201409:FDA行业指南：ANDA申报---拒绝受理杂质限度缺乏适当论述的申报（草案）

ANDA Submissions — Refuse to Receive for Lack of Proper Justification of Impurity Limits

Guidance for Industry

DRAFT GUIDANCE

行业指南：ANDA申报---拒绝受理杂质限度缺乏适当论述的申报（草案）

This guidance document is being distributed for comment purposes only. Comments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit electronic comments to http://www.regulations.gov. Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register.

本指南仅供征求意见。关于本草案的建议和意见请在联邦注册上的通知公布后60天内，电子提交至上述网站。书面意见提交给上述地址。所有建议均应标明联邦注册上的档案编号。

For questions regarding this draft document contact (CDER) Elizabeth Giaquinto 240-402-7930.

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

September 2014

Generic Drugs

ANDA Submissions —

Refuse to Receive for

Lack of Proper Justification of Impurity Limits

Guidance for Industry

Additional copies are available from:

Office of Communications

Division of Drug Information, WO51, Room 2201

Center for Drug Evaluation and Research

Food and Drug Administration

10903 New Hampshire Ave., Silver Spring, MD 20993

Phone: [phone]; Fax: [phone]

[e-mail]

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)

September 2014

Generic Drugs

TABLE OF CONTENTS

I. INTRODUCTION概述

II. BACKGROUND背景

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

A. Refusal to Receive for Lack of Impurities Information 因为缺少杂质资料而拒绝受理

B. Providing Proper Justification for Impurity Limits如何提交适当的杂质限度论述

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

Guidance for Industry[1]

行业指南：ANDA申报---拒绝受理杂质限度缺乏适当论述的申报

This draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA’s) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call 10 the appropriate number listed on the title page of this guidance.

I. INTRODUCTION 概述

This guidance is intended to assist applicants preparing to submit to the Food and Drug Administration (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] The guidance highlights deficiencies in relation to information about impurities that may cause FDA to refuse to receive an ANDA.[3] [4] A refuse-to-receive decision indicates that FDA determined that an ANDA is not sufficiently complete to permit a substantive review.[5]

本指南意在帮助申报人准备提交FDA的ANDA申报资料，及预批准变更PAS。申报人通过这些申报来获得制剂的一个新剂量的批准。本指南重点讨论了与杂质有关的资料缺陷，这些缺陷可能会导致FDA拒绝受理ANDA。拒绝受理表示FDA认为该ANDA申报资料不够完整，无法开展实质审核。

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

导致FDA拒绝受理的典型缺陷包括（1）未能充分论证所拟的原料药和制剂中已鉴别且水平高定性阈值的杂质限度（2）未能充分论证高于鉴别阈值的特定未鉴别杂质所拟的限度以及（3）对高于鉴别阈值的非特定杂质（例如，任意未知杂质）制订限度。

This guidance is not meant to be a comprehensive list of deficiencies in relation to impurity information that may or will lead to a refuse-to-receive determination by FDA. Instead, this guidance clarifies that a failure to provide proper justification for proposed impurity limits may lead FDA to refuse to receive an ANDA. It also makes recommendations to ensure that appropriate justification for impurities are submitted in ANDAs. This guidance is being issued concurrently with the guidance for industry ANDA Submissions – Refuse to Receive Standards.

本指南无意成为一份可能导致FDA拒绝受理的与杂质资料有关的缺陷完整清单。相反，本指南只是澄清如果未能提交对所拟定杂质限度的适当论述则可能会导致FDA拒绝受理ANDA。指南还给出一些建议，以保证申报人会在ANDA里提交杂质的适当论述。本指南将与行业指南“ANDA申报---拒绝受理标准”同步签署。

FDA’s guidance documents, including this guidance, do not establish legally enforceable 4responsibilities. Instead, guidances describe FDA’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or 43 recommended, but not required.[6]

FDA的指南文件，包括本指南并不建立法定的强制责任。相反，指南描述了当局目前对该问题的思考，应仅被看作是一种推荐，除非其中内容被法规或立法要求所引用。指南中的“应该”一词表示建议或推荐的事情，并不要求强制执行。

II. BACKGROUND 背景

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

在GDUFA实施后，仿制药办公室OGD承担了一些职责，包括“在计划进行的第一年度末，制订ANDA和其它相关申报拒绝受理标准……”。制订拒绝受理标准是非常重要的，因为如果公司提交一份不够完整的ANDA申报资料，然后在进一步审核期间进行“修补”会需要更多轮次的回复，申报人的修补不可能有效率，从而浪费资源。另外，ANDA也不能允许在实质性审核中产生额外的审核和信件。

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

FDA对每个提交的ANDA申报文件进行单独评估，以决定是否该ANDA可以受理供当局审阅。受理一份ANDA意味着FDA做出了一个是非判断，认为该ANDA的完整程度使得当局可以进行实质性审核。21CFR314.101中的条款给法规当局提供了依据，使得FDA可以在某些情况下拒绝受理ANDA。

Generally, FDA will not receive an ANDA unless it contains the information required under Section 505(j) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), as specified in more 65 detail in 21 CFR 314.101 and other regulations, for example:[11]

一般来说，FDA会拒绝受理ANDA申报，除非其中包括有

? 21 CFR 314.50 68

? 21 CFR 314.94 69

? 21 CFR 320.21 70

? 21 CFR 320.22 71

This guidance focuses on when FDA expects to refuse to receive an ANDA because it lacks proper justification for proposed impurity limits.

本指南关注的是FDA什么时候会因为一份ANDA缺乏对所拟定杂质限度的适当论证而拒绝受理该ANDA。

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

All ANDAs must contain a description of the composition, manufacture and specification of the drug substance and the drug product (see 21 CFR 314.94(a)(9) and 314.50(d)(1)). Applicants are required to submit a full description of the drug substance including, but not limited to: its method of synthesis (or isolation) and purification of the drug substance; the process controls used during manufacture and packaging; and the specifications necessary to ensure the identity, 83 strength, quality, and purity of the drug substance (§314.50(d)(1)(i)). Applicants are also 84 required to submit a list of all components used in the manufacture of the drug product[12] (regardless of whether they appear in the drug product) and a statement of the specifications for each component and the specifications necessary to ensure the identity, strength, quality, purity, potency, and bioavailability of the drug product (§314.50(d)(1)(ii)(a)). To ensure purity, applicants should propose and justify appropriate limits of the impurities in their drug substances and drug products.

所有的ANDA都必须包括有对原料药和制剂组成、生产和质量标准的描述（参见 21 CFR 314.94(a)(9)和 314.50(d)(1)）。申报人要提交一份关于原料药的全面描述，包括但不限于：原料药的合成方法（或分离方法）和纯化方法、生产和包装过程所使用的工艺控制、保证原料药性状、剂量、质量和纯度的质量标准（§314.50(d)(1)(i)）。申报人还要提交一份制剂生产中所用组分的清单（不论是否出现在制剂中），以及一份所有组分和其质量标准的申明，这些质量标准应可保证制剂的性状、剂量、质量、纯 度、效价和生物等效性（§314.50(d)(1)(ii)(a)）。为保证制剂的纯度，申报人应为原料药和制剂中的杂质拟定适当的限度，

A. Refusal to Receive for Lack of Impurities Information 拒绝受理缺少杂质资料的申报

FDA may refuse to receive an ANDA that is not sufficiently complete because it does not on its face contain information required under §314.50, which includes a demonstration of the purity of the drug substance and drug product and information on impurities and residues (§314.101(d)(3)) (see also Final Rule on Abbreviated New Drug Applications 57 FR 17950 at 17959).[13]

FDA可能会因为一份ANDA在表面上看不包括§314.50所要求的资料，而拒绝受理不够完整的ANDA申报。根据该条款，申报资料中应包括对原料药和制剂纯度的证明，以及杂质和残留的资料（§314.101(d)(3))）（也请参见ANDA最终规则57 FR 17950 at 17959）。

Accordingly, FDA may refuse to receive an ANDA for: (1) failing to provide adequate 99 justification for proposed limits in drug substances and drug products for specified identified impurities that are above qualification thresholds; (2) failing to provide adequate justification for proposed limits for specified unidentified impurities that are above identification thresholds; and (3) proposing limits for unspecified impurities (e.g., any unknown impurity) above identification thresholds.

因此，FDA可能会因为以下理由拒绝受理一份ANDA申报：（1）原料药和制剂中特定已鉴别杂质所拟限度超出定性阈值，但未能提交充分的论证（2）所拟特定未鉴别杂质限度高于鉴别阈值，但未能提交充分的论证（3）所拟非特定杂质（例如，任意未知杂质）的限度超出鉴别阈值

B. Providing Proper Justification for Impurity Limits 对杂质限度提供适当的论证

To help applicants ensure the appropriate purity of their drug substance (§314.50(d)(1)(i)) and drug product (§314.50(d)(1)(ii)(a)), FDA has published two guidances for industry ANDAs: Impurities in Drug Substances and ANDAs: Impurities in Drug Products. These guidances provide recommendations on what chemistry, manufacturing, and controls (CMC) information applicants should include regarding the reporting, identification, and qualification of impurities in drug substances and impurities that are classified as degradation products in drug products. These guidances provide the criteria for justifying appropriate impurity limits[14] in the drug substance and drug product.[15]

为帮助申报人保证其原料药和制剂具备适当的纯度，FDA已公布了2份行业指南“ANDA：原料药中的杂质”和“ANDA：制剂中的杂质”。这两份指南给出关于研发、生产和控制（CMC）方面申报人应包括的相关原料药中杂质报告阈、鉴别阈、定性的资料的建议，以及原料药中分类为降解物质的杂质。这些指南提供了判定原料药和制剂中杂质限度适当与否的标准。

If a generic product contains specified identified impurities that exceed the qualification thresholds[16] or specified unidentified impurities[17] that exceed identification thresholds,[18] [19] [20] the ANDA should propose impurity limits and include supporting data to demonstrate that:

如果一个仿制药品含有特定的已鉴别的杂质，超过定性阈值，或特定的未鉴别的杂质超过鉴别阈值，则在ANDA中要拟定杂质限度，并包括支持性的数据来证明：

(1) the observed impurity levels and proposed impurity limits do not exceed the level observed in the reference listed drug product; 观察到的杂质水平和拟定的杂质限度不超过对照清单中药品的水平

(2) the impurity is a significant metabolite of the drug substance;[21] 杂质是原料药的重要代谢产物

(3) the observed impurity levels and proposed impurity limits are adequately justified by the scientific literature; or 观察到的杂质水平和所拟定的杂质限度根据科学文献做了充分的论证

(4) the observed impurity levels and proposed impurity limits do not exceed the level that has been adequately evaluated in toxicity studies. 观察到的杂质水平和所拟定的杂质限度不超过毒性研究中经过充分评估的水平

FDA will refuse to receive an ANDA under §314.101(d)(3) if the ANDA lacks supporting data or information to justify the proposed limits for specified identified and/or specified unidentified impurities that exceed qualification thresholds and/or identification thresholds, respectively, as described above. FDA will refuse to receive an ANDA under §314.101(d)(3) with proposed limits for unspecified impurities that exceed identification thresholds.[22]

如果ANDA缺乏支持性数据或资料来论证所拟定的特定的已鉴别的和/或特定的未鉴别的杂质限度，而这些杂质水平超过定性阈值和/或鉴别阈值，如上所述，FDA会根据§314.101(d)(3)拒绝受理该ANDA。如果为非特定杂质拟定的限度超过鉴定阈值，则FDA会根据§314.101(d)(3) 拒绝受理该ANDA。

Applicants are encouraged to review the draft guidance for industry: ANDA Submissions - Content and Format of Abbreviated New Drug Applications for more information on the characterization of impurities for drug substances and drug products.

我们鼓励申报人审核行业指南草案：ANDA申报---简略新药申报ANDA内容和格式，获得更多关于原料药和杂质的定性信息。

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

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

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

[4] The following types of products are not covered in this guidance because there are currently no specifically defined identification and qualification thresholds for impurities: (1) biological/biotechnologicals; (2) peptides; (3) oligonucleotides; (4) radiopharmaceuticals; (5) fermentation products; (6) semisynthetic products derived from fermentation products; (7) herbal products; (8) crude products of animal or plant origin. See FDA’s guidances for industry ANDAs: Impurities in Drug Substances, ANDAs: Impurities in Drug Products, Q3A(R) Impurities in New Drug Substances (ICH Q3A(R)), and Q3B(R) Impurities in New Drug Products (ICH Q3B(R)). The guidances referenced in this document are available on FDA’s drugs guidance Web page at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. We update guidances periodically. To make sure you have the most recent version of a guidance, check FDA’s drugs guidance Web page.

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

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

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

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

[9] See 21 CFR 51 30404 51 15536 0 0 3805 0 0:00:07 0:00:04 0:00:03 3805 314.101(b)(1).

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

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

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

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

[14] The term impurity limit as used in this draft guidance and acceptance criterion used in the FDA guidances referenced in note 16 are synonymous.

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

[16] See guidances for industry ANDAs: Impurities in Drug Substances, ANDAs: Impurities in Drug Products, ICH Q3A(R), and ICH Q3B(R). Identification and qualification thresholds should be based on maximum daily dose (MDD) of the drug and total daily intake of impurities. These thresholds should be reported as a percentage, and percentages should be based on lower total daily intake (TDI) of impurities per ICH guidance tables for all impurities.

[17] See supra note 15. When specified unidentified impurities are listed in the specification, FDA recommends that applicants describe the identification efforts attempted and clearly identify the procedure used and assumptions made in establishing the level of the impurity. It is important that specified unidentified impurities are referred to by an appropriate qualitative analytical descriptive label (e.g., unidentified A, unidentified with relative retention of 0.9).

[18] See supra note 15. In some cases, it may be appropriate to decrease the threshold for qualifying impurities. For example, if there is evidence that an impurity in certain drug classes or therapeutic classes has previously been associated with adverse reactions in patients, it may be important to establish a lower qualification threshold. When such circumstances arise, these changes will not be evaluated during the filing review but will be addressed during the technical review of the ANDA.

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

[20] Acceptance criteria for unspecified impurities should be set not to exceed the identification threshold in ICH Q3A(R), even in the case when higher acceptance criteria for unspecified (other) impurities are listed in the United States Pharmacopeia (USP) monograph. If the acceptance criteria for unspecified (other) impurities in the USP monograph are lower than the identification threshold in ICH Q3A(R), the acceptance criteria for unspecified impurities should be set to the USP level.

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

[22] See guidances for industry ANDAs: Impurities in Drug Substances and ANDAs: Impurities in Drug Products. FDA may refuse to receive an ANDA for any unspecified and unidentified impurities that exceed the recommended identification thresholds found in current guidances referenced.

蒲公英 ouryaoinfo

制药行业最专业、最活跃的自媒体

聚焦行业动态、关心医药业务

贴近行业现状、关注行业变迁

免责声明：编辑对上述内容，对文中陈述、观点判断保持中立，不对所包含内容的准确性、可靠性或完整性提供任何明示或暗示的保证。仅作参考，并请各位自行承担全部责任。