此情形下，FDA建议可接受标准设定在宣限之前。

[24] If the applicant relies on published literature, complete and legible copies of each publication should be included in the ANDA submission.

如果申报者依赖公布的文献，则应在ANDA申报资料中放进每份文献完整清晰的复印件。

[25] The toxicity assessment should also include an evaluation of potentially genotoxic impurities (PGI) that may include in silico, in vitro and/or in vivo analyses.

毒性评估也包括潜在的基因毒性杂质（PGI）评估，可能包括电脑模拟、体内和/或体外分析。

来源：http://zhuyujiao1972.blog.163.com/blog/static/98694727201685104725628/