Guidance for Industry Changes to an
Approved
NDA or ANDA
已批准申请的新药变更指南
关于雷锋>洛洛的他春天在哪里儿歌U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Rearch (CDER)
April 2004
CMC
Revision 1
I. INTRODUCTION AND BACKGROUND
This guidance provides recommendations to holders of new drug applications (NDAs) and abbreviated new drug applications (ANDAs) who intend to make post approval changes in accordance with ction 506A of the Federal Food, Drug, and Cosmetic Act (the Act) and § 314.70 (21 CFR 314.70). The guidance covers recommended reporting categories for postapproval changes for drugs other than specified biotechnology and specified synthetic biological products. It superdes the guidance of the same title published November 1999. Recommendations are provided for postapproval changes in (1) components and composition,(2) manufacturing sites, (3) manufacturing process, (4) specifications, (5) container closure system, and (6) labeling, as well as (7) miscellaneous changes and (8) multiple related changes. 本
指南给打算将已批准变更的新药上市申请和新药报审简表申请的持有者提供建议，使其按照联邦食品、药品、化妆品法案的506A部分和§ 314.70 (21 CFR 314.70)。该指南包括建议对药品除了其他指定的生物技术和特定的合成生物制品的已批准变更进行报告类别。它取代了发表于1999年11月同一标题的指导原则。为以下已批准的变更提供建议（1）成分和组成（2）厂址（3）生产工艺（4）质量标准（5）包装（6）标签（7）其它变更（8）复杂相关变更
工伤补偿Recommendations on reporting categories for changes relating to specified biotechnology and specified synthetic biological products regulated by CDER are found in the guidance for industry
建议由药品评价和研究中心规定对有关指定生物技术和特定的合成生物制品的变更进行报告类别，出现在企业的指南中。
Paperwork Reduction Act Public Burden Statement: This guidance contains information collection provisions that are subject to review by the Office of Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (PRA) (44 U.S.C. 3501-3520). The collection(s) of information in this guidance were approved under OMB Control No. 0910-0538 (until August 31, 2005). 文书工作减少法案：本指南包含资料的收集贮藏受到管理和预算办公室（OMB）的审查，根据1995年的文书工作减少方案(44 U.S.C. 3501-3520)。在此指南下，收集的资料依据管理和预算办公室控制的第0910-0538获得批准（直到2005年8月31日）。
季承
On November 21, 1997, the President signed the Food and Drug Administration Modernization Act of 1997 (the Modernization Act).3 Section 116 of the Modernization Act amended the the Act by adding ction 506A, which provides requirements for making and reporting manufacturing changes to an approved application and for distributing a drug product made with such changes. The FDA has revid its regulations on supplements and other changes to an approved application (21 CFR 314.70) to conform to ction 506A of the Act.
1997年11月21日，总统签署了美国食品和药物管理局1997现代化法案（现代化法案）。第116条现
代化法修正法案，增加了第506A条，要求对已批准申请的任何变更以及销售变更后产品的行为必须报告。对一个获批准的申请(21 CFR 314.70)，FDA已经在补充和变更内容上修订规章，以符合法案第506A条。
This guidance does not provide recommendations on the specific information that should be developed by an applicant to asss the effect of the change on the identity, strength (e.g., assay, content uniformity), quality (e.g., physical, chemical, and biological properties), purity (e.g., impurities and degradation products), or potency (e.g., biological activity, bioavailability, bioequivalence) of a drug product as the factors may relate to the safety or effectiveness of the drug product. An applicant should consider all relevant CDER guidance documents for recommendations on the information that should be submitted to support a given change.4
作为可能关系到药品安全性和有效性的以下因素，药品的特征、剂量（例如含量测定、含量均一性）、质量（例如，物理、化学和生物学特性）、纯度（例如，杂质和降解产物），或药效（例如，生物活性、生物利用度、生物等效性），申请人评估以上因素变更效果的具体信息，本指南不提供建议。申请者应该考虑所有相关的药品评价和研究中心的指导文件，建议资料应该提交以支持某一特定的变更。
CDER has published guidances, including the SUPAC (scale-up and postapproval changes) guidances, that provide recommendations on reporting categories. To the extent that the recommendations on reporting categories in this guidance are found to be inconsistent with guidances published before this guidance was finalized, the recommended reporting categories in such previously published guidances are superded by this guidance. This guidance does not provide extensive recommendations on reporting categories for components and composition changes (e ction V). Therefore, recommended reporting categories for components and composition changes provided in previously published guidances, such as the SUPAC guidances, still apply. Section 506A of the Act and § 314.70(c) provide for two types of changes-beingeffected supplements (e ction II), while previously there was only one type. It is important for applicants to u this guidance to determine which type of changes-being-effected supplement is recommended. CDER intends to update the previously published guidances to make them consistent with this guidance.
逍遥游第一段
CDER已公布指南，包括SUPAC（扩大和批准后的变更）指南，对报告类别提供了建议。发现在本指南中报告类别的建议范围和以前已定案公布的指南不一致，推荐本指南的报告类别取代先前公布的。对成分和组成变更（查看第V条）的报告类别，本指南不提供广泛建议。因此，推荐先前公布的指南
提供的成分和组成变更的报告类别，例如SUPAC指南，目前还适用。法案的第506A和§ 314.70(c)提供了“有待生效的补充文件”的两种类型（查看第II），然而先前的只有一种类型。对于申请者，运用本指南来决定用哪个“有待生效的补充文件”是很重要的。CDER打算更新先前公布的指南使其和本指南一致。
If guidance for either recommended reporting categories or information that should be submitted to support a particular change is not available, the appropriate CDER
chemistry or microbiology review staff can be consulted for advice.
如果本指南中推荐的报告类别或者支持具体变更所提交的资料没有效，可以向合适的CDER化学或微生物检查人员征询意见。
FDA's guidance documents, in general, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The u of the word should in Agency guidances means that something is suggested or recommended, but not required. Insofar as this guidance adjusts reporting categories pursuant to ction 506A of the Federal Food, Drug, and Cosmetic Act and 21 CFR 314.70, it does have binding effect. If you have a
ny questions about the effect of any portion of this guidance, contact the Office of Pharmaceutical Science, Center for Drug Evaluation and Rearch (HFD-003), Food and Drug Association, 5600 Fishers Lane, Rockville, MD 20857.
FDA的指导文件，大体上没有建立依法强制执行的责任。相反，指南叙述该机构目前正在考虑的话题且仅作为建议，除非特定的法令要求被引用。词的使用在机构的指南应该意味着一些建议或推荐，但不是要求。在本指导的范围内调整报告类别，依据联邦食品、药品和化妆品法第506A和21 CFR 314.70 ，它确实有约束力。如果你有关于本指导任一部份作用的任何问题，联络医药科学办公室、药物评价和研究中心（ HFD-003 ）、美国食品和药物管理局、5600渔民巷，美国马里兰州罗克维尔市20857。
II. REPORTING CATEGORIES 报告类别
Section 506A of the Act and § 314.70 provide for four reporting categories that are distinguished in the following paragraphs.
法案的第506A和§ 314.70提供了在以下各段落中有区分的4个报告类别。
A major change is a change that has a substantial potential to have an adver effect on the identity,
strength, quality, purity, or potency of a drug product as the factors may relate to the safety or effectiveness of the drug product. A major change requires the submission of a supplement and approval by FDA prior to distribution of the drug product made using the change. This type of supplement is called, and should be clearly labeled, a Prior Approval Supplement (§ 314.70(b)). An applicant may ask FDA to expedite its review of a prior approval supplement for public health reasons (e.g., drug shortage) or if a delay in making the change described in it would impo an extraordinary hardship on the applicant. This type of supplement is called, and should be clearly labeled, a Prior Approval Supplement - Expedited Review Requested (§314.70(b)(4)).5 FDA is most likely to grant requests for expedited review bad on extraordinary hardship for manufacturing changes made necessary by catastrophic events (e.g., fire) or by events that could not be reasonably foreen and for which the applicant could not plan.皇家马德里队徽
大变更指对药品特征、剂量、质量、纯度或药效有重大潜在不良影响、与药品的安全性和有效性相关的变更。大变更后生产的产品需要提交补充申请，经FDA批准后方可销售。这类补充申请应有明显标识，称作“批准前变更申请”（314.70）。申请人可以以公众健康为由（如药品短缺）要求FDA加速批准前变更的审核，如果变更延迟会给申请人造成极大的困难，可以要求加速审批。这类变更称为“要求加速审批的批准前变更”（314.70(b)(4)）。由于灾难性事故或不可预见的事故造成生产变更，并对申报人造成极大的困难的情况，FDA 最有可能加速审批。
A moderate change is a change that has a moderate potential to have an adver effect on the identity, strength, quality, purity, or potency of the drug product as the factors may relate to the safety or effectiveness of the drug product. There are two types of moderate change. One type of moderate change requires the submission of a supplement to FDA at least 30 days before the distribution of the drug product made using the change. This type of supplement is called, and should be clearly labeled, a Supplement - Changes Being Effected in 30 Days (§ 314.70(c)(3)). The drug product made using a moderate change cannot be distributed if FDA informs the applicant within 30 days of receipt of the supplement that a prior approval supplement is required (§314.70(c)(5)(i)). For each change, the supplement must contain information determined by FDA to be appropriate and must include the information developed by the applicant
in asssing the effects of the change (§ 314.70(a)(2) and (c)(4)). If FDA informs the applicant within 30 days of receipt of the supplement that information is missing, distribution must be delayed until the supplement has been amended to provide the missing information (§ 314.70(c)(5)(ii)).
发现春天中等变更指对药品特征、剂量、质量、纯度或药效有中等程度的潜在不良影响、可能与药品的安全性和有效性相关的变更。有两种中等变更，一种要求变更后生产的产品销售前至少30天提交补充申请，这类补充申请应有明显标识，称作“30天后变更生效的补充文件”（314.70(c)(3)）。如果FDA收到补充
申请的30天内要求提交“批准前变更申请”
（314.70(c)(5)(i)），则变更后生产的产品不能销售。任何一种变更都必须包括FDA接受的信息，必须包括变更影响评估的信息（314.70(a)(2)和(c)(4)）。如果FDA在接收到补充申请后的30天内通知申请人信息不全，则必须延迟销售直到补充申请加入缺失的信息
（314.70(c)(5)(ii)）。
FDA may identify certain moderate changes for which distribution can occur when FDA receives the supplement (§ 314.70(c)(6)). This type of supplement is called, and should be clearly labeled, a Supplement - Changes Being Effected. If, after review, FDA disapproves a changes-being-effected-in-30-days supplement or
changes-being-effected supplement, FDA may order the manufacturer to cea distribution of the drug products made using the disapproved change (§314.70(c)(7)). FDA可能规定某些中等变更FDA接收到补充申请时产品可以销售，这类补充申请应有明显标识，称作“已完成变更的补充申请”。如果评审结束后，FDA不批准“30天后生效的变更补充文件”或“已生效的变更补充文件”，FDA可以要求生产厂家停止销售变更后生产的产品(§314.70(c)(7))。
