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1、美国 FDA分析方法验证指南中英文对照I. INTRODUCTION This guidance provides recommendations to applicants on submitting analytical procedures, validation data, and samples to support the documentation of the identity, strength, quality, purity, and potency of drug substances and drug products.1. 绪论本指南旨在为申请者提供建议，以帮助其提
2、交分析方法， 方法验证资料和样品用于支持原料药和制剂的认定，剂量，质量，纯度和效力方面的文件。This guidance is intended to assist applicants in assembling information, submitting samples, and presenting data to support analytical methodologies. The recommendations apply to drug substances and drug products covered in new drug applications (NDAs
3、), abbreviated new drug applications (ANDAs ), biologics license applications (BLAs ), product license applications (PLAs), and supplements to these applications.本指南旨在帮助申请者收集资料，递交样品并资料以支持分析方法。这些建议适用于 NDA ，ANDA ，BLA ，PLA及其它们的补充中所涉及的原料药和制剂。The principles also apply to drug substances and drug products
4、 covered in Type II drug master files (DMFs ). If a different approach is chosen, the applicant is encouraged to discuss the matter in advance with the center with product jurisdiction to prevent the expenditure of resources on preparing a submission that may later be determined to be unacceptable.这
5、些原则同样适用于二类DMF 所涉及的原料药和制剂。 如果使用了其它方法，鼓励申请者事先和FDA药品评审中心的官员进行讨论，以免出现这种情况， 那就是花了人力物力所准备起来的递交资料后来发现是不可用的。The principles of methods validation described in this guidance apply to all types of analytical procedures. However, the specific recommendations in this guidance may not be applicable to certain uni
6、que analytical procedures for products such as biological, biotechnological, botanical, or radiopharmaceutical drugs.本指南中所述的分析方法验证的原则适用于各种类型的分析方法。但是，本指南中特定的建议可能不适用于有些产品所用的特殊分析方法，如生物药，生物技术药，植物药或放射性药物等。For example, many bioassays are based on animal challenge models, 39 immunogenicity assessments, or
7、other immunoassays that have unique features that should be considered when submitting analytical procedure and methods validation information. 比如说，许多生物分析是建立在动物挑战模式，免疫原性评估或其它有着独特特性的免疫分析基础上的， 在递交分析方法和分析方法验证资料时需考虑这些独特的性质。名师资料总结 - - -精品资料欢迎下载 - - - - - - - - - - - - - - - - - - 名师精心整理 - - - - - - - 第 1
8、 页，共 41 页 - - - - - - - - - Furthermore, specific recommendations for biological and immunochemical tests that may be necessary for characterization and quality control of many drug substances and drug products are beyond the scope of this guidance document.而且， 许多原料药和制剂的界定和质量控制所需的生物和免疫化学检测并不在本指南的范围之
9、内。Although this guidance does not specifically address the submission of analytical procedures and validation data for raw materials, intermediates, excipients, container closure components, and other materials used in the production of drug substances and drug products, validated analytical procedu
10、res should be used to analyze these materials.尽管本指南并不专门叙述原料，中间体，赋形剂，包装材料及原料药和制剂生产中所用的其它物料的分析方法及分析方法验证资料的递交，但是应该应用验证过的分析方法来分析检测这些物质。For questions on appropriate validation approaches for analytical procedures or submission of information not addressed in this guidance, applicants should consult with
11、the appropriate chemistry review staff at FDA.对于本指南中未提及的关于分析方法验证和资料提交方面的问题，请向 FDA相关的化学评审人员咨询。This guidance, when finalized, will replace the FDA guidance for industry on Submitting Samples and Analytical Data for Methods Validation (February 1987). 本指南，一旦定稿，将取代FDA 于 1987 年 2 月份发布的工业指南：分析方法验证所需提交的样品和
12、分析资料。II. BACKGROUNDEach NDA and ANDA must include the analytical procedures necessary to ensure the identity, strength, quality, purity, and potency of the drug substance and drug product, including bioavailability of the drug product (21 CFR 314.50(d)(1) and 314.94(a)(9)(i).II. 背景每个 NDA 和 ANDA 都必需包
13、括必要的分析方法以确保原料药和制剂的认定，剂量，质量，纯度和效力，还包括制剂的生物利用度(21 CFR 314.50(d)(1) 和314.94(a)(9)(i)。FDA验证文件现场备查，可以不与DMF 一起交。Data must be available to establish that the analytical procedures used in testing meet proper standards of accuracy and reliability (21 CFR 211.165(e) and 211.194(a)(2).必须要有资料来论证所用的分析方法是符合一定的准确
14、度和可靠性标准的。Methods validation is the process of demonstrating that analytical procedures are suitable for their intended use. The methods validation process for analytical procedures begins with the planned and systematic 名师资料总结 - - -精品资料欢迎下载 - - - - - - - - - - - - - - - - - - 名师精心整理 - - - - - - - 第
15、2 页，共 41 页 - - - - - - - - - collection by the applicant of the validation data to support the analytical procedures.分析方法验证是论证某一分析方法适用于其用途的过程。分析方法的验证过程是从申请者有计划地系统性收集验证资料以支持分析方法开始的。The review chemist evaluates the analytical procedures and validation data submitted in the NDA or ANDA.审评化学家会对 NDA或 AND
16、A 中的分析方法和验证资料进行评审。On request from FDA, an NDA or ANDA applicant must submit samples of drug product, drug substance, noncompendial reference standards, and blanks so that the applicants drug substance and drug product analytical procedures can be evaluated by FDA laboratories (21 CFR 314.50(e) and 3
17、14.94(a)(10).一旦 FDA有要求，则 NDA 或 ANDA 的申请者必须提交制剂，原料药，非药典对照品和空白以使FDA实验室能对申请者所用分析方法进行评审(21 CFR 314.50(e) and 314.94(a)(10)。The FDA laboratory analysis demonstrates that the analytical procedures are reproducible by laboratory testing. The review chemists and laboratory analysts determine the suitability
18、 of the analytical procedures for regulatory purposes. FDA实验室的分析会论证该分析方法在实验室内是可以重现的。审评化学家和实验室分析家会从法规的角度确定该分析方法的适用性。FDA investigators inspect the analytical laboratory testing sites to ensure that the analytical procedures used for release and stability testing comply with current good manufacturing
19、practices (CGMPs) (21 CFR part 211) or good laboratory practices (GLPs) (21 CFR part 58), as appropriate.FDA检查官会对分析实验室进行检查确保用于放行和稳定性实验的分析方法符合现行的 GMP （21CFR part 211) 和 GLP (21 CFR part 58)。Each BLA and PLA must include a full description of the manufacturing methods, including analytical procedures,
20、 that demonstrate that the manufactured product meets prescribed standards of safety, purity, and potency (21 CFR 601.2(a) and 601.2(c)(1)(iv).每个 BLA和 PLA都必须要有详细的生产工艺描述，包括分析方法， 以说明所生产的产品是符合规定睥安全，纯充和效力标准的(21 CFR 601.2(a) and 601.2(c)(1)(iv)。Data must be available to establish that the analytical proc
21、edures used in testing meet proper standards of accuracy and reliability (21 CFR 81211.194(a)(2). For BLAs, PLAs, and their supplements, the analytical procedures and their validation are submitted as part of the license application or supplement and are evaluated by the review committee.必须要有资料证明所用的
22、分析方法是符合一定的准确度和可靠性要求的(21 CFR 81211.194(a)(2)。对于 BLA ，PLA及它们的补充，在所提交的许可证申请中应当要有分析方法和方法验证这部分的资料，审评委员会会对这部分资料进行评审。名师资料总结 - - -精品资料欢迎下载 - - - - - - - - - - - - - - - - - - 名师精心整理 - - - - - - - 第 3 页，共 41 页 - - - - - - - - - Representative samples of the product must be submitted and summaries of results
23、of tests performed on the lots represented by the submitted sample must be provided (21 CFR 601.2(a) and 601.2(c)(1)(vi). The review committee chair may request analytical testing by CBER laboratory analysts to evaluate the applicant=s analytical procedures and verify the test results.需提供代表性样品及该样品所代
24、表批号的检测结果总结(21 CFR 601.2(a) and 601.2(c)(1)(vi)。评审委员会主席会要求CBER 实验室的分析人员进行分析实验对申请者的分析方法进行评估，并确认其分析结果。All analytical procedures are of equal importance from a validation perspective. In general, validated analytical procedures should be used, irrespective of whether they are for in-process, release, ac
25、ceptance, or stability testing. Each quantitative analytical procedure should be designed to minimize assay variation. 从验证的角度来看， 所有的分析方法有着同样的重要性。一般来说， 应当要应用已验证过的分析方法，而不论其是被用于过程控制，放行，合格或稳定性实验。高等每个定量分析方法时都应当要减少其分析误差。Analytical procedures and validation data are submitted in the sections of the applica
26、tion on analytical procedures and controls. Recommendations on information to be submitted are included in sections III through IX and XI of this guidance. Information on submission of the methods validation package to the NDA or ANDA and samples to the FDA laboratories is provided in section X.分析方法
27、和验证资料应当摆在申请的分析方法和控制章节中提交。本指南的第 III到 IX 章和 XI 章给出了所需提供资料方面的建议。向 FDA实验室提供样品和递交 NDA 和 ANDA 中的分析方法验证资料的信息见第X章。III. TYPES OF ANALYTICAL PROCEDURES A. Regulatory Analytical Procedure A regulatory analytical procedure is the analytical procedure used to evaluate a defined characteristic of the drug substan
28、ce or drug product. The analytical procedures in the U.S. Pharmacopeia/National Formulary (USP/NF) are those legally recognized under section 501(b) of the Food, Drug, and Cosmetic Act (the Act) as the regulatory analytical procedures for compendial items. For purposes of determining compliance with
29、 the Act, the regulatory analytical procedure is used.III 分析方法的类型A. 法定分析方法法定分析方法是被用来评估原料药或制剂的特定性质的。USP/NF中的分析方法是法定的用于药典项目检测的分析方法。为了确认符合法规， 需使用法定分析方法。B. Alternative Analytical Procedure名师资料总结 - - -精品资料欢迎下载 - - - - - - - - - - - - - - - - - - 名师精心整理 - - - - - - - 第 4 页，共 41 页 - - - - - - - - - An alte
30、rnative analytical procedure is an analytical procedure proposed by the applicant for use instead of the regulatory analytical procedure. A validated alternative analytical procedure should be submitted only if it is shown to perform equal to or better than the regulatory analytical procedure.B. 替代分
31、析方法替代分析方法是申请者提出用于代替法定分析方法的分析方法。只有当一替代分析方法相当于或优于法定分析方法时，才可以应用验证过的替代分析方法。If an alternative analytical procedure is submitted, the applicant should provide a rationale for its inclusion and identify its use (e.g., release, stability testing), validation data, and comparative data to the regulatory anal
32、ytical procedure. 如果提交了替代分析方法， 申请者还应当提供其理由， 并标明其用途（如，放行，稳定性实验），验证资料及其与法定分析方法的对比资料。C. Stability-Indicating AssayA stability-indicating assay is a validated quantitative analytical procedure that can detect the changes with time in the pertinent properties of the drug substance and drug product.C. 稳定性
33、指示分析稳定性指示分析是能检测出原料药或制剂的某些性质随着时间的延长而出现的变化的定量分析方法。A stability-indicating assay accurately measures the active ingredients, without interference from degradation products, process impurities, excipients, or other potential impurities。稳定性指示分析能不受降解产物，工艺杂质， 赋形剂或其它潜在杂质的影响而准确测定其中的活性成分。If an applicant submit
34、s a non-stability-indicating analytical procedure for release testing, then an analytical procedure capable of qualitatively and quantitatively monitoring the impurities, including degradation products, should complement it. Assay analytical procedures for stability studies should be stability-indic
35、ating, unless scientifically justified.如果申请者递交了用于放行检测的非稳定性指示分析方法，则应当要有能定性和定量地监测杂质， 包括降解产物， 的分析方法对其进行补充。 稳定性试验中所用的含量分析方法应当要有稳定性指示能力，除非有科学的理由能证明其合理性。IV. REFERENCE STANDARDS A. Types of Standards A reference standard (i.e., primary standard) may be obtained from the USP/NF or other official sources (e.
36、g., CBER, 21 CFR 610.20). If there are questions on whether a source of a standard would be considered by FDA to be an official source, applicants should contact the appropriate chemistry review staff. When there is no official 名师资料总结 - - -精品资料欢迎下载 - - - - - - - - - - - - - - - - - - 名师精心整理 - - - -
37、- - - 第 5 页，共 41 页 - - - - - - - - - source, a reference standard should be of the highest possible purity and be fully characterized.IV 标准品A标准品的类型可以从 USP/NF处或其它官方 ( 比如说，CBER ， 21CFR 610.20) 获得标准品 ( 也就是一级对照品 )。 如果不能确定一标准品的来源是否会被FDA认为是官方来源，申请者应当要向适当的化学评审人员咨询。如果没有官方来源， 则被用来作标准品的物质应当要有尽可能高的纯度，并得到充分界定。A
38、 working standard (i.e., in-house or secondary standard) is a standard that is qualified against and used instead of the reference standard.工作对照品 ( 也就是内部标准品或二级标准品) 是根据一级对照品标定的，并用来代替一级对照品的。B. Certificate of AnalysisA certificate of analysis (COA) for reference standards from non-official sources shou
39、ld be submitted in the section of the application on analytical procedures and controls. For standards from official sources, the user should ensure the suitability of the reference standard. The standard should be stored correctly and used within the established use interval.B分析报告单对于非官方标准品， 在申请的分析方
40、法和控制章节中应当要提供该标准品的分析报告单。 对于从官方获得的标准品， 用户应当要确保标准品的适用性。应当正确储存标准品并在已确定的时间段内使用该标准品。C. Characterization of a Reference StandardReference standards from USP/NF and other official sources do not require further characterization. A reference standard that is not obtained from an official source should be of
41、the highest purity that can be obtained by reasonable effort, and it should be thoroughly characterized to ensure its identity, strength, quality, purity, and potency.C标准品的界定从 USP/NF及其它官方来源获得的标准品是不需要进一步界定的。非官方对照品要有尽可能高的纯度， 并进行充分地界定以确保其结构，剂量，质量，纯度和效力。The qualitative and quantitative analytical proced
42、ures used to characterize a reference standard are expected to be different from, and more extensive than, those used to control the identity, strength, quality, purity, and potency of the drug substance or the drug product. Analytical procedures used to Draft Not for Implementation characterize a r
43、eference standard should not rely solely on comparison testing to a previously designated reference standard. 用于界定标准品的定性和定量分析方法应当要不同于用于控制原料药或制剂的名师资料总结 - - -精品资料欢迎下载 - - - - - - - - - - - - - - - - - - 名师精心整理 - - - - - - - 第 6 页，共 41 页 - - - - - - - - - 结构，剂量，质量，纯度和效力的分析方法，要比它们更深入。用于标准品界定的分析方法不应仅仅是和先
44、前的指定标准品进行比较实验。Generally, this characterization information should include: A brief description of the manufacture of the reference standard, if the manufacturing process differs from that of the drug substance. Any additional purification procedures used in the preparation of the reference standard
45、should be described.一般来说，界定资料应当要包括：标准品的简单工艺描述， 如果其生产工艺是否于其相应的原料药的话。应当要叙述制备标准品时所用的补充精制过程。Legible reproductions of the relevant spectra, chromatograms, thin-layer chromatogram (TLC) photographs or reproductions, and other appropriate instrumental recordings. Data establishing purity. The data should b
46、e obtained by using appropriate tests, such as TLC, gas chromatography (GC), high-pressure liquid chromatography (HPLC), phase solubility analysis, appropriate thermometric analytical procedures, and others as necessary.相关光谱图，色谱图， TLC照片及其它仪器输出的清晰复印件。建立纯度的资料。应当要应用适当的检测方法来获得这些资料，比如说TLC ，GC ，HPLC ，相溶解分
47、析，适当的热分析方法及其它必要的分析方法。Appropriate chemical attribute information, such as structural formula, empirical formula, and molecular weight. Information to substantiate the proof of structure should include appropriate analytical tests, such as elemental analysis, infrared spectrophotometry (IR), ultraviol
48、et spectrophotometry (UV), nuclear magnetic resonance spectroscopy (NMR), and mass spectrometry (MS), as well as applicable functional group analysis. Detailed interpretation of the test data in support of the claimed structure should be provided.适当的化学性质资料， 比如结构式， 经验式和分子量等。 结构确证资料应当要包括适当的分析测试，比如元素分析
49、，IR，UV,NMR 和 MS ，及适用的官能团分析。还应当要提供具体的结构解析资料。A physical description of the material, including its color and physical form. Appropriate physical constants such as melting range, boiling range, refractive index, dissociation constants (pK values), and optical rotation. A detailed description of the ana
50、lytical procedures used to characterize the reference standard.物理性质的描述，包括颜色和物理形态。适当的物理常数，比如说熔程，沸程，折射率，离解常数(pK 值) 和旋光度。用于界定标准品的分析程序的详细叙述。For biotechnological/biological product reference standards, the recommendations on characterization information above may apply and should be considered. However,