Guidance for Industry
Analytical Procedures and
Methods Validation
Chemistry, Manufacturing, and Controls Documentation
DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.
Comments and suggestions regarding this draft document should be submitted within 90 days of
publication in the Federal Register of the notice announcing the availability of the draft guidance.
Submit comments to Dockets Management Branch (HFA-305), Foodand Drug Administration, 5630
Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket
number listed in the notice of availability that publishes in the Federal Register.
For questions on the contents of this draft document contact(CDER) Radhika Rajagopalan, 301-
827-5849 or (CBER) Alfred Del Grosso, 301-435-4988.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
Guidance for Industry
Analytical Procedures and
Methods Validation
Chemistry, Manufacturing, and Controls Documentation
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(Internet) http://www.fda.gov/cber/guidelines.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
目录Content
I INTRODUCTION 绪论... 5
II. BACKGROUND 背景... 6
III. TYPES OF ANALYTICAL PROCEDURES 分析方法的类型... 7
A. Regulatory Analytical Procedure 法定分析方法... 7
B. Alternative Analytical Procedure 替代分析方法... 7
C. Stability-Indicating Assay 稳定性指示分析... 8
IV. REFERENCE STANDARDS 标准品... 8
A. Types of Standards 标准品的类型... 8
B. Certificate of Analysis 分析报告单... 8
C Characterization of a Reference Standard 标准品的界定... 8
V. METHODS VALIDATION FOR INDs IND中的分析方法验证... 10
VI. CONTENT AND FORMAT OF ANALYTICAL PROCEDURES FOR NDAs,230 ANDAs, BLAs, AND PLAs NDA，ANDA，BLA和PLA中分析方法的内容和格式... 11
A. Principle 基本方法... 11
B. Sampling 取样... 11
C. Equipment and Equipment Parameters 仪器和仪器参数... 11
D. Reagents 试剂... 11
E System Suitability Testing 系统适应性实验... 12
F Preparation of Standards 标准品的制备... 12
G. Preparation of Samples 操作过程... 12
I. Calculations 计算... 12
J.Reporting of Results 结果报告... 13
VII. METHODS VALIDATION FOR NDAs, ANDAs, BLAs, AND PLAs NDA，ANDA，BLA和PLA中的分析方法验证13
A. Noncompendial Analytical Procedures 非药典分析方法... 13
B. Compendial Analytical Procedures 药典分析方法... 19
VIII. STATISTICAL ANALYSIS 统计分析... 19
A. General 基本原则... 19
B. Comparative Studies 对比研究... 20
C. Statistics 统计... 20
IX. REVALIDATION 重验证... 20
X. METHODS VALIDATION PACKAGE: CONTENTS AND PROCESSING 分析方法验证资料：内容和数据处理21
A. Methods Validation Package 分析方法验证资料... 21
1. Tabular List of All Samples to Be Submitted 所需递交样品的列表清单... 21
2. Analytical Procedures 分析方法... 21
3. Validation Data 验证资料... 21
4. Results 结果... 22
5. Composition 组分... 22
6. Specifications 质量标准... 22
7. Material Safety Data Sheets 安全数据表... 22
B. Selection and Shipment of Samples 样品的选择和运输... 22
C. Responsibilities of the Various Parties 各方职责... 23
1. Applicant 申请人... 23
2. Review Chemist 化学评审官... 24
3. FDA Laboratory FDA实验室... 24
4 Investigator 检查官... 24
XI METHODOLOGY 方法学... 25
A. High-Pressure Liquid Chromatography (HPLC) 高效液相色谱(HPLC) 25
1. Column 色谱柱... 25
2. System Suitability Testing 系统适应性研究... 25
3 Operating Parameters 操作参数... 26
B. Gas Chromatography (GC) 气相色谱(GC) 26
1. Column 色谱柱... 27
2. Operating Parameters 操作参数... 27
3. System Suitability Testing 系统适应性实验... 27
C. Spectrophotometry, Spectroscopy, Spectrometry and Related Physical Methodologies 分光光度法，光谱法和相关的物理方法... 27
D. Capillary Electrophoresis (CE) 毛细管电泳(CE) 28
1. Capillary 毛细管柱... 28
2. Operating Parameters 操作参数... 28
3. System Suitability Testing 系统适应性实验... 29
E. Optical Rotation 旋光度... 29
F Methodologies Relating to Particle Size Analysis 和粒径分析相关的分析方法... 29
1. Particle Size Methods 粒径分析方法... 30
2. Calibration and Validation Characteristics 校准和验证... 30
G. Dissolution 溶出度... 30
1. Dissolution Medium 溶解媒介... 31
2. Procedure 操作程序... 31
3. Validation Characteristics 验证... 31
H. Other Instrumentation 其它仪器分析方法... 31
1. Noncommercial Instrumentation 非商业化仪器... 31
2. Automated Analytical Procedures 自动分析方法... 32
ATTACHMENT A 附录A. 32
ATTACHMENT B 附录B. 33
GLOSSARY 术语表...33
I INTRODUCTION 绪论
This guidance providesrecommendations to applicants on submitting analytical procedures, validationdata, and samples to support the documentation of the identity, strength,quality, purity, and potency of drug substances and drug products.
本指南旨在为申请者提供建议，以帮助其提交分析方法，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 intendedto assist applicants in assembling information, submitting samples, andpresenting data to support analytical methodologies. The recommendations applyto drug substances and drug products covered in new drug applications (NDAs),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 applyto drug substances and drug products covered in Type II drug master files(DMFs). If a different approach is chosen, the applicant is encouraged todiscuss the matter in advance with the center with product jurisdiction toprevent the expenditure of resources on preparing a submission that may laterbe determined to be unacceptable.
这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 methodsvalidation described in this guidance apply to all types of analyticalprocedures. However, the specific recommendations in this guidance may not beapplicable to certain unique analytical procedures for products such asbiological, 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, manybioassays are based on animal challenge models, 39 immunogenicity assessments,or other immunoassays that have unique features that should be considered whensubmitting 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。
Furthermore, specific recommendationsfor biological and immunochemical tests that may be necessary forcharacterization and quality control of many drug substances and drug productsare 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内。
Although this guidancedoes not specifically address the submission of analytical procedures andvalidation data for raw materials, intermediates, excipients, container closurecomponents, and other materials used in the production of drug substances anddrug products, validated analytical procedures should be used to analyze thesematerials.
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 onappropriate validation approaches for analytical procedures or submission ofinformation not addressed in this guidance, applicants should consult with theappropriate 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, whenfinalized, will replace the FDA guidance for industry on Submitting Samples andAnalytical 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分析资料。
II. BACKGROUND背景
Each NDA and ANDA mustinclude the analytical procedures necessary to ensure the identity, strength,quality, purity, and potency of the drug substance and drug product, includingbioavailability of the drug product (21 CFR 314.50(d)(1) and 314.94(a)(9)(i)).
每个NDA和ANDA都必需包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))。
Data must be available toestablish that the analytical procedures used in testing meet proper standardsof 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度和可靠性标准的。
Methods validation is theprocess of demonstrating that analytical procedures are suitable for theirintended use. The methods validation process for analytical procedures beginswith the planned and systematic collection by the applicant of the validationdata 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 chemistevaluates the analytical procedures and validation data submitted in the NDA orANDA.
审评化学家会对NDA或ANDA中的分析方法和验证资料进行评审。
On request from FDA, anNDA or ANDA applicant must submit samples of drug product, drug substance,noncompendial reference standards, and blanks so that the applicant's drugsubstance and drug product analytical procedures can be evaluated by FDAlaboratories (21 CFR 314.50(e) and 314.94(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) and314.94(a)(10))。
The FDA laboratoryanalysis demonstrates that the analytical procedures are reproducible bylaboratory testing. The review chemists and laboratory analysts determine thesuitability 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 inspectthe analytical laboratory testing sites to ensure that the analyticalprocedures used for release and stability testing comply with current goodmanufacturing 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 mustinclude a full description of the manufacturing methods, including analyticalprocedures, that demonstrate that the manufactured product meets prescribedstandards 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 toestablish that the analytical procedures used in testing meet proper standardsof accuracy and reliability (21 CFR 81 211.194(a)(2)). For BLAs, PLAs, andtheir supplements, the analytical procedures and their validation are submittedas part of the license application or supplement and are evaluated by thereview committee.
必须要有资料证明所用的分析方法是符合一定的准确度和可靠性要求的(21CFR 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。
Representative samples ofthe product must be submitted and summaries of results of tests performed onthe 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 testingby CBER laboratory analysts to evaluate the applicant=s analytical proceduresand verify the test results.
需提供代表性样品及该样品所代表批号的检测结果总结(21 CFR601.2(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 proceduresare of equal importance from a validation perspective. In general, validatedanalytical procedures should be used, irrespective of whether they are forin-process, release, acceptance, or stability testing. Each quantitativeanalytical 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 andvalidation data are submitted in the sections of the application on analyticalprocedures and controls. Recommendations on information to be submitted areincluded in sections III through IX and XI of this guidance. Information onsubmission of the methods validation package to the NDA or ANDA and samples tothe FDA laboratories is provided in section X.
分析方法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 分析方法的类型
A. Regulatory Analytical Procedure 法定分析方法
A regulatory analyticalprocedure is the analytical procedure used to evaluate a defined characteristicof the drug substance or drug product. The analytical procedures in the U.S.Pharmacopeia/National Formulary (USP/NF) are those legally recognized undersection 501(b) of the Food, Drug, and Cosmetic Act (the Act) as the regulatoryanalytical procedures for compendial items. For purposes of determiningcompliance with the Act, the regulatory analytical procedure is used.
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 替代分析方法
An alternative analyticalprocedure is an analytical procedure proposed by the applicant for use insteadof the regulatory analytical procedure. A validated alternative analyticalprocedure should be submitted only if it is shown to perform equal to or betterthan the regulatory analytical procedure.
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 alternativeanalytical procedure is submitted, the applicant should provide a rationale forits inclusion and identify its use (e.g., release, stability testing),validation data, and comparative data to the regulatory analytical 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 Assay 稳定性指示分析
A stability-indicatingassay is a validated quantitative analytical procedure that can detect thechanges with time in the pertinent properties of the drug substance and drugproduct.
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-indicatingassay accurately measures the active ingredients, without interference fromdegradation products, process impurities, excipients, or other potentialimpurities。
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 submits anon-stability-indicating analytical procedure for release testing, then ananalytical procedure capable of qualitatively and quantitatively monitoring theimpurities, including degradation products, should complement it. Assayanalytical procedures for stability studies should be stability-indicating,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。
