FDA行业指南：ANDA Submissions –Refuse-to-Receive Standards拒收ANDA标准

A.        Miscellaneous Factors 其它因素

1.                  Study Information BE Table[1] 研究资料：BE表格

FDA will RTR an ANDA if the Study Information BE table is incomplete[2].   The Study Information BE table compiles importantinformation about study type and site locations and should be placed in Module 2.7 of the ANDA (along with the other BE summarytables).

如果ANDA中的研究信息BE表格不完整，FDA会拒收该ANDA。研究信息BE表格中汇总的是关于研究类型和场所位置的信息，应（与其它BE总结表一起）放在ANDA模块 2.7中。

Applicants should provide the requested information regarding sample storage and long-term storage.  Receipt of the ANDA is alsopredicated on the following information that is captured in the table:

申报人应提交关于样品存贮和长期存贮的所需信息。ANDA是否会被接受也可以从表格里包括的以下信息做出预测：

·         The number of days of long-term storage stability (LTSS) coverage should be equal to or more than the number of days for sample storage duration.

·         长期存贮稳定性（LTSS）天数应大于等于样品存贮天数

·         The temperature (°C) reported for LTSS coverage should be within or less than the temperature range for sample storage.

·         所报告的LTSS覆盖温度（°C）应小于样品存贮温度范围

2.                  Waiver of In Vivo BA or BE Studies for BCS Class I Drugs BCS（生药学分类系统） I 类药品的体内生物利用度（BA）或生物等效性（BE）豁免

If the applicant requests a Biopharmaceutics Classification System (BCS) Class 1 BA/BE waiver, FDA will RTR the ANDA if any of thedata needed to support such a waiver request are missing from the ANDA at the time of submission[3].   Applicants should refer toFDA’s guidance for industry Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System for details regarding waivers of any required in vivo bioavailability (BA) orBE studies for a BCS Class 1 drug substance.

如果申报人申请豁免其生物药分类系统（BCS）第1类BA/BE豁免，而ANDA在提交时缺失了任何支持豁免所需的数据，则FDA将拒收该ANDA。申报人应参考FDA行业指南《即释固体口服制剂基于生物药分析系统的体内生物利用度和生物等效性研究豁免》中关于BCS1类药物体内生物利用度（BA）和BE研究豁免申请的详细信息。

3.                  Office of Bioequivalence and Office of Pharmaceutical Quality Receipt Evaluations

生物等效性部门（DBE）和临床审评部门（DCR）的接收审评

FDA will RTR an ANDA, in certain cases, based on the recommendations of DBE, the Division of Clinical Review (DCR), and/or theOffice of Pharmaceutical Quality. Deficiencies in these modules are generally associated with, but not limited to, various concernswith an in vivo BE or clinical endpoint BE study, or statistical data and/or design.

在某些情况下，FDA会根据DBE、临床评审中心（DCR）和/或药品质量办公室的建议拒收一份ANDA。这些模块的缺陷通常是，但不仅限于，体内BE或临床终点BE研究或统计学数据和/或设计的不同问题。

4.                  Drug-Device Combination Products 药械组合产品

On a case-by-case basis and in consideration of preliminary evaluations performed by consultant offices, FDA will RTR an ANDA for adrug-device combination product if a device used to deliver the drug is not sufficiently similar to the device used to deliver the RLD.Any device used to deliver the drug should be similar enough to that used with/for the RLD so as to ensure, at a minimum, safe andproper administration of the product without the need for retraining by a health care professional and to ensure that its performancecharacteristics, operating principles, and critical design attributes will result in a product that will perform the same as the RLD underthe conditions of use described in the labeling.  In addition, the patient instructions in the labeling, as it concerns use of the device,should meet the same labeling requirement for ANDAs[4].

如果药械组合产品用于给药的器械部分与RLD中用于给药的器械部分相似度不够，根据各案情况，结合顾问办公室的初步评估，FDA将拒收该ANDA。所有用于给药的器械均应与RLD中所用的足够相似，以确保至少是安全的，并且能恰当给药而不需要由健康专业人士进行重新培训，以及确保其性能特点、动作原理、关键设计属性根据标签上所述的使用条件能够获得与RLD相同的表现。另外，由于关系到器械的使用，标签上的患者须知应符合对ANDA的相同标签要求。

5.                  Missing Case Report Forms 病例报告表缺失

FDA will RTR an ANDA if a clinical study conducted does not contain copies of individual case report forms for patients enrolled in thestudy[5].   Applicants should provide a random selection of at least 10% of all case report forms for any study that enrolls patients. Applicants should also include all case report forms for subjects removed from study analysis for any reason.  In addition, applicantsshould provide copies of individual case report forms for each patient who died during a clinical study or who did not complete thestudy because of an adverse event, whether believed to be drug-related or not, including patients receiving reference drugs orplacebo, consistent with 21 CFR 314.50(f)(2).

如果一个已进行的临床研究未包含该临床实验所有受试者的全部个案报告表副本，FDA 将拒收该ANDA 申请。申报人应在所有研究中入选患者的全部病例报告表格中随机抽取至少10%提交。申报人还应包括因任何原因中止研究分析的对象的病例报告表。此外，申报者应按21 CFR 314.50(f)(2)要求提交在临床试验中死亡和因为不良事件而未完成研究的所有患者各案报告表，不管其是否确认与药品相关，也不管患者接受的是对照药品还是安慰制剂。

DISPUTE OF A REFUSE-TO-RECEIVE DECISION 对于拒收决定的争议

If an applicant disagrees with or wishes to discuss an RTR decision, the applicant should submit its concerns first to the email addressidentified in the RTR letter.  If FDA’s subsequent response does not resolve the matter, a teleconference can be scheduled with theapplicant, a Division of Filing Review (DFR) Team Leader, DFR Supervisor, and, if needed, the appropriate division director.  If thematter still remains unresolved, the applicant can use the dispute resolution procedure (see 21 CFR 314.103 and guidance forindustry Formal Dispute Resolution: Appeals Above the Division Level).

如果申报人不同意FDA拒收决定或希望与FDA讨论其拒收决定，则申报人应先向拒收函中所指定的邮箱提交其问题。如果FDA随后的回复未解决此问题，则可以计划与申报人、注册资料审核中心（DFR）团队领导、DFR主管，以及需要的话，还包括适当的中心主任一起召开电话会议。如果还是不能解决问题，则申报人可以采用争端处理程序（参见21 CFR 314.103和行业指南《正式争端处理：向部门上级申诉》。

APPENDIX A: EXAMPLES OF MINOR DEFICIENCIES 附录A：轻微缺陷举例

1.      An ANDA is required to contain either an environmental assessment (EA) or a claim of categorical exclusion[6].   Pursuant to 21CFR 25.15(a) and in reference to FDA’s guidance for industry Environmental Assessment of Human Drug and BiologicsApplications (EA guidance), all applications or petitions requesting FDA action require the submission of either (1) an EA or (2) aclaim of categorical exclusion, as defined in 21 CFR 25.31[7].   A claim of categorical exclusion shall include a statement ofcompliance with the categorical exclusion criteria and shall state that to the applicant’s knowledge, no extraordinarycircumstances exist[8].   If FDA does not receive an EA or claim of categorical exclusion made by the applicant within 7 calendar days of notification of the omission(s), FDA will RTR the ANDA.

ANDA中要求包括一份环境评估（EA）或者是属于例外类别的声明。根据21 CFR 25.15(a)和FDA行业指南《人药和生物制品申报资料的环境保护》（EA指南），所有请求FDA动作的申报资料和申诉都要求提交（1）一份EA或（2）一份21CFR25.31中指定的属于例外类别的声明。在例外类别声明中应包括一份与例外类别标准相符合的声明，声称申报人根据其所有知识，不存在特殊情形。如果FDA在通知该遗漏后的7个自然日内未收到申报人提交的EA或分类例外声明，则FDA会拒收该ANDA。

2.      An ANDA must contain an accurate and complete English translation of each part of the application that is not in English[9].   Thisrequirement includes the translation of all sections of the document (e.g., headers, titles). FDA will accept an ANDA with theEnglish translation on a blank page next to the original text. FDA recommends that the translation be legible in size 12 font. Theapplicant should use its best judgment in determining how to fit the necessary information on a page without impacting thereviewer’s ability to read the information. If FDA does not receive English translation of each part of the application that is not inEnglish within 7 calendar days of notification of the omission(s), FDA will RTR the ANDA.

ANDA必须包含有所有非英语申报部分的一份准确完整的英文翻译件。此要求包括文件所有部分的翻译（例如，页眉、标题）。FDA会接受在原非英语文本后面空白页上的英语翻译ANDA。FDA建议翻译文本应保持清晰，采用12号字。申报人应尽最大努力确定如何将必要的信息排版在同一页上，不会影响审核人员读出信息的能力。如果FDA在通知申报者翻译件缺失后7个自然日内没有收到所有非英文部分的英文翻译版本，则FDA会拒收该ANDA。

3.      An ANDA must contain either a daily elemental iron calculation for products that contain iron[10] or a statement that the amountof elemental iron ingested per day does not exceed 5 milligram (mg), in accordance with 21 CFR73.1200(c).                                                                      A daily elemental iron calculation should be included in module 3.2.P.1 inaddition to all other inactive ingredient justification data/information.  If FDA does not receive either the calculation oraforementioned statement within 7 calendar days of notification of the omission(s), FDA will RTR the ANDA.

在含有铁成分的药品ANDA中必须包括一份药品中日服用元素铁的计算，如果不含铁成分，则必须包括一份声明，写明每日摄入的元素铁数量不超过5mg，符合21 CFR 73.1200(c)。在模块3.2.P.1中，除了所有其它非活性成分的论证数据/资料外，还应放入日服用铁元素的计算。如果FDA在发出此缺失通知后7个自然日内没有收到计算内容或前述声明，则FDA会拒收该ANDA。

4.      An applicant should complete the Pharmacy Bulk Package Sterility Assurance table[11] for pharmacy bulk packages and placethis table in section 1.14.1.4 of Module 1 of the ANDA. If FDA does not receive the completed table within 7 calendar days ofnotification of the omission, FDA will RTR the ANDA.

申报人应完整填写药房散装无菌保证表，用于药房散装包装，并将此表放在ANDA的模块1的1.14.1.4部分。如果FDA在发出缺失通知之后 7个自然日内未收到填写完整的表格，则FDA会拒收该ANDA。

5.      An applicant should include all of the facility information that is listed in Modules 3.2.S.2 and 3.2.P.3.1 (drug substance and drugproduct, respectively) of the application in Field 29 of the 356h form, using continuation pages for Field 29 when needed[12].  FDA will notify the applicant if there are any facilities listed in either of the aforementioned modules of the ANDA that are notcaptured in Field 29 and/or on its continuation pages.  If FDA does not receive a revised 356h form within 7 calendar days ofnotification of the facility omission(s), FDA will RTR the ANDA.

申报人应在申报资料模块3.2.S.2和3.2.P.3.1（原料药和制剂）内分别包括所有的场所信息，并且在356h表29号域中也包括这些信息（表格不够时可以续页）。如果在上述ANDA申报资料的指定模块中列出的任何场所没有列在29号域和/或其续页中，则FDA会通知申报者。如果FDA在发出场所信息缺失后7个自然日内没有收到修订的356h表，则FDA会拒收该ANDA。

6.      If there is a patent listed in FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations (commonly referred to asthe Orange Book) for the RLD, the ANDA must include a patent certification as to that patent, with one exception.  If the patent is amethod of use patent and the labeling of the RLD includes uses that are not covered by the patent, an ANDA applicant may beable to submit[13] a patent statement[14] explaining that the method of use patent does not claim any of the uses in the proposedlabeling of the ANDA product.  If the applicant submits such a patent statement, the proposed labeling in the ANDA must notinclude methods of use (or indications) that are covered by the use codes in the Orange Book for the patent in question. Where alisted patent claims the drug substance and/or drug product and one or more methods of use, the applicant may provide a “splitcertification” to the patent (i.e., the applicant provides a statement that the applicant is not seeking approval for one or moremethods of use claimed by the patent based on the use code(s) listed in the Orange Book (sometimes referred to as a “sectionviii” statement) and a patent certification to the remaining claims). If, upon filing review of such an ANDA, OGD determines that thelabeling submitted in the ANDA does refer to a use described in such use codes, OGD will not provide guidance or suggestions asto how the proposed labeling should be amended. Instead, OGD will inform the applicant that it must either revise its labeling orwithdraw the patent statement.  If, within 7 calendar days of being informed of this issue, an applicant fails to withdraw the patentstatement or revise the proposed labeling so as not to refer to the use claimed by the patent, FDA will RTR the ANDA.

如果RLD在FDA橙皮书中有一个列出的专利，则ANDA中必须包含一份该专利的专利证书，有一种例外如下。如果专利是一种使用方法专利，并且RLD的标签中包括该专利范围以外的用法，则ANDA申报人可以提交一份专利声明，解释使用方法专利并未声明ANDA药品所拟标签中的用法。如果申报人提交了这样一份专利声明，则ANDA中所拟的标签不得包括橙皮书中关于该专利使用规则所覆盖的用法（或适应症）。如果所列出的专利声明了原料药和/或制剂和一个或多个用法，则申报人可以提供一份专利“拆分证明”（即申报人提交一份声明，说明申报人并未要求批准一个或多个橙皮书中列出的使用规则里该专利所声明的用法）。如果在审核此类ANDA时，OGD认为ANDA中提交的标签引用了此类规则中的一个用法，则OGC将不会提供如何修改所拟标签的指导或建议。相反，OGD会通知申报人，必须修订其标签，或者撤回专利声明。如果在通知申报人此问题后的7个自然日后，申报人未能撤回专利声明或修订所拟标签，使得其不再引用专利所声明的用法，则FDA会拒收该ANDA。

7.      The listed drug that is relied on as the ANDA’s basis of submission is ordinarily the drug product that is designated as the RLD in the Orange Book[15].   If a listed drug that is not designated the RLD is cited as the basis of submission for an ANDA, FDA willnotify the applicant of the error.  If the correct information is not submitted within 7 calendar days, FDA will RTR the ANDA.

在ANDA申报中所列出的对照药品通常应该是橙皮书中的RLD。如果不是，则FDA会通知申报人该错误。如果在7个自然日内未提交正确的信息，则FDA会拒收该ANDA。

8.      For those ANDAs using APIs that do not make reference to a Type II API DMF, an evaluation of the API information presentedwithin Module 3 (drug substance)[16] of the application will be performed.  Any deficiencies[17] will be communicated to the ANDAapplicant for correction.  If a response to the API deficiencies is not received within 7 calendar days, FDA will RTR the ANDA.

如果ANDA中使用的API并没有引用II类API DMF，则将会对申报资料中在第3模块提交的API信息进行审核。FDA将与ANDA申报人就所有缺陷进行沟通要求更正。如果在7个自然日内未收到对API缺陷的回复，则FDA将会拒收该ANDA。

9.      In accordance with 21 CFR 314.94(a)(8)(iv), an ANDA’s proposed labeling must be the same as the labeling approved for theRLD, except for (1) changes required because of differences approved under a petition filed under 21 CFR 314.93, or (2)because the drug product and the RLD are produced or distributed by different manufacturers. Differences between theapplicant’s proposed labeling and labeling approved for the RLD can include differences in expiration date, formulation,bioavailability or pharmacokinetics, labeling revisions made to comply with current FDA labeling guidelines or other guidance, oromission of an indication or other aspect of labeling protected by patent or accorded exclusivity under section 505(j)(5)(F) of theFD&C Act. Applicants must submit a side-by- side comparison of the RLD and the proposed labeling[18].   In accordance with 21CFR 314.94(d)(1)(iii), the content of labeling must be submitted in an electronic format that FDA can process, review, andarchive.  FDA periodically issues and updates its guidance on how to provide electronic submissions[19].   If responses to these deficiencies are not received within 7 calendar days of being informed of these issues, FDA will RTR the ANDA.

根据21 CFR 314.94(a)(8)(iv)，ANDA所拟定的标签与RLD批准标签不一致的例外情形只有（1）根据21CFR314.93提交的请愿要求对标签进行变更并且被批准，（2）该申报药品与RLD是由不同生产商生产或销售的。申报人所拟的标签与批准的RLD标签差异可以包括以下方面：有效期、配方、生物利用度或药动学、根据当前FDA标签指南或其它指南而对标签进行的修订，以及减省由于专利或FDCA第505(j)(5)(F)部分排他条款所保护的一个适应症或其它方面。申报人必须提交一份RLD和所拟标签的并列对照表。根据21 CFR314.94(d)(1)(iii)，标签内容必须采用FDA可以处理、审核和存档的电子格式提交。FDA会定期签发和更新如何提供电子申报的指南。如果FDA在通知这些问题后7个自然日内没有收到对这些缺陷的回复，则FDA会拒收该ANDA。

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[1] A copy of this BE table can be found on FDA’s Web site at the following location:  此BE表格可以在以下FDA官网找到http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/Approv  alApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM120957.pdf.

[2] 21 CFR 314.94(a)(7).

[3] 21 CFR 314.94(a)(7).

[4] Section 505(j)(2)(A)(v) of the FD&C Act and 21 CFR 314(a)(8)(iv).84 21 CFR 314.101(d)(3).

[5] 21 CFR 314.101(d)(3).

[6] 21 CFR 314.101(d)(4).

[7] See the EA guidance for information as to which types of drug products require an EA

参见EA指南中哪类药品需要EA的信息。

[8]21 CFR 25.15(a).

[9] 21 CFR 314.101(d)(5).

[10] 21 CFR 314.50(d)(1)(i).

[11] http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/Appr

ovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM352612.pdf.  

[12] 21 CFR 314.101(d)(1).

[13] Pursuant to section 505(j)(2)(A)(viii) of the FD&C Act and 21 CFR 314.94(a)(12)(iii), and also referred to as a “Section viii carve-out.”

根据FDCA的505(j)(2)(A)(viii)部分和21 CFR 314.94(a)(12)(iii)，也被称为“第8部分拆分”。

[14] See Abbreviated New Drug Application Regulations; Patent and Exclusivity Provisions; Final Rule, 59 FR 50338, 50347 (Oct. 3, 1994).

参见简略新药申报规范，专利和排他性条款，最终规定，59 FR 50338, 50347 (Oct. 3, 1994)。

[15] 21 CFR 314.94(a)(3).

[16] Specifically, section 3.2.S.2 and its accompanying subsections, though this does not preclude review of the other sections and subsections that make up3.2.S so that the completeness of the API section in its entirety may be assessed.

[17] Note that the minor deficiencies found during the API review are not counted against the total for all other ANDA

deficiencies, as described in the introduction to Section III.

[18] See 21 CFR 314.94(a)(8)(iv).

[19] See guidance for industry Providing Regulatory Submissions in Electronic Format—Content of Labeling.

谢谢楼主分享

ANDA Submissions –Refuse-to-Receive Standards

Guidance for Industry

行业指南：ANDA申报----拒收标准

U.S. Department of Health and Human Services Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

December 2016

Generics

Revision 2

ANDA Submissions –Refuse-to-Receive Standards

Guidance for Industry

行业指南：ANDA申报----拒收标准

Additional copies are available from:

更多副本请从以下获取：

Office of Communications, Division of Drug Information Center for Drug Evaluation and Research

Food and Drug Administration

10001 New Hampshire Ave., Hillandale Bldg., 4th Floor Silver Spring, MD 20993-0002

Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353

Email: 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)

美国卫生福利部食品药品管理局（FDA）

化药审评中心（CDER）

December 2016

2016年12月

Generics

仿制药

Revision 2

第二版

目录

INTRODUCTION 概述

BACKGROUND 背景

GENERAL POLICY 通则

A........ Form FDA 356h (356h) FDA365h 表格 (365h)

B......... Submission, Format, and Organization 申报资料、格式和文件结构

C........ Non-Payment of GDUFA Obligations 未付清GDUFA费用

D........ Lack of a Designated U.S. Agent for a Foreign Applicant 外国申请人未指定美国代理人

E......... Citing a Pending Suitability Petition as a Basis of Submission 引用尚未裁决的适用性请愿作为申报的基础

REVIEWS FOR API  原料药评审

A........ Starting Material 起始物料

B......... Sterility Assurance Data 无菌保证数据

PRODUCT QUALITY DEFICIENCIES 药品质量缺陷

A........ Inactive Ingredients 非活性成分

B......... Inadequate Stability 稳定性不充分

C........ Packaging Amount Considerations 包装数量考虑

D........ Batch Records 批记录

E......... Method Validation/Verification Reports 分析方法验证/确认报告

F......... Special Consideration for Transdermal Patches 对透皮贴剂的特殊考虑

G........ Scoring and Conditions of Use 刻痕与使用条件

H........ Microbiology Considerations 微生物学考虑

BIOEQUIVALENCE AND CLINICAL DEFICIENCIES 生物等效性和临床缺陷

A........ Failed In Vivo BE Studies 体内BE 研究失败

B........ Alternate BE Studies 替代BE 研究

C........ Q1/Q2 Sameness Requirement for Consideration of an In Vivo BE Study Waiver

D........ Inadequate Dissolution Data (In Vitro Studies) 溶出不充分（体外研究）

E......... Miscellaneous Factors 其它因素

DISPUTE OF A REFUSE-TO-RECEIVE DECISION 对于拒收决定的争议

APPENDIX A: EXAMPLES OF MINOR DEFICIENCIES 附录A：轻微缺陷举例

ANDA Submissions – Refuse-to-Receive Standards

Guidance for Industry[1]

行业指南：ANDA申报---拒收标准

This guidance represents the current thinking of the Food and Drug Administration (FDA orAgency) on this topic. It does not establish any rights for any person and is not binding on FDAor the public. You can use an alternative approach if it satisfies the requirements of theapplicable statutes and regulations. To discuss an alternative approach, contact the FDA officeresponsible for this guidance as listed on the title page. 本指南代表了FDA目前对此主题的想法。指南并未赋予任何人任何权力，对FDA和公众均不具备约束力。如果满足适用的法律和法规要求，可以使用其它的替代方法。如需对替代方法进行讨论，请联系本指南标题页上列出的FDA负责办公室。

INTRODUCTION 概述

This guidance is intended to assist applicants preparing to submit to FDA 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].   Theguidance highlights deficiencies that may cause FDA to refuse to receive (RTR) an ANDA[3].   An RTR decision indicates that FDAdetermined that an ANDA is not substantially complete[4].   A substantially complete ANDA is “an ANDA that on its face is sufficientlycomplete to permit a substantive review.”[5]

本指南旨在帮助申报人为了获得药品新剂量而准备向FDA提交简略新药申报（ANDA）和ANDA预批准补充申报（PAS）。本指南着重说明了可能会导致FDA拒收（RTR）一份ANDA的缺陷。RTR决定表示FDA判定一份ANDA不是实质上完整的。实质上完整的ANDA是“表面足够完整的ANDA，可以开始进行实质性评审”。

This guidance is not meant to be a comprehensive list of the deficiencies that may or will lead to an RTR determination by FDA. Instead, this guidance identifies certain deficiencies and certain recurrent deficiencies that in FDA’s experience have led FDA to RTRan ANDA. This guidance also describes how FDA will assess deficiencies identified during FDA’s filing review to determine whether an ANDA should be received.  We note that industry is aware of many of the standards described in this guidance because FDA hashistorically applied many of these standards in its RTR determinations.

本指南无意成为一份可能会或可能引发FDA的RTR决定的所有缺陷清单。相反，本指南只是指出根据FDA经验已经导致FDA拒收ANDA的一些缺陷和反复发生的缺陷。本指南还描述了FDA将如何评估在FDA归档审核期间所发现的缺陷，以确定是否应接受该ANDA。我们注意到制药行业其实明白在本指南中所述的许多标准，因为FDA已经在其RTR决定中采用了这些标准。

FDA’s guidance documents, including this guidance, generally do not establish legally enforceable responsibilities.  Instead, guidancesdescribe FDA’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutoryrequirements are cited.

FDA的指南文件，包括本指南，通常并不会产生法定强制义务。相反，指南只是描述FDA当前对某个主题的态度，除了所引用的特定法规或法律要求外，其它内容应被当作是建议。

The use of the word “should” in Agency guidances means that something is suggested or recommended, but not required[6].

FDA指南中使用“SHOULD”一词时表示的是建议或推荐某事，但并不是强制要求。

BACKGROUND 背景

Pursuant to the enactment of the Generic Drug User Fee Amendments of 2012 (GDUFA)[7], the Office of Generic Drugs (OGD) istasked with a number of activities, including the development of “enhanced refusal to receive standards for ANDAs and other relatedsubmissions by the end of year 1 of the program….”[8]   Enhanced RTR standards are important because the practice of submittingan ANDA that is not sufficiently complete to permit a substantive review and then “repairing” it in the course of an extended reviewperiod that needs several cycles of FDA response and applicant repair is inherently inefficient and wasteful of resources.  In addition,ANDAs that are not sufficiently complete to permit a substantive review generate extra reviews and letters.

随着2012年GDUFA法案的实施，仿制药办公室（OGD）承担了一系列活动任务，包括“到计划开始的第1年底建立加强ANDA和其它相关申报资料的拒收标准……”。由于提交一份不够完整而无法进行实质性评审的ANDA，然后在深入审核期间进行“修补”，会需要多轮FDA反馈和申报者修补，这样会降低效率，浪费资源，因此加强RTR标准是很重要的。另外，不够完整而无法进行实质性审核的ANDA会产生额外的审核和信函。

FDA evaluates each submitted ANDA individually to determine whether the ANDA can be received. The receipt of an ANDA meansthat FDA made a threshold determination that the ANDA is a substantially complete application, that is, an ANDA that on its face is sufficiently complete to permit a substantive review[9].   Sufficiently complete means that the ANDA contains all the informationrequired under section 505(j)(2)(A) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) and does not contain a deficiencydescribed in 21 CFR 314.101(d) and (e)[10].

FDA会对收到的ANDA逐个评估，以确定是否可以接受。接受一份ANDA意味着FDA做出了一个决定，确定该ANDA是否是一份实质性完整的申报资料，也就是该ANDA表面上足够完整，可以开始实质性评审。足够完整意味着ANDA包括了所有根据FDCA 505(j)(2)(A)部分中所要求的所有资料，并且没有21 CFR 314.101(d)和 (e)里所述的缺陷。

Our regulations at 21 CFR 314.101 provide the regulatory authority by which FDA may in certain cases, and will in others, RTR anANDA that does not satisfy the criteria for a threshold determination that the application is substantially complete[11] .

我们在21 CFR 314.101中的法规要求让FDA有权在某些情形下可以拒收不满足确定申报资料实质性完整标准的ANDA。

Between Fiscal Years (FY) 2013 to 2015, FDA refused to receive 379 ANDAs for reasons other than failure to pay a GDUFA fee. Ofall original ANDA submissions, FDA refused to receive:

在2013财年至2015财年之间，FDA由于GDUFA费用支付以外的原因拒收了379份ANDA。在所有ANDA初始申报中，FDA拒收比例为：

?  14% in FY 2013

?  10% in FY 2014

?  14% in FY 2015[12]

?  2013财年：14%

?  2014财年：10%

?  2015财年：14%

In FY 2015, the five most frequent bases for an RTR determination were (in order of frequency): inadequate stability data; incomplete information request response; inadequate dissolution; drug product was not qualitatively and quantitatively the same (Q1/Q2 same)as the reference listed drug (RLD); and failure to respond to information request within the prescribed timeframe).

在2015财年，RTR决定最频繁的5个原因（根据其频繁程度）为：稳定性数据不充分、所需回复信息不完整、溶出度不充分、制剂定量或定性方面与RLD参比制剂不相同（Q1/Q2相同），以及未能在指定时间内回复所要求的资料。

GENERAL POLICY 通则

FDA considers the nature (e.g., major or minor) of the deficiencies, including the number of deficiencies in the ANDA, in determiningwhether an ANDA is incomplete on its face[13].   During FDA’s filing review of a submitted ANDA, FDA will determine if there are anymajor or minor deficiencies. Generally, a major deficiency is one that in FDA’s judgment is significant in nature such as certaindeficiencies found in 21 CFR 314.101(d) or 21 CFR 314.101(e)[14]; other major deficiencies are discussed in this and other guidances. Numerous minor deficiencies (discussed below) also constitute a major deficiency. A major deficiency will result in adetermination by FDA that the ANDA is incomplete on its face under 21 CFR 314.101(d)(3), and FDA will therefore RTR an ANDAcontaining a major deficiency.

FDA在决定一份ANDA是否表面完整的时候，会考虑ANDA中缺陷的情况，包括缺陷的数量。在FDA对提交的ANDA进行归档审核期间，FDA会决定是否有重大缺陷或轻微缺陷。通常，重大缺陷是FDA认为比较严重的情况，例如发现违反21 CFR 314.101(d) 或 21 CFR 314.101(e)中要求的某些缺陷，其它的重大缺陷将在本指南和其它指南中进行讨论。大量轻微缺陷（以下将进行讨论）也会构成重大缺陷。一个重大缺陷就会使得FDA依据21 CFR 314.101(d)(3)判定该ANDA是表面不完整的，因此FDA将会RTR含有一个重大缺陷的ANDA。

A minor deficiency is one that in FDA’s judgment is minor in nature and can be easily remedied[15].  As a result, FDA will allow theapplicant a prescribed time period (described below in this section) to provide a response to such deficiencies.  In particular, if FDA determines that an ANDA contains fewer than ten minor deficiencies (i.e., nine deficiencies or fewer), FDA will notify the applicant ofthe deficiencies, by phone, fax, or through the primary method for communication, which is email.  FDA, in its discretion, providesapplicants with the opportunity to correct minor deficiencies or amend the ANDA, within seven (7) calendar days[16].    If within 7calendar days the requested information is not received, FDA will RTR the ANDA.

轻微缺陷是指FDA认为情况比较轻微，很容易补正的缺陷。因此，FDA会允许申报者在指定时间段内（在本部分的以下部分说明）提交对这些缺陷的回复。尤其是如果FDA确定一份ANDA含有小于10个轻微缺陷的时候（即，9个缺陷或更少），则FDA会通过电话、传真、或基本沟通方法即电子邮件方式将这些缺陷告知申报者。在通知中，FDA会告知申报人在7个自然日内有机会纠正轻微缺陷或修订ANDA。如果在7个自然日内没有收到所索取的信息，FDA则会拒收该ANDA。

However, if FDA determines that an ANDA contains ten or more minor deficiencies or one or more major deficiencies, FDA will notconsider the ANDA to be a substantially complete application under 21 CFR 314.101(b)(1).  In such cases, FDA will notify theapplicant that FDA considers the ANDA not to have been “received.”  If the applicant decides to submit additional materials to correctthe deficiencies, the resulting amended ANDA will be considered a new ANDA submission, received as of the date the amended ANDAis submitted (if deemed substantially complete), and the applicant will be required to pay a new ANDA fee.  If an ANDA is not receivedand the applicant takes no action, FDA may consider the ANDA withdrawn after 1 year[17].   An ANDA applicant’s failure to take actionafter a refuse-to-receive decision on an ANDA may be considered a request by the applicant to withdraw the ANDA, unless theapplicant requests an extension of time in which to resubmit the ANDA[18].   There may be circumstances, however, under which anexception to, or a waiver of, a regulatory requirement may be granted.  FDA will consider the merits of such circumstances on a case-by-case basis[19].

但是，如果FDA认为一份ANDA中含有10个或更多轻微缺陷，或1个或更多重大缺陷，则FDA会认为该ANDA根据是21 CFR 314.101(b)(1)实质不完整的。在此情形下，FDA会通知申报人FDA将视该ANDA为未被接收。如果申报人决定提交更多资料来纠正这些缺陷，则所导致的修订后的ANDA会被当作一份新的ANDA来处理，修订后的ANDA提交日期会被作为是申报接收日期（如果修订后的资料是实质性完整的话），FDA会要求申报人支付一份新ANDA的费用。如果提交的ANDA没有被接受，而申报人在收到ANDA被拒收的决定后又没有采取措施，除申报人申请延期提交ANDA以外，视作申报人要求撤回该ANDA。当然，也有一些情形下会有例外，或者是豁免，这时FDA会各案考虑此种情形。

The following sections discuss deficiencies that FDA considers to be major deficiencies. A selection of minor deficiencies is providedin Appendix A.

下节讨论FDA 认为重大的缺陷。附录A中给出了轻微缺陷项目。

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

本指南由食品药品管理局（FDA）的化药评审中心（CDER）的仿制药办公室（OGD）起草制订。

[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，ANDA一词代表ANDA和新剂量PAS申报。

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

不应将拒收（RTR）决定与拒绝批准决定相混淆。

[4] 21 CFR 314.101(b)(1).

[5] 21 CFR 314.3(b).

[6] At various points in this guidance, it is noted that when a particular type of deficiency in an ANDA is seen, FDA will RTR the ANDA. It is important tounderstand that these statements do not create legal obligations, on applicants or on FDA, but rather are included for purposes of transparency. This meansthat 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 ANDAapplicant may be able to demonstrate, in particular circumstances, that the regulatory requirements for receiving an ANDA have been met even when, asdescribed in this guidance, FDA would in the normal course find the application not sufficiently complete to permit a substantive review and RTR it.

在本指南的不同地方，要注意如果FDA在一份ANDA中发现了某种类型的缺陷，则会拒收该ANDA。因此，理解这些声明并不对申报人或FDA产生任何法律义务，而只是为了使得程序更为透明。这意味着FDA在通常程序下会根据本指南所述拒收某份ANDA。本指南并不排除ANDA申报人可能在特殊情形下证明一份ANDA符合本指南中所述的法规接收要求，但FDA仍在正常流程中发现申报资料不够完整无法开始实质性评审，从而拒收的可能性。

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

2012年仿制药用户费用修正案（GDUFA）（公共法112-114，标题III）。

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

参见仿制药费用法案项目绩效目标和程序。

[9] See 21 CFR 314.101(b)(1) and 314.3(b).

[10] 21 CFR 314.3(b).

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

[12] See FY 2015 Performance Report to Congress for the Generic Drug User Fee Amendments, available at http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Reports/UserFeeReports/PerformanceReports/U   CM493026.pdf.

参见2015财年FDA呈交议会的《仿制药费用修订案》绩效报告，可以从上述网址获得。

[13] 21 CFR 314.101(d)(3).

[14] Pursuant to 21 CFR 314.101(d), FDA “may” not consider an ANDA to be received if any of the deficiencies under that regulation applies. FDA willdetermine on a case-by-case basis whether a deficiency under certain provisions of § 314.101(d) is a major or minor deficiency, in accordance with theprinciples described in this guidance.

根据21 CFR 314.101(d)，如果根据适用的法规被判定为缺陷，则FDA可以认为该ANDA不能被接收。FDA会按照本指南中所述的原则，依据§314.101(d)的某些条款各案决定一个缺陷是重大缺陷还是轻微缺陷。

[15] Though the focus of this guidance is to highlight major deficiencies, select minor deficiencies are listed in Appendix A — the list is not a comprehensivelist of minor deficiencies.

尽管本指南重点是强调重大缺陷，但在附录A中仍列出了一些轻微缺陷-----该清单并不是轻微缺陷的穷尽列表。

[16] The response period will begin the day after notification is provided. If the 7th calendar day falls on a Saturday, Sunday, or Federal holiday, the deadlinefor amending the ANDA to correct the deficiencies will be the next day that is not a Saturday, Sunday, or Federal holiday.

回复期限从发出通知日起算。如果第7个自然日是周六、周日或联邦假日，则补正ANDA的时间期限依次顺延至周末或假期后第一个工作日。

[17] 21 CFR 314.101(b)(3)(iii).

[18] Abbreviated New Drug Applications and 505(b)(2) Applications; Final Rule, 81 FR 69580, 69622 (October 6, 2016).

简略新药申报和505(b)(2)申报。最终规则 ，81FR 69580, 69622 (2016年10月6日)

[19] 21 CFR 314.99(b).

A.        Form FDA 356h (356h) FDA365h 表格 (365h)

An ANDA must contain a completed application form (i.e., Form FDA 356h).  If this form is not included, or is not signed, whichindicates that the applicant is not attesting to the material contained in the application, FDA will RTR the ANDA[1].

申请必须包含一份完整的申请表格（即FDA 356h 表格）。如果申报资料中该表缺失，或者是表格没有签字，则表示申报人没有证明申报中所包含的资料，则FDA会拒收该ANDA。

B.        Submission, Format, and Organization 申报资料、格式和文件结构

The ANDA should be formatted according to the eCTD format, and it should be submitted electronically for GDUFA metric goals to apply to the ANDA[2].  Under Section 745A(a) of the FD&C Act, electronic submissions of applications to FDA will be required at least24 months after the issuance of the final guidance for industry, Providing Regulatory Submissions in Electronic Format – CertainHuman Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (the eCTD guidance), whichpublished on May 5, 2015.  Accordingly, the electronic submission of ANDAs in a format specified by FDA is required as of May 5,2017[3].

应根据eCTD格式要求制作ANDA，并按GDUFA对ANDA的量度目标进行电子提交。根据FDCA的745A(a)部分要求，在行业指南《以电子格式提交法规申报资料----使用eCTD标准提交指定人药产品的申报和相关申报》签发后最迟24个月，即应以电子方式向FDA提交申报资料。该指南是在2015年5月5日发布的，因此，要求自2017年5月5日起按照FDA指定的电子格式提交ANDA申报资料。

C.         Non-Payment of GDUFA Obligations 未付清GDUFA费用

FDA will RTR an ANDA in certain cases if there are outstanding user fee obligations[4]:

FDA将在某些情形下拒收用户费用有突出问题的ANDA：

·         If an applicant fails to pay the GDUFA ANDA or PAS fee within 20 calendar days of submitting the application[5]

·         申报人在提交申报资料之后20个自然日内未支付ANDA或PAS的GDUFA费用

·         If an ANDA references a Type II active pharmaceutical ingredient (API) Drug Master File (DMF) that is not on the public available forreference list because of non-payment of the GDUFA DMF fee[6]

·         ANDA所引用 的II类原料药（API）DMF由于没有支付GDUFA费用而不在可引用清单上

·         If an ANDA references a facility that is on the facility arrears list for failure to pay the GDUFA facility fee(s)[7]

·         ANDA所引用 的生产厂址由于未支付GDUFA场所费用而被录入了拖欠清单

·         If the applicant is the owner of or is affiliated with the owner of a facility on the facility arrears list[8]

·         申报人是场所费用拖欠清单上某场所的所有者或者是关联方

·         If the applicant is listed on the backlog arrears list[9]

·         申报人被列入了积压费拖欠清单中

·         If the applicant is affiliated with an applicant on the backlog arrears list[10].

·         申报人是积压费拖欠清单上申报人的关联方

In all of these cases, FDA will RTR an ANDA for nonpayment of GDUFA user fee obligations. Upon satisfaction of all applicable userfee obligations, CDER’s Office of Management will issue a formal correspondence to the applicant indicating the adjusted receipt date (i.e., the date on which all outstanding user fee obligations were satisfied in full) for which the ANDA is eligible.

上述所有情形下，FDA都将拒收未支付GDUFA用户费的ANDA。在所有相关用户费用全部缴清后，CDER管理办公室将签发一份信函给申报人，写明调整后的接收日期（即所有欠费付清的日期）。自该日期开始，该ANDA具备合法地位。

D.        Lack of a Designated U.S. Agent for a Foreign Applicant 外国申请人未指定美国代理人

FDA will RTR an ANDA if a foreign applicant does not designate a U.S. agent.  If the person signing the application form (i.e., FormFDA 356h) does not reside or have a place of business within the United States, the application form is required to contain the nameand address of, and be countersigned by, an attorney, agent, or other authorized official who resides or maintains a place ofbusiness within the United States[11].

如果ANDA由国外申报人提交，且未指定美国代理，则FDA会拒收该ANDA。如果签署申报表格（即FDA356h表）的人不居住在美国，或者是在美国没有业务地址，则申报资料中需要包括有一位居住在美国或在美国有业务地址的律师、代理或其它授权人员的姓名和地址，并由其会签。

E.         Citing a Pending Suitability Petition as a Basis of Submission 引用尚未裁决的适用性请愿作为申报的基础

If an applicant submits a copy of, or refers to, a pending suitability petition, FDA will RTR the ANDA because it lacks a legal basis forthe submission[12]. An ANDA can rely on a suitability petition as a basis of submission only after the petition has been approved byFDA.  ANDAs can be submitted for drug products that differ from the listed drug, provided that a suitability petition requesting achange is submitted pursuant to section 505(j)(2)(C) of the FD&C Act and in accordance with 21 CFR 314.93 and 10.30, and thesuitability petition is approved by FDA.  The changes (from the RLD) that can be requested in a suitability petition are:

如果一个ANDA提交或引用了一份尚未裁决的请愿书，则FDA将因该申报缺陷法律依据而拒收该ANDA。只有在一个请愿被FDA批准之后，ANDA才可以依赖于该请愿将其作为申报依据。如果根据FDCA的505(j)(2)(C)部分和21CFR314.93和10.30提交了适用性请愿书申请进行变更，并且该适用性请愿获得FDA批准，则所提交的ANDA中的药品可以与参比药物有差异。通过适用性请愿可以要求的变更（与RLD相比较的变更）有：

·         Change in route of administration

·         给药途径变更

·         Change in dosage form

·         剂型变更

·         Change in strength

·         剂量变更

·         One active ingredient is substituted for one of the active ingredients in a listed combination drug

·         将复方药品中的一种活性成分被另一种活性成分取代

An applicant who wishes to rely on an approved suitability petition as the basis of submission for an ANDA can do so by identifying thelisted drug cited in the approved petition as the basis for the ANDA, subject to the limitation described in 21 CFR 314.93(f)(2)[13].   Inaddition, the docket number and a copy of FDA’s correspondence approving the petition must be included in the ANDAsubmission[14].,

期望将一份经过批准的请愿书作为其ANDA申报资料基础的申报人可以通过指明在批准的请愿书中所引用的参比制剂作为其ANDA的基础，该引用受到21 CFR 314.93(f)(2)中所述的限制。另外，在ANDA申报资料中还要包括文档编号和FDA批准该请愿的通信副本。

REVIEWS FOR API  原料药评审A.        Starting Material 起始物料

FDA will RTR an ANDA if the active pharmaceutical ingredient (API) review, whether in an ANDA or in a referenced drug master file (DMF), reveals that the starting material for the API is not justified according to the principles in the ICH Q11 guidance[15][16].

如果API 审评发现该API 指定的起始物料是不恰当的，不管是在ANDA 申请或引用的DMF 中， FDA 都将拒收该ANDA 申请。

B.        Sterility Assurance Data 无菌保证数据

FDA will RTR an ANDA if the API review, whether in an ANDA or a referenced DMF, reveals that sterility assurance data are missingfor a sterile API[17].

如果API 审评发现无菌API 的无菌保证数据缺失，不管是在ANDA 申请或引用的DMF 中， FDA 都将拒收该ANDA 申请。

PRODUCT QUALITY DEFICIENCIES 药品质量缺陷A.        Inactive Ingredients[18] 非活性成分

1.                  Inactive Ingredients Exceeding the Inactive Ingredient Database Limit 非活性成分超出非活性成分数据库限度

FDA will RTR an ANDA if the submission proposes to use an inactive ingredient at a level that exceeds any of the inactive ingredientdatabase (IID) listings without the justification described below[19].[20]   Applicants can justify inactive ingredient levels by reference to the IID, which is a listing of inactive ingredients and their maximum levels of use (per dosage unit or percent composition), arrangedby either route of administration or dosage form[21].   An inactive ingredient is considered justified, for receipt purposes, if theproposed level is at or below the amount indicated in the IID for the corresponding route of administration of the drug product.  If anapplicant wishes to use an inactive ingredient at a level per unit that is higher than what is proposed in the IID, options are available tofacilitate receipt of the ANDA:

如果申报资料要求使用的非活性成分数量超出非活性成分数据库（IID）列表，而没有下述论证，则FDA会拒收ANDA。申报人可以引用IID来论证非活性成分水平。IID是一份非活性成分及其最大使用量（每一剂量单位或百分比）清单，按给药途径或剂型排序。如果所提议的一个非活性成分用量等于或低于IID中对应给药途径对应剂型的数量，则该非活性成分就可以作为经过论证，不影响ANDA接收。如果申报人希望使用的非活性成分数量高于IID中所建议的数量，可以通过以下方式来促成FDA接收该ANDA：

·         Submit complete pharmacology/toxicology information. 提交完整的药学/毒理学资料

In the draft guidance, FDA described the type of pharmacology/toxicology information that should be submitted for ANDA submissionsthat propose to use an inactive ingredient at a level that exceeds any of the IID listings to avoid FDA refusing-to-receive the ANDA.After additional consideration, FDA believes that this issue bears further evaluation, and the Agency is not prepared to offer itscurrent thinking on this subject at this time. The Agency anticipates addressing this issue in a separate guidance.

在指南草案中，FDA描述了使用一种非活性成分超出IID清单水平，但为了避免FDA拒收该ANDA而在ANDA中提交的药学/毒理学资料类型。在深入考虑之后，FDA相信此问题还需要进一步评估，目前尚无法提供当局对此问题的看法。当局预期会在另一份指南中单独说明此问题。

·         Cite a specific example of a CDER-approved drug product. 引用一个CDER已批准药品的特定样例

Applicants should cite a specific example of a CDER-approved drug product that contains the inactive ingredient at or above theproposed level of use[22] for the appropriate route of administration.

申报人应引用一个包括非活性成分水平等于或高于所拟适当给药途径使用水平，且CDER已批准药品的特定样例。

·         Refer to an FDA controlled correspondence response. 引用一份FDA受控通信回复

Applicants should refer to a controlled correspondence in which FDA issued a response indicating that the proposed level of use is acceptable for receipt purposes[23].   Applicants should calculate the maximum daily intake (MDI) for the inactive ingredient andprovide the name of the RLD, if applicable.  No more than three inactive ingredient queries should be submitted per controlledcorrespondence.

申报人应引用一份FDA签发的认为所拟使用水平是不会导致拒收的回复受控通信。申报人应计算非活性成分最大日摄入量（MDI），适用时提供RLD名称。在每个受控通信所提交的非活性成分不应超过3个。

Inactive ingredient justification for oral liquid drug products should not be based on a listed percentage in the IID. This is because thecomponents of liquid dosage forms are generally expressed in terms of milligrams per milliliter (%w/v), and as a result, the amount ofinactive ingredient delivered per dose cannot be properly ascertained by simply comparing the %w/v composition of a particular inactive ingredient to a threshold percentage in the IID.  Instead, the applicant should calculate the amount of inactive ingredient that isdelivered per dose or per day (MDI) based on dosing recommendations indicated in the RLD label.  In addition, the applicant should justify the calculated amount based on an amount-per-unit IID listing that corresponds to an oral dosage form (e.g., solid oral dosage form).  Alternatively, for the ANDA to be considered for receipt, one of the previously discussed options in this section can be used.

口服液体制剂的非活性成分论证不应基于IID上列出的百分比。这是因为液体剂型的成分通常是以毫升每毫克（%w/v）的形式表达，因此，每一剂量所给药的非活性成分数量无法通过简单地将制剂里某个非活性成分的%w/v与IID里的百分比阈值进行比较来恰当地确定。相反，申报人应根据RLD标签上显示的剂量建议计算每剂或每日给药的非活性成分数量（MDI）。此外，申报人应根据IID中列出的口服剂型（例如固体口服剂型）中每单位数量所计算出的数量进行论证。为了让ANDA可以接受，也可以使用在本部分前面所讨论的方法之一。

Inactive ingredients that are included in powders for oral suspension should be justified as described in the preceding paragraph, with calculations of amounts delivered per dose based on the dry powder composition (i.e., prior to reconstitution).

口服混悬剂用的粉末中的非活性成分应按前段中所述根据干粉成分（即调配之前）中每剂给药数量的计算进行论证。

When justifying inactive ingredients for semi-solid and topical dosage forms, applicants can refer to listed percentages in the IID. However, the percent concentration of each inactive ingredient should be converted into an amount expressed in one of the followingforms: mg/mL, mg/g, mL/mL, etc.

在论证半固体剂型和局部给药剂型中的非活性成分时，申报人可以引用IID中列出的百分比。但是，每种非活性成分的百分比浓度应转换成以下形式之一所表达的数量：mg/mL、mg/g、mL/mL。

2.                  Changes to Non-Exception Inactive Ingredients in Parenteral, Ophthalmic, and Otic Products

注射剂、眼用和耳用药品中非例外非活性成分的变更

FDA will RTR an ANDA if certain concerns with respect to non-exception inactive ingredients are not addressed in the ANDA[24].

如果在ANDA中没有说明关于非例外非活性成分的特别注意事项，FDA将会拒收该ANDA。

Parenteral drug products generally must contain the same inactive ingredients and in the same concentration as the RLD[25].  However, specific changes (from the RLD drug product) are permitted for certain inactive ingredients (i.e., preservatives, buffers, andantioxidants), which are considered exception inactive ingredients. Applicants should identify and characterize the differences andshould submit information demonstrating that the differences do not affect the safety or efficacy of the proposed drug product[26].  This justification is a critical aspect of the exception inactive ingredient allowance and should be provided in the ANDA to support theproposed exception inactive ingredient change.

一般来说，注射剂中必须包括有与RLD相同的非活性成分，且浓度相同。当然，允许对某些例外非活性成分（即防腐剂、缓冲剂和抗氧化剂）进行变更（不同于RLD药品）。申报人应写明这些差异，并说明差异的属性，提交资料证明这些差异不会影响所申报药品的安全性和有效性。这些论证对于例外非活性成分允差来说是非常关键的内容，应在ANDA中提交以支持所拟的例外非活性成分变更。

For all other inactive ingredients, an ANDA whose subject is a parenteral drug product must be qualitatively and quantitatively thesame (Q1/Q2 same) as the RLD, with certain allowable differences permitted under 21 CFR 314.94(a)(9)(iii)[27].   Before submittingan ANDA, the applicant can submit a controlled correspondence to request a Q1/Q2 evaluation of proposed formulations to minimizethe risk of FDA refusing-to-receive the ANDA[28].   Even if an inactive ingredient is determined to be quantitatively the same as theRLD, the proposed concentration should be justified with reference to the IID in the event that it falls within the upper limit of theQ1/Q2 threshold.  In other words, if an inactive ingredient is demonstrated to be quantitatively the same as the RLD (same implies≥95% but ≤105% of the RLD concentration or amount) yet exceeds the IID limit for the applicable route of administration, FDA will RTRthe ANDA[29].

至于其它所有非活性成分，注射剂的ANDA中必须保持其定性定量均与RLD相同（Q1/Q2相同），其允许差异根据21 CFR 314.94(a)(9)(iii)规定执行。在提交ANDA之前，申报人可以提交一份受控通信索取对所拟配方的Q1/Q2评估，以最大程度减少FDA拒收该ANDA的风险。即使非活性成分与RLD含量相同，如果是落在Q1/Q2阈值的上限，则仍需参照IID对所拟浓度进行论证。换句话说，如果一种非活性成分被证明其含量与RLD相同（相同表示≥95% 但≤105%RLD浓度或数量），但超过了IID对应用给药途径的限度，则FDA还是会拒收该ANDA。

An ANDA concerning an ophthalmic drug product should be Q1/Q2 the same as the RLD with respect to all of its components, orinclude data from appropriate BE studies[30].   Despite a similar allowance (to parenteral products) provided for ophthalmic drugproducts in 21 CFR 314.94(a)(9)(iv), FDA has determined that, as a scientific matter, any qualitative or quantitative deviations fromthe RLD should be accompanied by an appropriate in vivo BE study or studies.

眼用制剂的ANDA中所有组分的浓度在Q1/Q2均应与RLD完全相同，否则需要在申报资料中包括适当的BE研究数据。尽管在21 CFR314.94(a)(9)(iv)中对眼用制剂也规定了（与注射剂）的类似允差，但FDA已经决定，从科学角度，任何数量或质量方面与RLD的差异均需实施适当的体内BE研究。

For otic drug products, differences with respect to the types of inactive ingredients listed in 21 CFR 314.94(a)(9)(iv) are permitted,provided that these differences are identified and characterized and information is submitted demonstrating that these differences do not affect the safety or efficacy of the proposed drug product.

对于耳用制剂，允许对21 CFR 314.94(a)(9)(iv)中列出的非活性成分类别有所差异，但这些差异需要进行列出并说明其属性，还要提交资料证明这些差异不会影响所提交药品的安全性和有效性。

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[1] 21 CFR 314.101(d)(1).

[2] To ensure receipt of an electronic submission, please follow the current eCTD specifications as provided in FDA’s Data Standards Catalog available at http://www.fda.gov/downloads/ForIndustry/DataStandards/StudyDataStandards/UCM340684.xls.

为确保FDA收到电子申报资料，请遵守在上述网址中FDA的数据标准目录上给出的现行eCTD规范。

[3] To ensure receipt of an electronic submission, please follow the current eCTD specifications as provided in FDA’s Data Standards Catalog available at

http://www.fda.gov/downloads/ForIndustry/DataStandards/StudyDataStandards/UCM340684.xls.

为确保FDA收到电子申报资料，请遵守在上述网址中FDA的数据标准目录上给出的现行eCTD规范。

[4] See Generic Drug User Fee Amendments of 2012; Public Law 112-144, Title III. See also [url]http://www.fda.gov/ForIndustry/UserFees/GenericDrugUserFees/ucm319567.htm [/url]and the guidance for industry Generic Drug User Fee Amendments of 2012uestions and Answers Related to User Fee Assessments.

参见2012年仿制药用户费用修正案：公共法112-144，题III。也参见上述网址和2012年仿制药用户费用修正案行业指南：与用户费用评估的问答。

[5] Section 744B(g)(3) of the FD&C Act. 参见FDCA法案第744B(g)(3)部分。

[6] Section 744B(g)(2) of the FD&C Act. 参见FDCA法案第744B(g)(2)部分。

[7] Section 744B(g)(4)(A)(ii) of the FD&C Act 参见FDCA法案第744B(g)(4)(A)(ii)部分。

[8] Section 744B(g)(4)(A)(i) of the FD&C Act. 参见FDCA法案第744B(g)(4)(A)(i)部分。

[9] Section 744B(g)(1) of the FD&C Act. 参见FDCA法案第744B(g)(1)部分。

[10] Id.

[11] 21 CFR 314.94(a)(1) (incorporating by reference 21 CFR 314.50(a)(1), (3), (4), and (5)).

[12] 21 CFR 314.101(d)(3).

[13] 21 CFR 314.94(a)(3)(i).

[14] 21 CFR 314.94(a)(3)(iii).

[15] See International Conference on Harmonisation (ICH) (2012), Q11 Development and Manufacture of Drug Substances (Chemical Entities andBiotechnological/Biological Entities).

参见ICH(2012)，Q11《药用物质（化学实体和生物技术/生物制品实体）研发和生产》。

[16] 21 CFR 314.50(d)(1)(i).

[17] 21 CFR 314.50(d)(1)(i) and 21 CFR 314.50(d)(1)(ii).

[18] In general, although considered supportive, GRAS certification, FEMA certification, DMF authorization, or composition are not considered sufficientjustification to support safety of an inactive ingredient or level at which it is used in the drug product.

一般来说，尽管可以接受GRAS认证、FEMA认证、DMF授权或组成作为支持性材料，但并不会作为可以支持某个非活性成分本身或其所用数量的充分论证。

[19] If the inactive ingredient is determined to be a novel inactive ingredient for the corresponding route of administration of the drug product (unless it is aphysical mixture of components found in the IID and within acceptable IID maximum levels), FDA will RTR the ANDA. Use of a novel inactive ingredient willgenerally require submission as a 505(b)(2) application.

如果确定一种非活性成分对于对应的给药途径来说是新的（在IID里发现的成分混合物，且各成分均在可接受的IID最大水平内除外），则FDA会RTR该ANDA。使用一种新的非活性成分一般会要求按505(b)(2)申报要求提交资料。

[20] 21 CFR 314.94(a)(9)(ii).

[21] See http://www.accessdata.fda.gov/scripts/cder/iig/index.cfm.

[22] That is, amount per dosage unit or maximum daily intake (MDI) that is based on the calculated maximum daily dose (MDD) of the active ingredient in thedrug product.

即根据制剂中活性成分的计算最大日剂量（MDD）测算的每个剂量单位或最大日摄入量（MDI）。

[23] Controlled correspondences are submitted via e-mail through GenericDrugs@fda.hhs.gov. See  [url]http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm120610.htm        [/url]for more information.

受控通信通过上述邮箱通过邮件提交。参见上述网址获取更多信息。

[24] 21 CFR 314.94(a)(9)(ii).

[25] 21 CFR 314.94(a)(9)(iii).

[26] Id.

[27] Id. (Also, quantitative sameness generally is interpreted by OGD to mean a concentration that is within 95-105% of the RLD concentration. That is,sameness as discussed herein does not suggest an exact value, but rather a range of values).

数量等同性一般由OGD解释为浓度在RLD浓度的95-105%之间。也就是说这里讨论的等同性并不是指绝对值完全相同，而是指数值在一定范围内。

[28] As with other inactive ingredient queries, FDA requests that the applicant submit no more than three proposed formulations for evaluation per controlledcorrespondence. See, guidance for industry Controlled Correspondence Related to Generic Drug Development.

关于其它非活性成分查询，FDA要求申报人在每个受控通信评估中提交的配方不得超过3个。参见行业指南《仿制药研发相关受控通信》。

[29] The assumption should not be made that any listed IID concentration incorporates the 105% Q1/Q2 allowance.

不应假设所有列出的IID浓度均有105%的Q1/Q2允许范围。

[30] See 21 CFR 320.22(b)(1). An applicant proposing to submit an ANDA for a non-Q1/Q2 same ophthalmic drug product is strongly urged to contact theDivision of Bioequivalence for guidance prior to submitting an application.

参见21 CFR 320.22(b)(1)。申报人想要提交一份非Q1/Q2相同眼膏剂的ANDA时，强烈敦促其联系生物等效性办公室获取申报提交前指导。

A.        Inadequate Stability 稳定性不充分

1.                  Number of Batches and Length of Studies  批次数量及实验长度

FDA will RTR an ANDA if certain batch size and study recommendations are not satisfied[1][2]. The applicant should provide three pilot-scale batches or two pilot-scale and one small-scale batch with both accelerated and long-term data provided for each batchcovering a period of no less than 6 months (180 days), with data from three time points (e.g., 0, 3, and 6 months)[3]. However, if 6 months of accelerated data show a significant change[4] or failure of any attribute in one or more batches, the applicant should alsoinclude 6 months of intermediate[5] stability studies at the time of submission.

如果不满足批量要求和研究建议，FDA会拒收该ANDA。申报人应提交3批中试批量批次，或2批中试批量加一批小批量批次的加速和长期稳定性试验数据，数据应覆盖不少于6个月时间长度（180天），并且检测时间点要有3个（即0、3、6个月）。但是，如果6个月的加速数据显示在一个或一个以上批次中有任何属性有重大变化或不合格，则申报人还应在提交申报时包括6个月的中间条件稳定性研究数据。

The initiation date for each of the stability studies, along with individual pull dates (removal from the storage chamber) for eachstability time point should also be provided as part of the data to verify that each study covers the recommended 6-month (180 days)minimum hold time.

还应提交每次稳定性试验的起始日期，以及每个稳定性检测时间点样品取出日期（从存贮的考察箱中取出的日期）作为数据的一部分，用以核对稳定性试验是否包括了所建议的6个月（180天）的最短保存时间。

2.                  Container Orientation 容器朝向

FDA will RTR an ANDA if both worst-case scenario and non-worst-case stability data adhering to the recommendations described in section V.B.1 and this section are not submitted for the described drug product batches:  liquids, solutions, semi-solids, andsuspensions[6].

对于液体、溶液、半固体和混悬液制剂，如果根据建议所做的最差情形和非最差情形稳定性数据都放在第V.B.1部分，但该部分没有提交，则FDA会拒收该ANDA。

B.        Packaging Amount Considerations 包装数量考虑

FDA will RTR an ANDA if the ANDA does not package a minimum (threshold) amount of the finished drug product in thecontainer/closure systems that are proposed for marketing, as discussed in FDA’s guidance for industry ANDAs: Stability Testing ofDrug Substances and Products, Questions and Answers[7].   Also as discussed in the guidance, the threshold amount that should bepackaged is governed by the specific dosage form (e.g., solid oral dosage forms, oral powders/solutions/suspensions, parenteral drugproducts, ophthalmic/otic drug products, transdermal patches, and topicals such as creams/lotions/gels and inhalation solutions/nasalsprays) of the finished drug product that is the subject of the ANDA submission.

如果ANDA中制剂成品包装不是按FDA行业指南《ANDA：药用物质和制剂稳定性测试问答》中所讨论的采用上市最小包装容器/密闭系统包装最小（阈值）数量，则FDA会拒收该ANDA。在指南中还讨论到，应包装的阈值数量是由ANDA申报中的剂型来决定的（例如，固体口服剂型、口服粉末/溶液/混悬液，注射剂药品、眼膏/耳用制剂、透皮贴剂和局部用药例如膏剂/霜剂/胶和吸入溶液/鼻用喷雾）。

To qualify the dosage units that are packaged toward the applicable threshold, the following three recommended criteria for eachcontainer/closure configuration should be satisfied:

一个制剂包装单位所适用的阈值数量，应满足以下容器/密闭器参数建议标准：

·         Stability data (as described in section V.B.1 of this guidance).

·         稳定性数据（按本指南中V.B.1部分所述）

·         Container/closure system information should be submitted in ANDA section 3.2.P.7. If bracketing or matrixing is used, an ANDAshould include the container/closure system information applicable to configurations that were excluded from stability studiesbecause of bracketing or matrixing.

·         容器/密闭系统信息应在ANDA第3.2.P.7部分提交。如果使用了括号法或矩阵法，则ANDA中应包括括号法或矩阵法研究所不包括的容器/密闭系统参数信息。

·         Container and carton (if applicable) labeling for each packaging configuration containing dosage units to be counted in theoverall packaged total should be provided in section 1.14.1 of the ANDA.

·         在ANDA的1.14.1部分中应提交大包装中所有包装的每个包装参数的容器和纸盒（适用时）标签信息。

C.         Batch Records 批记录

FDA will RTR an ANDA if blank and executed batch records are not provided, regardless of whether commercial scale-up isproposed[8].   For example, both commercial (blank) and executed (pilot) batch records for the pilot batches that are manufactured tosupport an ANDA should be submitted, along with any accompanying reconciliation sheets.

如果没有提交已填写的批记录，不管是否已拟进行商业化放大，FDA均会拒收该ANDA。例如，应提交商业批次的空白批记录和生产用于支持ANDA的中试批次的已填写批记录，同时还有相关的数量平衡表格。

D.        Method Validation/Verification Reports 分析方法验证/确认报告

FDA will RTR an ANDA if method validation/verification reports are not provided[9].   It is critical that method validation/verificationreports for all analytical methods be provided in sections 3.2.S.4.3 and 3.2.P.5.3 of the ANDA, for both the drug substance (API) anddrug product, respectively.  That is, for drug products for which a relevant official United States Pharmacopeia (USP) drug productmonograph exists, verification[10] of the USP analytical procedures should be provided.  Verification should also be submitted for methods used from outside sources, such as a Type II API DMF holder, unless the methods have been fully validated in house.  Forany in-house methods used, validation of the analytical procedure should be submitted in either of the appropriate sections of theANDA (i.e., sections 3.2.S.4.3 or 3.2.P.5.3). In-house methods used in lieu of USP methods should be compared to the USP method tosupport a demonstration that the in-house method is sufficient.

FDA将拒收未提交分析方法验证/确认报告的ANDA。在ANDA的3.2.S.4.3和3.2.P.5.3部分中分别提交原料药（API）和制剂的所有分析方法验证/确认报告是很关键的。也就是说，对于在USP药品各论中已有的药品，应提交USP分析方法的确认。外包所用方法也要提交确认，例如II类原料药DMF持有人所用方法，否则应在公司实施全面验证。所有内部分析方法，均应在ANDA的适当部分（即3.2.S.4.3或3.2.P.5.3）提交分析方法验证资料。使用内部方法代替USP方法的，应将该方法与USP方法进行比较，以支持证明内部方法是充分的。

In addition, for ANDAs not submitted electronically[11], the applicant should submit three copies of the method validation/verificationpackage for the API, the drug product, or both[12].

此外，非电子提交的ANDA应提交3份原料药和/或制剂的分析方法验证/确认副本。

E.         Special Consideration for Transdermal Patches 对透皮贴剂的特殊考虑

FDA will RTR an ANDA for a transdermal patch if the ANDA does not address certain special considerations[13][14].

对于透皮贴剂，如果ANDA没有说明某些特殊考虑，则FDA会拒收该ANDA。

·         Matrix Systems 基质系统

ANDAs for matrix transdermal systems should be supported by stability data on three batches of drug product manufactured fromthree distinct laminates, where each batch of laminate is made using different lots of API, adhesives, backing, and/or other criticalelements in the drug product.  If an applicant is seeking approval for multiple strengths of a particular drug product, the applicant canchoose to use a bracket approach by manufacturing three batches of the highest and lowest strengths and at least one batch of eachof the bracketed strengths.  An example is given below.

基质透皮系统的ANDA应采用3种明显不同的层压法生产的3个批次的稳定性数据来支持，其中每批层压应使用不同批次的原料药、粘合剂和/或其它制剂中的关键要素。如果申报者想要一种特定药品的多个剂量获得批准，则可以选择使用括号法，即生产最高和最低剂量各3批，包括在其中的每个剂量各1批。举例如下：

-   Laminate Batch # 1 (pilot-scale):  All strengths (highest, lowest, and bracketed)

-   层压批次1（中试批量）：所有剂量（最高、最低和其中所覆盖的）

-   Laminate Batch # 2 (pilot-scale):  Highest and lowest strengths

-   层压批次2（中试批量）：最高和最低剂量

-   Laminate Batch # 3 (pilot- or small-scale): Highest and lowest strengths

-   层压批次3（中试或小批量）：最高和最低剂量

·         Reservoir Systems 储库系统

Applicants are strongly encouraged to consult the Office of Lifecycle Drug Products, within the Office of Pharmaceutical Quality beforemaking a decision to develop a reservoir transdermal system product.  ANDAs for reservoir transdermal systems should be supportedby stability data on three batches of drug product manufactured from three distinct reservoir gels. Each batch of drug product should use different lots of API, adhesives, gel excipients, backing membrane, rate controlling membrane, and/or other critical elements in thedrug product.  If multiple strengths of a reservoir transdermal system are prepared from reservoir gels containing differentconcentrations of API, three batches of each strength should be manufactured. A bracket approach is usually not acceptable.

强烈鼓励申报人在决定研发储库型透皮系统药品之前，咨询药品质量办公室下的药品生命周期办公室。储库型透皮系统的ANDA应有采用3种截然不同的储库胶所生产的3批产品的稳定性数据来支持。每批产品应使用不同批次的原料药、粘合剂、背衬膜、速度控制膜和/或其它药品中的关键要素。如果采用了含有不同浓度原料药的储库胶制备不同剂量的储库透皮系统，则每种剂量应各生产3个批次。通常不接受采用括号法。

F.         Scoring and Conditions of Use 刻痕与使用条件

1.                  Functional Scoring Configurations That Are Inconsistent With the RLD 功能性片剂刻痕与RLD不一致

FDA will RTR an ANDA if there are inconsistencies in the scoring configuration between the RLD and the test product and thoseinconsistencies have not been reviewed and approved by FDA before submission of the ANDA. Scoring configurations often facilitatedose titration and other patient-specific regimens that would be imprecise because of the difficulty of splitting an unscored tablet (formore information, see FDA’s guidance for industry Tablet Scoring: Nomenclature, Labeling, and Data for Evaluation (Tablet Scoringguidance)).  FDA’s Tablet Scoring guidance recommends that the “scoring configuration of generic drug products should be thesame as the RLD” and so demonstrate that the test product can be administered in a manner consistent with the dosingrecommendations of the RLD.

如果RLD和受试药品在刻痕参数方面不一致，并且这些差异在ANDA申报提交之前没有获得FDA审核批准，则FDA会拒收该ANDA。刻痕参数通常会有利于剂量分度，以及其它患者特有的不精确的方法，因为没有刻痕的片剂难以分割（更多信息参见FDA行业指南《片剂刻痕：名称、标签和评估数据》（片剂刻痕指南））。FDA的片剂刻痕指南建议“仿制药的刻痕参数应与RLD相同”，这样才能证明受试药品的服用方式与RLD所建议的给药剂量是一致的。

Inconsistencies in scoring configuration between the RLD and the test product may not facilitate this demonstration.  For example, ifan RLD 10 mg tablet is scored to enable administration of a 5 mg dose (and a 5 mg dose is supported by the label) and the testproduct is unscored and does not offer a 5 mg strength, an ANDA applicant will be unable to demonstrate that the test product can beadministered in a manner consistent with the dosing recommendations of the RLD.

RLD和受试药品之间的刻痕参数可能对上述证明不利。例如，如果一个RLD是10mg片剂，加了刻痕后使得服用剂量可以是5mg每剂（标签支持每服用剂量为5mg），受试药品则没有刻痕，并不提供5mg的剂量，这时ANDA的申报人则无法证明受试药品的服用剂量能够与RLD的建议剂量一致。

Conversely, if the ANDA product (e.g., 10 mg) is manufactured with a score mark and the RLD 10 mg tablet is unscored and the labelindicates no recommended dose lower than 10 mg, the test product offers the potential for delivering a dose (5 mg) that is notreflected in the label, which would be considered a new dosing regimen.  As a result, an ANDA applicant will be unable todemonstrate that the test product would be administered only in a manner consistent with the dosing recommendations of the RLD.

相反，如果生产的ANDA 药品（例如 10mg）带有刻痕，但RLD 10 mg 的片剂无刻痕，而且标签中未推荐低于10 mg 的用药剂量，受试药品提供了标签中没有标示的5mg 的使用的可能，这种情况将被视为一个新的给药剂量方案。这时，ANDA申报人就不能证明受试药品只能按RLD建议的给药剂量服用。

2.                  Fill Volumes for Parenteral Drug Products That Differ From the RLD 非肠道用药的装量与RLD不同

FDA will RTR an ANDA whose subject is a parenteral drug product if its fill volume deviates from the RLD drug product and thedeviation is not permitted[15] [16].    ANDA parenteral (injectable) drug products should contain the same concentration and total drugcontent per container as the RLD.  Therefore, a deviation from the fill volume (total drug content) of the RLD parenteral drug product may constitute a change in strength. A change in strength must first be approved via the suitability petition process (see section III.Fof this guidance) before it can be proposed in an ANDA submission.

ANDA 非肠道药品每一容器应与RLD装量上的偏差（总的药物含量）可能会导致规格上出现变化。规格变更必须在ANDA 申报中提出前通过稳定性请求流程批准（参见本指南的III.G.2 部分）。因此，任何未经批准的与RLD 不一致的装量改变都将导致FDA 拒收该ANDA。

3.                  Differences in Packaging and/or Labeling That May Be Associated With the Safe/Effective Use of the Drug Product 可能与药品安全/有效使用有关的包装上的差异

FDA will RTR an ANDA on a case-by-case basis if the ANDA contains differences in packaging and/or labeling from the RLD that maybe associated with safe/effective use of the drug product[17].   Generally, if the RLD is packaged with certain labeling in a manner to ensure its proper administration, the test product should be packaged and labeled similarly.  For example, an RLD product mayincorporate labeling on its packaging that contains a combination of visual and/or typographical aids, beyond the direct label text, tofacilitate patient compliance and safety. Blister packaging is an example of such packaging, whereby certain drug productscommunicate crucial patient information directly on the blister carton (and/or the blister itself) to both improve patient compliance andreduce the incidence of harm or injury that may result from improper administration of the drug product.  A blister carton may alsobetter allow any supplemental patient information to be attached directly to it, which in turn ensures that each patient receives thenecessary drug product information upon dispensing from a pharmacy.  Such a proposed product should generally be packagedsimilarly to the RLD to account for these considerations.

如果一份ANDA中的药品包装和/或标签不同于RLD，并且可能与药品的安全/有效使用有关，则FDA会拒收该ANDA。通常，如果RLD所采用的包装和标签是为了确保其服用正确，则受试药品的包装和标签应与RLD相似。例如，RLD药品可能会在其包装上放置标签，在标签上印制可见和/或图形，不仅仅是文字，以提高患者依从性，保证安全性。泡罩包装就是这类包装的一个例子，有些药品会直接在泡罩盒（和/或泡罩）上标注关键的患者信息，以提高患者依从性，减少可能会引发不当服药而导致的事故伤害。泡罩盒也可以直接将补充患者信息更好展现出来，同时确保每位患者在药房取药时接收到必要的信息。基于此种考虑，所申报的药品通常应与RLD包装类似。

4.                  Other Inconsistencies 其它不一致情况

FDA will RTR an ANDA if the ANDA contains certain other inconsistencies.  In accordance with 21 CFR 314.94(a)(4), an ANDA mustinclude a statement that the conditions of use prescribed, recommended, or suggested in the labeling proposed for the drug producthave been previously approved for the RLD.  However, there are certain exceptions (e.g., for labeling differences permitted pursuant to an approved suitability petition that is cited as an ANDA’s basis of submission (see section III.F for further details)).  Any otherproposed condition-of-use changes would not be acceptable. Examples of proposed condition-of-use changes may include, but arenot limited to, citing a sprinkle capsule dosage form as a basis of submission but producing a capsule that cannot be administered in the same manner as the RLD, or proposing alterations to either the amount of active ingredient delivered per dose or the dosingregimen such that neither are consistent with those described in the RLD labeling.

如果一份ANDA中包括其它的不一致情形，FDA将拒收该ANDA。根据21 CFR 314.94(a)(4)，ANDA必须包括一份声明，说明拟在申报药品的标签上注明的对之前批准的RLD处方使用条件的建议和推荐。但是，也会有一些例外（例如，在申报资料中引用已批准的适用性申诉，获得批准的差异性标签（更多信息参见第III.F部分））。此外提议的其它任何使用条件变更都不会接受。提议的使用条件变更例子可能包括但不仅限于，引用微粒胶囊剂型作为申报依据，但生产的胶囊并不能使用与RLD相同的方法服用；或者是提议了替代的每剂活性成分给药量和给药方案，但两者都与RLD标签所述的内容不一致。

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[1] ANDAs submitted and date-stamped by the Agency prior to June 20, 2014 (the date of implementation of FDA stability guidance), will be evaluated for filingreview purposes using ANDA stability recommendations in place prior to June 20, 2014.

2014年6月20日（FDA稳定性指南实施之日）之前提交并且已由FDA确定接受日期的ANDA，FDA将使用2014年6月20日之前的ANDA稳定性建议来进行归档审核。

[2] 21 CFR 314.50(d)(1)(i) and 21 CFR 314.50(d)(1)(ii).

[3] Guidance for industry ANDAs: Stability Testing of Drug Substances and Products. See also FDA’s guidance for industry ANDAs: Stability Testing ofDrug Substances and Products, Questions and Answers.

行业指南《ANDA：新原料药和新制剂稳定性试验》，也请参见FDA行业指南《ANDA：药用物质和制剂稳定性试验问答》。

[4] The ICH guidance for industry entitled Q1A(R2) Stability Testing of New Drug Substances and Products defines “significant change” as one or moreof the following (as appropriate for the dosage form): (1) a 5% change in assay from its initial value, or failure to meet the acceptance criteria for potencywhen using biological or immunological procedures; (2) a degradation product’s exceeding its acceptance criterion; (3) failure to meet the acceptancecriteria for appearance, physical attributes, and functionality test (e.g., color, phase separation, resuspendibility, caking, harness, dose delivery peractuation); however, some changes in physical attributes (e.g., softening of suppositories, melting of creams) may be expected under acceleratedconditions; (4) failure to meet acceptance criterion for pH; and (5) failure to meet the acceptance criteria for dissolution for 12 dosage units.

ICH行业指南Q1A（R2）《新原料药和制剂稳定性测试》定义“重大变化”为以下一种或多种情形（剂型适当时）：（1）含量与初始值相差5%，或者使用生物或免疫学方法检测时不符合效价的可接受标准，（2）药品降解超过其可接受标准；（3）外观、物理属性、功能测试（例如：颜色、相分离、重新混悬能力、结块、硬度、单次驱动给药剂量）任何一项不符合可接受标准。但是，有些物理属性（例如，栓剂软化、膏剂融化）在加速条件下发生变化是可预见的；（4）pH值不符合可接受标准以及（5）12个制剂单位溶出度不符合可接受标准。

[5] Intermediate storage condition testing does not apply to drug products intended for storage in a refrigerator.

中间存贮条件测试不适用于在冰箱中存贮的药品。

[6] See 21 CFR 314.94(a)(9)(i) stating that ANDAs must include chemistry, manufacturing, and controls information required under 21 CFR 314.50(d)(1).

参见21 CFR 314.94(a)(9)(i)，其中说明了21 CFR 314.50(d)(1)项下ANDA必须包括的研发、生产和检测信息。

[7] 21 CFR 314.50(d)(1)(ii).

[8] 21 CFR 314.50(d)(1)(ii)(b).

[9] 21 CFR 314.50(d)(1) and 314.94(a)(9)(i).

[10] EP (European Pharmacopoeia)/BP (British Pharmacopoeia)/JP (Japanese Pharmacopoeia) methods may be allowed, for which, in many cases, verification(versus full validation) may suffice.

在许多情形下，如果采用EP（欧洲药典）、BP（英国药典）和JP（日本药典）方法，只进行确认（相对于全面验证）可能就够了。

[11] On May 5, 2017, the electronic submission of ANDAs in a format specified by FDA will be required. See discussion in section III.B.

2017年5月5日，FDA将要求采用指定的格式电子提交ANDA。参见第III.B部分讨论。

[12] 21 CFR 314.50(e)(2)(i).

[13] 21 CFR 314.50(d)(1).

[14] In addition to the considerations identified in this section, FDA has provided recommendations on the submission of studies evaluating the adhesiveperformance of a Transdermal Delivery System (TDS) or topical patch in support of an ANDA in the guidance for industry Assessing Adhesion withTransdermal Delivery Systems and Topical Patches for ANDAs.  The recommendations provided in the guidance will supersede the recommendationsrelated to adhesion studies provided in individual product-specific recommendations published before the guidance was issued. Accordingly, FDA willRTR an ANDA for failure to follow the recommendations in the guidance once the final guidance is issued.

除了本部分所指出的所需考虑内容外，FDA还在行业指南《ANDA中透皮给药系统和局部贴剂粘性评估》中为用以支持ANDA的透皮给药系统（TDS）和局部贴剂的粘性研究评估申报资料提供了建议。指南中给出的建议将取代该指南发布之前已发布的具体药品建议中给出的粘性研究相关建议。相应地，一旦该指南定稿并发布，FDA会拒收未遵守该指南中建议的ANDA。

[15]That is, alterations beyond overfill allowances that are within USP recommendations in a relevant drug product monograph.

这是指超出USP相关药物各论中建议溢装范围的装量。

[16] See generally 21 CFR 314.50(d)(1).

[17] 21 CFR 314.94(a)(8)

A.        Microbiology Considerations 微生物学考虑

Generally, FDA will RTR an ANDA if it contains certain deficiencies related to microbiology considerations.

通常，如果申报中缺少任何无菌保证的验证研究，FDA 将会拒收该ANDA 申请。

An ANDA should contain all sterility assurance validation studies for terminally sterilized drug products and aseptically filled drugproducts, as described below[1]:

一份ANDA应包括终端灭菌药品和无菌灌装药品的所有无菌保证验证研究，具体如下：

1.      Terminally sterilized drug products 最终灭菌药品

·         Validation of production terminal sterilization process

·         药品最终灭菌工艺验证

·         Validation of depyrogenation of product containers and closures

·         产品容器和密封系统除热原验证

·         Validation of container-closure package integrity

·         容器-密封系统完整性验证

2.      Aseptically filled drug products 无菌灌装药品

·         Validation of the sterilizing grade filters (bacterial retention studies)

·         除菌过滤器等级验证（细菌截留实验）

·         Validation of the sterilization of sterile bulk drug or product contact equipment, components, containers, and closures

·         无菌待包装药品和产品接触到的设备、包材、容器和密封系统灭菌验证

·         Validation of the depyrogenation of product containers and closures

·         药品容器和密封系统除热原验证

·         Validation of the aseptic filling process/line/room (media fills/process simulations)

·         无菌灌装工艺/灌装线/灌装间验证（培养基灌装/工艺模拟）

·         Validation of container-closure package integrity

·         容器-密封系统完整性验证

In addition, an ANDA should include at the time of submission, at minimum, summaries of validation studies.

另外，ANDA应至少包括在提交时所有验证研究的摘要。

BIOEQUIVALENCE AND CLINICAL DEFICIENCIES 生物等效性和临床缺陷

As a general matter, ANDA applicants should refer to FDA’s “Product Specific Recommendations for Generic Drug Development”website for Bioequivalence (BE) guidances regarding recommended in vivo and/or in vitro BE and other recommended studies[2].

一般情况下，ANDA申报人应参考FDA的《仿制药研发具体品种建议》官网上的BE指南，获取推荐的体内和/或体外BE和其它推荐的研究。

A.        Failed In Vivo BE Studies 体内BE 研究失败

FDA will RTR an ANDA if only a failed in vivo BE study is submitted[3].   FDA regulations require applicants to submit information onfailed BE studies[4].   Typically, a failed study is one that does not satisfy the 90% confidence interval (CI) criterion (e.g., falls outsideof the 0.8-1.25 acceptance criterion limits) for either the area under curve (AUC) or peak plasma concentration (Cmax) parameter.  Ifthis occurs for highly variable drug products, the applicant may submit a study using a replicate study design and analyze data using areference-scaled average (RSA) approach for the failed parameter.  Applicants should refer to FDA’s “Product SpecificRecommendations for Generic Drug Development” website for BE guidances or submit BE guidance requests for proposed productsto Generic [url=mailtorugs@fda.hhs.gov]Drugs@fda.hhs.gov.[/url]

如果在ANDA中只提交了一份失败的体内BE试验，则FDA会拒收该ANDA。FDA的法规要求申报人提交失败的BE研究信息。一般来说，如果曲线下的区域（AUC）或血浆峰值浓度（Cmax）参数不满足90%置信区间（CI）标准（例如，落在0.8-1.25可接受标准限度以外），则认为该试验失败。如果这种情况发生在高变异药品上，则申报人可以提交一份使用同样设计的研究，采用参比校正平均（RSA）方法对失败参数进行数据分析。申报人应参考FDA的《仿制药研发具体品种建议》官网上的BE指南，或者是提交拟申报药品BE指南索取要求给仿制药办公室。

B.     Alternate BE Studies 替代BE 研究

FDA will RTR an ANDA if the ANDA contains one or more in vivo studies that were not recommended in the BE guidance, withoutadequate justification[5].  Adequate justification should include justification for an approach that deviates from FDA posted guidance,including data (Module 2.7 and Module 5) and appropriate references. Applicants should refer to FDA’s “Product Specific Recommendations for Generic Drug Development” website for BE guidances or submit BE guidance requests for proposed products to Generic [url=mailtorugs@fda.hhs.gov]Drugs@fda.hhs.gov.[/url]

如果一份ANDA包括一个或多个在BE指南中未曾推荐的体内研究，而没有充分的论证，则FDA会拒收ANDA。充分的论证应包括对偏离FDA发布的指南的方法的论证，包括数据（模块2.7和模块5）和适当的参考文献。申报人应参考FDA的《仿制药研发具体品种建议》官网上的BE指南，或者是提交拟申报药品BE指南索取要求给仿制药办公室。

C.         Q1/Q2 Sameness Requirement for Consideration of an In Vivo BE Study Waiver

体内BE 研究的豁免要求提供Q1/Q2 同一性

Certain drug products may be eligible for a waiver from conducting in vivo BE studies typically required to support an ANDA. Forexample, in accordance with 21 CFR 320.22(b)(1), parenteral drug products, in addition to both ophthalmic and otic solutions, may beeligible for a waiver of BE studies, provided that their formulations are considered Q1/Q2 same as the RLD[6].   If such a drugproduct is determined not to be Q1/Q2 same as the RLD, FDA will RTR the ANDA based on the determination that the drug product isineligible for a waiver because of permissible formulation differences[7].

某些特定的药品可能有资格豁免支持ANDA 申报通常需要的体外生物等效性研究。例如，根据21 CFR 320.22(b)(1)，除眼用及耳用溶液剂之外，如果配方被认为与RLD在Q1/Q2上相同，非肠道用药也可能有资格获得生物等效性研究豁免。如果药品被认定为与RLD在 Q1/Q 2上不相同，根据药品由于未准许的配方差异而没有资格得到豁免，FDA 将拒收该ANDA 申报。

For ophthalmic solutions, it is critical to also complete and include the BE table Comparative Physicochemical Data of OphthalmicSolution Drug Products[8] in Module 2.7 of the ANDA submission to further support the waiver request.  This table captures keyinformation/data relevant to both the test product and the RLD.  If this table is omitted, FDA will RTR the ANDA despite adetermination that the test formulation is Q1/Q2 same as the RLD[9].

对于滴眼液，在ANDA 申报中完成滴眼液药物产品理化数据比较表，并放入模块2.7 中，对于进一步支持申请豁免是至关重要的。该表格捕捉了与受试药品和橙皮书收录参照药品（RLD）均有关的关键信息/数据。若该表格缺失，即使认定受试配方与RLD 的Q1/Q2 相同，FDA 也将拒收该ANDA 申请。

D.        Inadequate Dissolution Data (In Vitro Studies) 溶出不充分（体外研究）

For any recommended dissolution study, it is critical that appropriate comparison data (i.e., test product and RLD) be provided[10].   Ifthere is evidence within the ANDA that the appropriate dissolution studies were not conducted or a supplemental study is omitted,FDA will RTR the ANDA.

提交所有推荐的溶出度研究的适当的比较数据（即受试药品与RLD）是很关键的。如果在ANDA中有证据证明没有实施适当的溶出度试验，或者是省略了补充研究，则FDA会拒收该ANDA.

The BE guidances discussed in this section contain important details about the types of dissolution studies appropriate for the RLDand test products, along with information on waiver of an in vivo BE data requirement for any additional strengths for which approval issought[11].   In addition, these BE guidances may reference dissolution methods available through FDA’s Web site that are specificto a particular drug product[12].

在本部分所讨论的BE指南中包括了溶出度研究类型的重要细节，适合于RLD和受试药品，以及需要批准的其它剂量的体内BE数据要求豁免信息。此外，这些BE指南可能引用 了FDA官网上可以获得的特殊药品专用 的溶出度方法。

Other suggested types of comparative (i.e. test product and RLD) supplemental dissolution studies include:

其它建议的补充比较性（即受测药品和RLD）溶出度研究包括：

·         Alcohol dose-dumping

·         酒精剂量倾卸

·         Half-tablet dissolution for modified-release drug products with functional score marks[13] performed for each strength of test andRLD in the recommended media, or quality control (QC) media if there is no recommendation (alcohol dose-dumping studies arenot recommended for half-tablet dissolution studies)

·         在推荐的介质中对每个剂量的受试药品和RLD进行具有刻痕的改释药品半片溶出度试验，如果没有建议的介质，可以采用质量控制（QC）介质（不建议在半片溶出度试验中进行酒精剂量倾卸研究）

·         Any other product-specific dissolution study described in the BE recommendations for the relevant product

·         所有相关产品的BE建议中所述的其它产品相关溶出度研究

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[1] 21 CFR 314.50(d)(1).

[2] FDA’s BE recommendations for specific products can be found at  FDA特定药品的BE建议参见以下网址http://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/guidances/ucm075207.htm.

[3] It is also recommended that a brief CMC summary of any failed studies be included in the Pharmaceutical Development report. 也建议在药物研发报告中放进一份所有失败研究的简要CMC摘要。

[4] 21 CFR 314.94(a)(7)(i).

[5] 21 CFR 314.94(a)(7).

[6] In such instances, bioequivalence is considered to be self-evident. 在此情形下，认为生物等效性是自证的。

[7] 21 CFR 314.94(a)(7).

[8] BE tables can be found on FDA’s Web site at the following location:  BE表格可以在FDA官网上找到http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/Approv  alApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM120957.pdf.

[9]  21 CFR 314.94(a)(7).

[10] 21 CFR 314.50(d)(1).

[11]See 21 CFR 320.22(d)(2)(ii).

[12] For examples of FDA-recommended dissolution methods, see FDA建议的溶出度方法举例参见以下网址http://www.accessdata.fda.gov/scripts/cder/dissolution/index.cfm.

[13] A functional score mark enables delivery of a dose that is supported by RLD labeling.

功能性刻痕让药品能够按RLD标签所指定的剂量给药。