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