FDA对注射药品包装类型术语的新要求_黄芳华_百度文库
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FDA-已批准申请的新药变更指南(中英文)
Guidance for IndustryChanges to an Approved&NDA or ANDA已批准申请的新药变更指南U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)April 2004CMCRevision 1&I. INTRODUCTION AND BACKGROUNDThis 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 section 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 supersedes 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. ).& The collection(s) of information in this guidance were approved under OMB Control No.
(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. )。在此指南下，收集的资料依据管理和预算办公室控制的第获得批准（直到日）。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 section 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 revised its regulations on supplements and other changes to an approved application (21 CFR 314.70) to conform to section 506A of the Act.&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 assess 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 these 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 superseded by this guidance. This guidance does not provide extensive recommendations on reporting categories for components and composition changes (see section 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 (see section II), while previously there was only one type.& It is important for applicants to use 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 use 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 section 506A of the Federal Food, Drug, and Cosmetic Act and 21 CFR 314.70, it does have binding effect.& If you have any questions about the effect of any portion of this guidance, contact the Office of Pharmaceutical Science, Center for Drug Evaluation and Research (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 adverse effect on the identity, strength, quality, purity, or potency of a drug product as these 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 impose 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 based on extraordinary hardship for manufacturing changes made necessary by catastrophic events (e.g., fire) or by events that could not be reasonably foreseen 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 adverse effect on the identity, strength, quality, purity, or potency of the drug product as these 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 assessing 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)).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 cease 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 adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety or effectiveness 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))。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 absence of an adverse effect from specified types of changes.& A comparability protocol can be used to reduce the reporting category for specified changes. A proposed 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 used. 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 section (§ 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 section 506A of the Act must also conform to other applicable laws and regulations, including current good manufacturing practice (C) 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 include 12 copies of the final printed labeling (§ 314.70(c)(1)). In accordance with § 314.70(a)(4), an applicant also must promptly revise 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。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. Assessment of the Effects of the Change 评估变更效果The holder of an approved application under section 505 of the Act must assess the effects of the change before distributing a drug product made with a manufacturing change (§ 314.70(a)(2)).7 For each change, the supplement or annual report must contain information determined by FDA to be appropriate and must include the information developed by the applicant in assessing the effects of the change (section 506A(b), (c)(1), (d)(2)(A), and (d)(3)(A) of the Act). The type of information that must be included in a supplemental application or an annual report is specified in § 314.70(b)(3), (c)(4), and (d)(3).按照法案第505条，在发行有生产变更的药品前(§ 314.70(a)(2))，已批准申请的持有人必须评估变更效果。对每个变更，增刊或年报必须包含由FDA确定的合适的资料和申请者在评估变更效果所取得的资料(section 506A(b), (c)(1), (d)(2)(A), and (d)(3)(A) of the Act)。该类型的资料必须包括在补充申请或年报里，特别是在§ 314.70(b)(3), (c)(4), and (d)(3)中。1. Conformance to SpecificationsAn assessment of the effects of a change on the identity, strength, quality, purity, and potency of the drug product should include a determination that the drug substance intermediates, drug substance, in-process materials, and/or drug product affected by the change conform to the approved specifications.8 A specification is a quality standard (i.e., tests, analytical procedures, and acceptance criteria) provided in an approved application to confirm the quality of drug substances, drug products, intermediates, raw materials, reagents, components, in-process materials, container closure systems, and other materials used in the production of a drug substance or drug product. Acceptance criteria are numerical limits, ranges, or other criteria for the tests described (§ 314.3(b)). Conformance to a specification means that the material, when tested according to the analytical procedures listed in the specification, will meet the listed acceptance criteria.对药品的特征、剂量、质量、纯度和药效变更效果进行评估，应该包括原料药中间体、原料药、中控物料和/或被符合已批准质量标准变更影响的制剂。规格是一个（例如，试验、分析步骤、可接受标准）在已批准的申请里提供证实原料药、成品、中间体、原材料、反应物、成分、中控物料、包装，和原料药或制剂生产过程中使用的其它物质的质量标准。可接受标准是个描述测试的数值界限，范围，或其他的标准(§ 314.3(b))。符合质量标准的意思是，当物料根据质量标准中所列出的分析步骤检验，将符合所列出的可接受标准。2. Additional Testing 附加试验In addition to confirming that the material affected by manufacturing changes continues to meet its specification, we recommend that the applicant perform additional testing, when appropriate, to assess whether the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product have been or will be affected. The assessment should include, as appropriate, evaluation of any changes in the chemical, physical, microbiological, biological, bioavailability, and/or stability profiles. This additional assessment could involve testing of the postchange drug product itself or, if appropriate, the material directly affected by the change. The type of additional testing that an applicant should perform would depend on the type of manufacturing change, the type of drug substance and/or drug product, and the effect of the change on the quality of the drug product. For example:除了证实被生产变更影响的物料仍然符合它的质量标准，我们建议申请者实行附加试验，适当的时候评估可能关系到药品安全性和有效性的特征、剂量、质量、纯度或药效是否已经或将被影响 。评估应该适当包括化学的、物理的、微生物的、生物的、生物利用度和/或稳定性的任何变化。这个附加评估包含变更后药品自身的试验或受变更直接影响的物料。申请者实行该类型的附加试验，取决于该类型的生产变更、该类型药用物质和/或成品，和在高质量药品的变更效果。例如：&&Evaluation of changes in the impurity or degradant profile could first involve profiling using appropriate chromatographic techniques and then, depending on the observed changes in the impurity profile, toxicology tests to qualify a new impurity or degradant or to qualify an impurity that is above a previously qualified level.9&&&&&对于变更对杂质或降解物档案的评估，首先必须包括使用合适的色谱技术进行分析，然后根据观测到的杂质归档变更状况，对新的杂质或是降解物进行毒理试验确认，或是在确认杂质在一个先前确认的水平之上。&&Evaluation of the hardness or friability of a tablet after certain changes.&&&在一些变更后必须考虑对片剂的硬度或脆度进行评估。&&&&Assessment of the effect of a change on bioequivalence when required under 21 CFR part 320 could include, for example, multipoint and/or multimedia dissolution profiling and/or an in vivo bioequivalence study.根据21CFR320条款的要求，评估变更对于生物等效性的影响。例如，进行多因素和/或多介质溶解性试验，或是体外生物等效性研究。&&Evaluation of extractables from new packaging components or moisture permeability of a new container closure system. 对新包装组分通透性或新的容器密封系统的水份渗透性进行评估测试。An applicant should refer to all relevant CDER guidance documents for recommendations on the information that should be submitted to support a given change. If guidance for information that should be submitted to support a particular change is not available, applicants can consult the appropriate CDER chemistry or microbiology review staff for advice.&申请者应该参考所有相关的CDER指导文件，建议为支持给定的变更提交资料。如果在本指南中，为支持一个特定的变更所提交的资料没有效，申请者可以向合适的CDER化学或微生物检查人员征询意见。B. Equivalence 等价When testing is performed, the applicant should usually assess the extent to which the manufacturing change has affected the identity, strength, quality, purity, and potency of the drug product. Typically this is accomplished by comparing test results from pre- and postchange material and determining if the test results are equivalent. Simply stated: Is the drug product made after the change equivalent to the drug product made before the change?实行检测后，申请者应该经常评估哪个生产变更范围会影响到药品的特征、剂量、质量、纯度和药效。通常这是通过比较变更前和变更后物料的检验结果来完成的，确定检验结果是否等价。简单说明：药品是在药品变更前后等价的情况下生产的吗？&An exception to this general approach is that when bioequivalence is redocumented for certain ANDA postapproval changes, FDA recommends that the comparator be the reference listed drug. Equivalence comparisons frequently have a criterion for comparison with calculation of confidence intervals relative to a predetermined equivalence interval.这方面的例外情况是，如果要对某个已批准的ADDA进行变更，要求重新进行生物等效性研究， FDA 建议该参考对照物必须是参考的药物。在相对一个预定的等价区间里，等价比较经常有一个标准作为比较置信区间的计算结果。For this, as well as for other reasons, equivalent does not necessarily mean identical. Equivalence may also relate to maintenance of a quality characteristic (e.g., stability) rather than a single performance of a test.对此，和其它原因一样，等价并不是意味着相等。等价还可能关系到质量特征的维持（例如，稳定性）而不是简单的一项测试行为。C. Adverse Effect 不良作用Some manufacturing changes have an adverse effect on the identity, strength, quality, purity, or potency of the drug product. In many cases, the applicant chooses not to implement these manufacturing changes, but sometimes the applicant wishes to do so.& If an assessment indicates that a change has adversely affected the identity, strength, quality, purity, or potency of the drug product, FDA recommends that the change be submitted in a prior approval supplement regardless of the recommended reporting category for the change.& For example, a process change recommended for a changes-being-effected-in-30¬days supplement could cause the formation of a new degradant that requires qualification and/or identification.10 The applicant's degradation qualification procedures may indicate that there are no safety concerns relating to the new degradant. Even so, we recommend that the applicant submit this change in a prior approval supplement with appropriate information to support the continued safety and effectiveness of the drug product.& During the review of the prior approval supplement, the FDA will assess the impact of any adverse effect on the drug product as this change may relate to the safety or effectiveness of the drug product.&一些生产变更对药品的特征、剂量、质量、纯度或药效有不良作用。在许多情况下，申请者选择不去实行这些生产变更，但有时申请者希望那样做。如果评估表明变更对药品的特征、剂量、质量、纯度或药效有不良影响，FDA建议这种变更将提交在批准前变更申请里而不管变更报告范围的建议。例如，一个工序的变更，能引起新降解产物的生成，要求其合格和/或能识别，建议30天后进行变更补充申请。申请者的降解合格操作可能表明没有关于新降解产物的安全隐患。即使如此，我们建议申请者在批准前变更申请中提交此变更，以适当的资料支持药品持续的安全性和有效性。Applicants are encouraged to consult with the appropriate CDER chemistry or microbiology review staff if there are any questions on whether a change in a characteristic would be viewed by CDER as adversely affecting the identity, strength, quality, purity, or potency of the drug product.&不论药品的特征是否改变，CDER人员将当作影响药品特性、浓度、质量、纯度或药效的不利方面来检查，如果有任何问题，鼓励申请者咨询合适的CDER化学或微生物检查人员。V. COMPONENTS AND COMPOSITION 成分和组成Changes in the qualitative or quantitative formulation, including inactive ingredients, as provided in the approved application, are considered major changes requiring a prior approval supplement, unless exempted by regulation or guidance (§ 314.70(b)(2)(i)). The deletion or reduction of an ingredient intended to affect only the color of the drug product may be reported in an annual report (§ 314.70(d)(2)(ii)). Guidance on changes in components and composition that may be submitted in a changes-being-effected supplement or annual report is not included in this document because of the complexity of the recommendations, but may be covered in one or more guidance documents describing postapproval changes (e.g., SUPAC documents).处方质量或数量改变，包括费活性成分，认为是大变更，要求提交“批准前变更申请”，除非有法规或指南豁免(§ 314.70(b)(2)(i))。只是影响药品颜色的某种成分的取消或减少可以在年度报告中报告(§314.70(d)(2)(ii))。本指南不包括在“有待生效的变更补充文件”或年度报告中提交的变更。VI. MANUFACTURING SITES11 厂址A. General ConsiderationsCDER must be notified when a manufacturer changes to a manufacturing site that is different from those specified in the approved application (314.70(a)).& Sites can include those used by an applicant to (1) manufacture or process drug products,12 in-process materials, drug substances, or drug substance intermediates, (2) package drug products, (3) label drug products, and (4) test components, drug product containers, closures, packaging materials, in-process materials, or drug products.& Sites include those owned by the applicant or contract sites used by an applicant. Testing sites include those performing physical, chemical, biological, and microbiological testing to monitor, accept, or reject materials, as well as those performing stability testing. Sites used to label drug products are considered those that perform labeling of the drug product's primary or secondary packaging components. Sites performing operations that place identifying information on the dosage form itself (e.g., ink imprint on a filled capsule) are considered to be facilities that manufacture or process the drug product. FDA recommends that the supplement or annual report identify whether the proposed manufacturing site is an alternative to or replacement for the site or sites provided for in the approved application.当变更生产地址时，如果变更的地点不包括在批准的申请中，必须通知CDER(314.70(a))。生产地址变更的包括申请人用于制造或处理制剂药品、中控物料、原料药、原料药中间体，包装药品、贴标签，检测成分、药品容器、密封材料、包材、中控物料或药品的场所的地址变更厂址包括申请人所有的或合同场所。检测厂址包括物理、化学、生物学、微生物检测场所，用于物料控制、接收、拒收，以及稳定性检测。贴标签场所指对产品内包装和外包装贴标签的场所。FDA建议在增补或年度报告中必须说明提交的生产地址是否时原来已批准的地址的替代选择，还是完全替代地址。FDA recommends that a move to a different manufacturing site, when it is a type of site routinely subject to FDA inspection, be submitted as a prior approval supplement if the site does not have a satisfactory CGMP inspection13 for the type of operation14 being moved (see sections VI.B.1 and 2).搬迁后的另一个生产厂址如果只需进行常规检查，尚未通过GMP检查，FDA建议提交“批准前的变更申请”。For labeling, secondary packaging, and testing site changes, the potential for adverse effect on the identity, strength, quality, purity, or potency of a drug product as these factors may relate to the safety or effectiveness of the drug product is considered to be independent of the type of drug product dosage form or specific type of operation being performed.& Therefore, the recommended reporting category for any one of these manufacturing site changes will be the same for all types of drug products and operations. For manufacturing sites used to (1) manufacture or process drug products, in-process materials, drug substances, or drug substance intermediates or (2) perform primary packaging operations, the potential for adverse effect depends on factors such as the type of drug substance or drug product and operation being performed.& Therefore, recommended reporting categories may differ depending on the type of drug product and operations.对于贴标签、外包装和检测地点的变更，对关系到药品安全性或有效性的特性、剂量、质量、纯度或药效有不良作用的潜在因素，被认为独立于药品剂型或正在执行的具体操作。因此，建议这些生产场所任一变更的报告范围要和所有类型的制剂和操作一样。对于生产场所用于（1）生产药品、中控物料、原料药、原料药中间体（2）实行内包装的操作，潜在的不良反应，取决于该类型的原料药或药品和正在执行的操作。因此。建议报告类别可以不同于依赖该类制剂和操作。Except for the situations described in sections VI.B.4, VI.C.1.b, and VI.D.5, construction activities at a manufacturing site or moving production operations within a building or between buildings at the same manufacturing site do not have to be reported to CDER.&除了描述VI.B.4, VI.C.1.b, and VI.D.5的情况，在生产场所或活动的生产操作里、在相同生产场所、一个建筑物或两个建筑物之间的建筑活动不需要报告给CDER 。We recommend that a move to a manufacturing site that involves other changes (e.g., process, equipment) be evaluated as a multiple related change (see section XII) to determine the appropriate reporting category.&我们建议生产场所的移动牵涉到被看作是复杂的相关其他变更（例如，工序、设备），再决定合适的报告范围。B.&Major Changes (Prior Approval Supplement) 大变更The following are examples of changes considered to have a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of a drug product as these factors may relate to the safety or effectiveness of the drug product.&下面的例子是对药品特征、剂量、质量、纯度或药效有重大的潜在不良影响，可能与药品的安全性和有效性相关的变更。1&A move to a different manufacturing site, except one used to manufacture or process a drug substance intermediate, when the new manufacturing site has never been inspected by FDA for the type of operation that is being moved or the move results in a restart at the new manufacturing site of a type of operation that has been discontinued for more than two years.&进行该项操作的新厂址从未接受过FDA现场检查，或该厂址的该项操作已中止2年以上，生产原料药中间体的厂址除外。2&A move to a different manufacturing site, except one used to manufacture or process a drug substance intermediate, when the new manufacturing site does not have a satisfactory CGMP inspection for the type of operation being moved.&进行该项操作的新厂址GMP检查不合格，生产原料药中间体的厂址除外。3&A move to a different manufacturing site for (1) the manufacture, processing, or primary packaging of drug products when the primary packaging components control the dose delivered to the patient or the formulation modifies the rate or extent of availability of the drug, or (2) the manufacture or processing of in-process materials with modified-release characteristics. Examples of these types of drug products include modified-release solid oral dosage forms,15 transdermal systems, liposomal drug products, depot drug products, oral and nasal metered-dose inhalers (MDIs), dry powder inhalers (DPIs), and nasal spray pumps.新厂址（1）进行生产、加工、内包装，内包装控制患者的给药剂量或处方改变了药物吸收的速度或程度，（2）生产或加工具有缓释特性的中控物料，包括控释口服固体制剂，透皮吸收制剂，脂质体制剂、缓释制剂、MDIs、DPIs和鼻喷雾泵。4&Transfer of the manufacture of an aseptically processed sterile drug substance or aseptically processed sterile drug product to (1) a newly constructed or refurbished aseptic processing facility or area or (2) an existing aseptic processing facility or area that does not manufacture similar (including container types and sizes) approved drug products. An example would be transferring the manufacture of a lyophilized drug product to an existing aseptic process area where no approved lyophilized drug products are manufactured or where the approved lyophilized drug products being manufactured have different container types and/or sizes than the container of the drug product being transferred. See section VI.C.1.b for recommendations for other manufacturing site changes relating to aseptically processed sterile drug substance or aseptically processed sterile drug product.无菌原料药或无菌制剂转移到（1）新建的或改造的无菌厂房或厂区（2）现有的无菌加工厂房或厂区，但是不未生产过类似的产品（包括包装类型和规格）。例如冻干粉剂转移到现有的未生产冻干粉剂的无菌生产区，或生产的产品的包装类型和规格与批准的产品不相符。其他无菌工艺相关的原料药或制剂的生产厂址变更见sectionVI.C.1.b5.&Transfer of the manufacture of a finished drug product sterilized by terminal processes to a newly constructed facility at a different manufacturing site. Once this change has been approved, subsequent site changes to the facility for similar drug product types and processes may be submitted as a changes-being-effected-in-30-days supplement (see section VI.C.1.a).使用终端灭菌工艺生产的制剂产品转移至不同厂址的新建厂房。一旦此变更被批准，后来的相似药品类型和工艺的场所变更可以作为“30天后进行的变更补充申请”提交。C.&Moderate Changes (Supplement - Changes Being Effected) 中等变更（即将进行的变更的补充申请）The following are examples of changes considered to have a moderate potential to have an adverse effect on the identity, strength, quality, purity, or potency of a drug product as these factors may relate to the safety or effectiveness of the drug product. If the new site does not have a satisfactory CGMP inspection for the type of operation being moved (see sections VI.B.1 and 2), then FDA recommends that the changes listed below (excluding changes relating to drug substance intermediate manufacturing sites) be submitted in a prior approval supplement.&下面的例子是对药品特征、剂量、质量、纯度或药效有中等的潜在不良影响，可能与药品的安全性和有效性相关的变更。如果对正在被移动的该类型操作(see sections VI.B.1 and 2)，其新地点没有令人满意的CGMP检查，FDA建议变更清单（包括有关原料药中间体的变更）提交在“批准前变更补充申请”。1.&Supplement - Changes Being Effected in 30 Days& 补充文件-30后变更生效a.&A move to a different manufacturing site for the manufacture or processing of any drug product, in-process material, or drug substance that is not otherwise provided for in this guidance.本指南未提及的生产或加工制剂、中控物料、原料药的新厂址b.&For aseptically processed sterile drug substance or aseptically processed sterile drug product, a move to an aseptic processing facility or area at the same or different manufacturing site except as provided for in section VI.B.4.无菌原料药或制剂搬迁至相同或不同厂址的无菌加工厂房或加工区域，section VI.B.4除外c.&A move to a different manufacturing site for the primary packaging of (1) any drug product that is not otherwise listed as a major change and (2) modified-release solid oral dosage form drug products.内包装搬迁至不同的厂址（1）不属于大变更的范畴（2）控制口服固体制剂d.&A move to a different manufacturing site for testing if (1) the test procedures approved in the application or procedures that have been implemented via an annual report are used, (2) all postapproval commitments made by the applicant relating to the test procedures have been fulfilled (e.g., providing methods validation samples), and (3) the new testing facility has the capability to perform the intended testing.搬迁至不同的检测厂址（1）使用申请中或年度报告中批准的检测规程（2）所有检测规程相关的批准后承诺都已完成（如提供方法验证样品），（3）新的检测场所有足够的检测能力。2.&Supplement - Changes Being Effected 补充文件-变更已生效A move to a different manufacturing site for the manufacture or processing of the final intermediate.&搬迁至不同的厂址生产或加工最终中间体D.&Minor Changes (Annual Report) 小变更（年度报告）The following are examples of changes considered to have a minimal potential to have an adverse effect on the identity, strength, quality, purity, or potency of a drug product as these factors may relate to the safety or effectiveness of the drug product. If the new site does not have a satisfactory CGMP inspection for the type of operation being moved, then FDA recommends that the changes listed below (excluding changes relating to drug substance intermediate manufacturing sites) be submitted in a prior approval supplement (see sections VI.B.1 and 2).下面的例子是对药品特征、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。如果新厂址针对搬迁的操作没有通过GMP检查，FDA建议以下的情况提交“批准前的补充申请”，不包括原料药中间体的生产厂址。1&A move to a different manufacturing site for secondary packaging.&不同的外包装厂址2&A move to a different manufacturing site for labeling.不同的贴标签厂址3&A move to a different manufacturing site for the manufacture or processing of drug substance intermediates other than the final intermediate.不同的原料药中间体生产加工厂址，不包括最终中间体4&A change in the contract sterilization site for packaging components when the process is not materially different from that provided for in the approved application包材的合同灭菌场所与申请中批准的不同5&A transfer of the manufacture of a finished product sterilized by terminal processes to a newly constructed building or existing building at the same manufacturing site.采用终端灭菌工艺生产的制剂产品转移至新建厂房或同一厂址的现有厂房6&A move to a different manufacturing site for the ink imprinting of solid oral dosage form drug products.口服固体制剂喷墨厂址改变VII.&MANUFACTURING PROCESS 生产工艺A.&General Considerations&The potential for adverse effects on the identity, strength, quality, purity, or potency of a drug product as these factors may relate to the safety or effectiveness of the drug product depends on the type of manufacturing process and the changes being instituted for the drug substance or drug product. In some cases, there may be a substantial potential for adverse effect regardless of direct testing of the drug substance or drug product for conformance with the approved specification. When there is a substantial potential for adverse effects, a change must be submitted in a prior approval supplement (section 506A(c) of the Act).&可能对药品的安全性和有效性有关的特征、剂量、质量、纯度或药效的潜在不良影响，对于原料药或制剂，取决于该类型生产工艺和正在开始的改变。在某些情况下，可能有重大的潜在不良影响不管原料药或制剂的直接检测和已批准的质量标准一致。当有重大潜在不良影响时，变更必须提交在“批准前变更补充申请” (section 506A(c) of the Act)。&B.&Major Changes (Prior Approval Supplement) 大变更The following are examples of changes considered to have a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of a drug product as these factors may relate to the safety or effectiveness of the drug product.&下面的例子是对药品特征、剂量、质量、纯度或药效有重大的潜在不良影响，可能与药品的安全性和有效性相关的变更1&Changes that may affect the controlled (or modified) release, metering or other characteristics (e.g., particle size) of the dose delivered to the patient, including the addition or deletion of a code imprint by embossing, debossing, or engraving on a modified-release solid oral dosage form.可能改变控释、定量给药或其他给药特性的变更，包括加入或取消刻字2.&Changes that may affect drug product sterility assurance including, where appropriate, process changes for sterile drug substances and sterile packaging components. These include:可能影响产品无菌保证的变更，包括无菌原料药和无菌包材的工艺变更，包括&&Changes in the sterilization method (e.g., gas, dry heat, irradiation). These include changes from sterile filtered or aseptic processing to terminal sterilization, or vice versa.无菌方法变更（如汽、干热、放射），包括无菌过滤或无菌工艺改为终端灭菌&&Addition, deletion, or substitution of sterilization steps or procedures for handling sterile materials in an aseptic processing operation.&&无菌步骤或规程的增加、减少或替代&&Replacing sterilizers that operate by one set of principles with sterilizers that operate by another principle (e.g., substituting a gravity displacement steam process with a process using superheated water spray).&&灭菌原理改变&&Addition to an aseptic processing line of new equipment made of different materials (e.g., stainless steel versus glass, changes between plastics) that will come in contact with sterilized bulk solution or sterile drug components, or deletion of equipment from an aseptic processing line.&&加入不同材料制造的新设备的无菌工艺线，与无菌溶液或药品成分直接接触，或从无菌生产线上取消设备&&Replacing a Class 100 aseptic fill area with a barrier system or isolator for aseptic filling. Once this change has been approved, subsequent process changes for similar product types in the same barrier system or isolator may be submitted as a changes-being-effected-in-30-days supplement.&&用隔离系统或无菌灌装代替100级无菌灌装区，后续工艺变更可提交“30天后进行的变更的补充申请”。&&Replacement or addition of lyophilization equipment of a different size that uses different operating parameters or lengthens the overall process time.&&不同规格、不同冻干参数、或延长工艺总时间的冻干设备的替换或添加&&Changes from bioburden-based terminal sterilization to the use of an overkill process, and vice versa.&&使用生物灭菌柜的终端灭菌方法改为使用过度杀伤工艺，反之亦然&&Changes to aseptic processing methods, including scale, that extend the total processing, including bulk storage time, by more than 50 percent beyond the validated limits in the approved application.&&改为无菌工艺方法，包括工艺能力放大，包括贮存时间超过申报资料的验证限度50％以上&&Changes in sterilizer load configurations that are outside the range of previously validated loads.&&灭菌器负荷超过预先验证的限度&Changes in materials or pore size rating of filters used in aseptic processing.&无菌工艺中物料或过滤器的孔径规格改变3.&The following changes for a natural product下述产品变更&Changes in the virus or adventitious agent removal or inactivation methods.&病毒或外源性物质或去活方法的改变&This applies to any material where such procedures are necessary, including drug substance, drug product, reagents, and excipients.&适用于任何物料，包括原料药、制剂、试剂、辅料&&For drug substance and drug product, changes in the source material (e.g., microorganism, plant) or cell line.&&对于原料药和制剂，来源（如微生物、培养）或细胞链改变&&For drug substance and drug product, establishment of a new master cell bank or seed.&&对于原料药和制剂，建立新的细胞库或种子4.&Any fundamental change in the manufacturing process or technology from that currently used by the applicant. For example:现行生产工艺或技术的基本变更，例如：&&a.&Drug product 制剂Dry to wet granulation or vice versa. 干法改为湿法或反之Change from one type of drying process to another (e.g., oven tray, fluid bed, microwave).&由一种干燥工艺改为另一种（如烘箱、流化床、微波炉）&&b.&Drug substance 原料药Filtration to centrifugation or vice versa. 过滤改为离心或反之Change in the route of synthesis of a drug substance 原料药合成途径改变5.&The following changes for drug substance 原料药下述变更Any process change made after the final intermediate processing step in drug substance manufacture.&原料药生产过程中，最终中间体以后的工艺步骤的任何变更Changes in the synthesis or manufacture of the drug substance that may affect its impurity profile and/or the physical, chemical, or biological properties.可能影响原料药杂质和/或物理、化学或生物学特性的合成或生产的变更6.&Addition of an ink code imprint or change to or in the ink used for an existing imprint code for a solid oral dosage form drug product when the ink as changed is not currently used on CDER-approved drug products.17&&加入或改变喷墨，如果当前使用的喷墨已不用于CDER批准的产品7.&Establishing a new procedure for reprocessing a batch of drug substance or drug product that fails to meet the approved specification.&制定不合格原料药或制剂的新的再加工规程C.&Moderate Changes (Supplement - Changes Being Effected) 中等变更The following are examples of changes considered to have a moderate potential to have an adverse effect on the identity, strength, quality, purity, or potency of a drug product as these factors may relate to the safety or effectiveness of the drug product.&下面的例子是对药品特征、剂量、质量、纯度或药效有中等的潜在不良影响，可能与药品的安全性和有效性相关的变更1.&Supplement - Changes Being Effected in 30 Days& 30天后进行的变更补充申请&&a.&For drug products, any change in the process, process parameters, and/or equipment except as otherwise provided for in this guidance.&&本指南未提及的制剂产品的所有工艺、工艺参数和/或设备变更&&b.&For drug substances, any change in process and/or process parameters except as otherwise provided for in this guidance.&&本指南未提及的原料药的工艺和/或工艺参数变更&&c.&For natural protein drug substances and natural protein drug products:&&蛋白质原料药和制剂&&Any change in the process, process parameters, and/or equipment except as otherwise provided for in this guidance (e.g., section VII.B.5, VII.D.7).&&本指南未提及的任何工艺、工艺参数和/或设备变更&&An increase or decrease in production scale during finishing steps that involves different equipment.&&涉及不同设备的生产结束步骤的增加或减少&&Replacement of equipment with equipment of different design that does not affect the process methodology or process operating parameters.&&不同设计的设备变更，不影响工艺方法和工艺参数&&d.&For sterile drug products, drug substances, and components, as appropriate:&&对于无菌制剂、原料药、成分&&Changes in dry heat depyrogenation processes for glass container systems for drug substances and drug products that are produced by terminal sterilization processes or aseptic processing.&&终端灭菌或无菌工艺生产的原料药或制剂的玻璃容器的干热除热原工艺的变更&&Changes to filtration parameters for aseptic processing (including flow rate, pressure, time, or volume, but not filter materials or pore size rating) when additional validation studies for the new parameters should be performed.&&无菌工艺（包括流速、压力、时间、体积、不包括过滤器材料或孔径）过滤参数的变更，新参数需进行额外验证&&Filtration process changes that provide for a change from single to dual sterilizing filters in series, or for repeated filtration of a bulk.&&过滤工艺变更，从单一过滤器变为双重过滤器或重复过滤&&Changes from one qualified sterilization chamber to another for in-process or terminal sterilization that result in changes to validated operating parameters (time, temperature, F0, and others).&&一个验证过的灭菌柜改为另一个中控或终端灭菌，导致验证参数改变（时间、温度、F0、其他）&&Changes in scale of manufacturing for terminally sterilized drug products that increase the bulk solution storage time by more than 50 percent beyond the validated limits in the approved application when bioburden limits are unchanged.&终端灭菌产品的生产规模改变，导致原液贮存时间增加50％以上，在生物负荷限度不变的情况下超过申报资料中的验证限度e.&For drug substances, redefinition of an intermediate, excluding the final intermediate, as a starting material.&对于原料药、中间体再定义、不包括最终中间体，作为起始物料2.&Supplement - Changes Being Effected& 已进行的变更补充申请&&a.&A change in methods or controls that provides increased assurance that the drug substance or drug product will have the characteristics of identity, strength, quality, purity, or potency that it purports or is represented to possess.&&方法或控制变更，提高原料药或制剂成分、剂量、质量、纯度、药效的保证&&b.&For sterile drug products, elimination of in-process filtration performed as part of the manufacture of a terminally sterilized drug product.&&&无菌制剂，取消终端灭菌生产的中控过滤步骤&&D.&Minor Changes (Annual Report) 小变更（年报）The following are examples of changes considered to have a minimal potential to have an adverse effect on the identity, strength, quality, purity, or potency of a drug product as these factors may relate to the safety or effectiveness of the drug product.&下面的例子是对药品特征、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。1&For drug products, changes to equipment of the same design and operating principle and/or changes in scale except as otherwise provided for in this guidance (e.g., section VII.C.1.c, VII.D.7).&本指南未涉及的制剂产品设备设计和操作原理和/或规模变更2&A minor change in an existing code imprint for a dosage form.& For example, changing from a numeric to alphanumeric code.制剂刻字喷墨的变更，如由数字改为文字数字3&Addition of an ink code imprint or a change in the ink used in an existing code imprint for a solid oral dosage form drug product when the ink is currently used on CDER-approved drug products.加入喷墨或改变喷墨4&Addition or deletion of a code imprint by embossing, debossing, or engraving on a solid dosage form drug product other than a modified-release dosage form.非控制制剂的口服固体制剂加入或取消刻字代码5&A change in the order of addition of ingredients for solution dosage forms or solutions used in unit operations (e.g., granulation solutions).单剂量使用的液体制剂或溶液剂成分加入次序改变1&Changes in scale of manufacturing for terminally sterilized drug products that increase the bulk solution storage time by no more than 50 percent beyond the validated limits in the approved application when bioburden limits are unchanged.终端灭菌的制剂产品生产规模改变，延长原液贮存时间50％以上，在生物负荷限度不变的情况下超过申报资料中的验证限度&&7.&For natural protein drug products and natural protein drug substances:&&对于蛋白质制品和天然蛋白质原料药&&An increase or decrease in production scale during finishing steps that does not involve an equipment change.&&生产末期增加或降低生产规模，没有设备变更&&Replacement of equipment with equipment of the same design, operating principle, and capacity with no change in production scale.&&设备变更，变更前后的设备的设计、操作原理、产能、生产规模相同VIII.&SPECIFICATIONS 质量标准A.&General ConsiderationsAll changes in specifications from those in the approved application must be submitted in a prior approval supplement unless otherwise exempted by regulation or guidance (§ 314.70(b)(2)(i)). Specifications (i.e., tests, analytical procedures, and acceptance criteria) are the quality standards provided in an approved application to confirm the quality of drug substances, drug products, intermediates, raw materials, reagents, components, in-process materials, container closure systems, and other materials used in the production of a drug substance or drug product. For the purpose of defining specifications, acceptance criteria are numerical limits, ranges, or other criteria for the tests described. Examples of a test, an analytical procedure, and an acceptance criterion are, respectively, an assay, a specific, fully described high pressure liquid chromatography (HPLC) procedure, and a range of 98.0–102.0 percent.& The recommendations in this section also apply to specifications associated with sterility assurance that are included in NDA and ANDA submissions.18&从那些已批准申请的质量标准里的所有变更必须提交在“批准前变更补充申请”，除非另有被规章或指导原则豁免的(§ 314.70(b)(2)(i))。规程（例如，检测、分析步骤、可接受标准）是在已批准的申请里提供证实原料药、制剂、中间体、原材料、反应物、成分、中控物料、包装，和原料药或制剂生产过程中使用的其它物质的质量标准。质量标准和可接受标准的目的是明确数值界限，范围，或为检验所描述的其他标准。实例检验，一个分析规程和一个可接受标准为各自检测、完全特定的高效液相步骤、范围98.0%-102.0%。本条中的建议也适用于和无菌保证有联系的质量标准，包括在NDA和ANDA。A regulatory analytical procedure is the procedure in the approved application that is designated for use in evaluating a defined characteristic of the drug substance or drug product. Section 501(b) of the Act recognizes the analytical procedures in the U.S. Pharmacopeia/National Formulary (USP/NF) as the regulatory analytical procedures for compendial items. Tests and associated acceptance criteria and regulatory analytical procedures in addition to those specified in the USP/NF may be required for approving compendial items (section 505 of the Act).&获批准的法定分析规程是能被指定用于评估原料药或制剂的确定性质的规程。美国药典/国家处方集的法定分析规程是根据法案的第501(b)确定的分析规程。对正在批准的简明条款除了那些在USP/NF中详细说明的，还有检测和有联系的可接受标准，法定分析规程，可能都被要求在其中。(section 505 of the Act)The applicant may include in its application alternatives to the approved regulatory analytical procedures for testing the drug substance and drug product. However, for purposes of determining compliance with the Act, regulatory analytical procedures are used.&申请人可以在其申请书中包括其可实施的用于检验原料药和制剂的不同于法定分析规程的替代方法。不过，为了和法案相一致，使用法定分析规程来判断决定。In sections B through D below, the use of the term analytical procedure without a qualifier such as regulatory or alternative refers to an analytical procedure used to test materials other than the drug substance or drug product.&在B部分到以下D，没有限定分析规程的使用范围，例如法定或可替代的指的是被用于检测物料而不是原料药或制剂的分析规程。B.&Major Changes (Prior Approval Supplement) 大变更The following are examples of changes in specifications considered to have a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of a drug product as these factors may relate to the safety or effectiveness of the drug product.&下面的例子是对药品特征、剂量、质量、纯度或药效重大的潜在不良影响，可能与药品的安全性和有效性相关的变更。1&Relaxing an acceptance criterion except as otherwise provided for in this guidance (e.g., section VIII.C.1.b, VIII.C.1.e).本指南未提及的可接受限度变宽2&Deleting any part of a specification except as otherwise provided for in this guidance (e.g., section VIII.D.2).&本指南未提及的质量标准项目的删除3&Establishing a new regulatory analytical procedure including designation of an alternative analytical procedure as a regulatory procedure.制定新的法定分析规程，包括替代规程4&A change in a regulatory analytical procedure that does not provide the same or increased assurance of the identity, strength, quality, purity, or potency of the material being tested as the regulatory analytical procedure described in the approved application.&对申报资料中的法定分析规程的变更，但是不能等效或更好地保证被测物的特征、剂量、质量、纯度或药效5&A change in an analytical procedure used for testing components, packaging components, the final intermediate, in-process materials after the final intermediate, or starting materials introduced after the final intermediate that does not provide the same or increased assurance of the identity, strength, quality, purity, or potency of the material being tested as the analytical procedure described in the approved application except as otherwise noted. For example, a change from an HPLC procedure that distinguishes impurities to (1) an HPLC procedure that does not, (2) another type of analytical procedure (e.g., titrimetric) that does not, or (3) an HPLC procedure that distinguishes
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