Guidance for Industry
Changes to an Approved
集体备课记录NDA or ANDA
已批准申请的新药变更指南
女童短发发型
U.S. Department of Health and Human Services
3次方的完全平方公式Food and Drug Administration
Center for Drug Evaluation and Rearch (CDER)
茶道人生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
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）。
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-being¬effected 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.
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
北京高考作文any 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.
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)).
微课设计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))。
A minor change is a change that has minimal 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 eff
ectiveness of the drug product. The applicant must describe minor changes in its next Annual Report (§ 314.70(d)).
小变更指对药品特征、剂量、质量、纯度或药效有最小的潜在不良影响、可能与药品的安全性和有效性相关的变更。申请人必须在下一次年度报告中描述小变更(§ 314.70(d))。
走路脚后跟疼是什么原因
Under § 314.70(e), an applicant can submit one or more protocols (i.e., comparability protocols) describing tests, studies, and acceptance criteria to be achieved to demonstrate the abnce of an adver effect from specified types of changes. A comparability protocol can be ud to reduce the reporting category for specified changes. A propod comparability protocol that was not approved as part of the original application must be submitted as a prior approval supplement (314.70(e)). On February 25, 2003, FDA issued a draft guidance on comparability protocols entitled Comparability protocols - Chemistry, Manufacturing, and Controls Information.
根据314.70(e)，申请人可以提交1个或多个方案（如相比性方案），描述检测、研究、可接受标准，以证明特定的变更不会有不良影响。相比性方案可减少特定变更的报告范围。提交的相比性方案在原始申报资料中没有包括，必须作为“批准前变更申请”提交。见Comparability protocols - Chemistry, Manufacturing, and Controls Information。
III. GENERAL REQUIREMENTS 常规要求
Other than for editorial changes in previously submitted information (e.g., correction of spelling or typographical errors, reformatting of batch records), an applicant must notify FDA about each change in
each condition established in an approved application beyond the variations already provided for in the application (§ 314.70(a)(1)).
除编辑上的改动，在以往提交的资料（如更正拼写或打字错误，重新格式化的一批纪录），申请人必须通知FDA了解在每个确立的情况、获批准的申请的各个改变，超出了变更在申请中应用(§ 314.70(a)(1))。
A supplement or annual report must include a list of all changes contained in the supplement or annual report. On the list, FDA recommends that the applicant describe each change in enough detail to allow FDA to quickly determine whether the appropriate reporting category has been ud. For supplements, this list must be provided in the cover letter (§ 314.70(a)(6)). In annual reports, the list should be included in the summary ction (§ 314.81(b)(2)(i)). The applicant must describe each change fully in the supplement or annual report (§ 314.70(a)(1)).
增补或年报必须包括一列所有变更，载于增补或年报。在目录上，FDA建议申请者对每个变更叙述详尽，使FDA迅速决定是否合适的报告范围已被使用。对于增刊，此目录必须在信封面上(§
314.70(a)(6))。在年报里，目录应包括在简节中(§ 314.81(b)(2)(i))。申请者必须说明每个变更都在增刊和年报里。
An applicant making a change to an approved application under ction 506A of the Act must also conform to other applicable laws and regulations, including current good manufacturing practice (CGMP) requirements of the Act (21 U.S.C. 351(a)(2)(B)) and applicable regulations in Title 21 of the Code of Federal Regulations (e.g., 21 CFR parts 210, 211, 314). For example, manufacturers must comply with relevant CGMP validation and recordkeeping requirements and ensure that relevant records are readily available for examination by authorized FDA personnel during an inspection.
申请者依据法案的第506A部分对已批准的申请作出变更，必须同时符合其它适用的法律和规章，包括现行的药品生产管理规范（CGMP）要求的法案(21 U.S.C. 351(a)(2)(B))和美国联邦行政法规(e.g., 21 CFR parts 210, 211, 314)的21部中适用的规章。例如，生产厂家必须服从相关CGMP验证和保留记录的要求，确保有关的记录在检查期间随时可供获授权的FDA工作人员检查。
A changes-being-effected supplement providing for labeling changes under § 314.70(c)(6)(iii) must i
nclude
12 copies of the final printed labeling (§ 314.70(c)(1)). In accordance with § 314.70(a)(4), an applicant also must promptly revi all promotional labeling and drug advertising to make it consistent with any labeling change implemented in accordance with § 314.70(b) or (c).
“已生效的变更补充”提供了标签变更，依据§ 314.70(c)(6)(iii)必须包括12份最后打印的标签(§
314.70(c)(1))。按照§ 314.70(a)(4)，申请者还必须及时修改所有宣传标识和药品广告，使之符合任何标签变更，应按照§ 314.70(b) or (c)实施。春暖花开性8有你
Except for supplements providing only for a change in labeling, an applicant must include in each supplement and amendment to a supplement a statement certifying that a field copy has been provided in accordance with 21 CFR 314.440(a)(4)6 (§ 314.70(a)(5)).
除了在标签中只补充一个变更，申请者必须包括有每个补充和修改的资料来补充说明，证明副本已按照21 CFR 314.440(a)(4)6 (§ 314.70(a)(5))提供。
IV. ASSESSING THE EFFECT OF MANUFACTURING CHANGES 对生产变更的评估
A. Asssment of the Effects of the Change 评估变更效果
