FDA发布行业指南ANDA申报: 拒绝接受缺乏杂质限度论证的申报

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

ANDA申报 – 拒绝接受缺乏杂质限度论证的申报行业指南

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U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

August 2016

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

Additional copies are available from:

Office of Communications

Division of Drug Information, WO51, Room 2201

Center for Drug Evaluation and Research

Food and Drug Administration

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

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

druginfo@fda.hhs.gov

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

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

August 2016

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TABLE OF CONTENTS 目录

I. INTRODUCTION 前言

II. BACKGROUND 背景

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

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

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

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

ANDA申报—拒收缺乏杂质限度论证的资料

Guidance for Industry[1]

行业指南

This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the title page.

本指南代表FDA当前对此主题的相当。它并不赋予任何人任何权力，对FDA和公众亦不形成强制。在满足本适用法律法规的要求时可以使用替代的方法。关于替代方法的讨论，请联系FDA办公室负责此本指南的人员，联系方式在标题页给出。

I. INTRODUCTION 前言

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

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

Typical deficiencies leading to an RTR decision include: (1) failing to provide justification for proposed limits in drug substances and drug products for specified identified impurities that are above qualification thresholds; (2) failing to provide justification for proposed limits 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.

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

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

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

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

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

II. BACKGROUND 背景

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

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

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

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

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

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

◦21 CFR 314.50

◦21 CFR 314.94

◦21 CFR 320.21

◦21 CFR 320.22

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

杂质是原料药的重要代谢物；

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

所检出的杂质水平和所拟定的杂质限度经过科学文献的充分论证；

or 或者

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

所检出的杂质水平和所拟定的杂质限度不超过毒性研究中经过充分评估的水平。

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

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

来源：Julia Blog，