美国FDA药物分析程序及方法验证指导原则(中文版)

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８９７・体或具有相似生理功能。

１．４可能的ＰＫ相互作用药动学相互作用的产生可能有多种方式，有些可以在体内进行监测而有些则不能。

一个药物可能改变另一个药物的吸收、排泄、组织分布，或改变代谢类型或速率。

药物也可能竞争性结合血浆蛋白，引起某个药物的游离型浓度升高和组织分布增加。

１．５毒理学的相互作用若单药的毒性靶器官相似，复方制剂中单药的无毒剂量会降低或单药对毒性靶器官的毒性会增强。

ＦＤＡ建议关注单药的全部毒理学信息［如一般毒性、生殖毒性、致癌性和安全药理学（心血管、中枢神经系统和呼吸系统）］。

１．６单药的安全范围如果某一单药的安全范围较窄，在临床治疗的暴露水平存在严重毒性，应特别关注单药间的相互作用，尤其当毒性是不可逆或在临床无法进行监测时。

１．７可能竞争或改变同一酶或其他细胞内分子内源物质的水平或活性，如２个氧化剂同时给药可能导致内源性谷胱甘肽的耗竭。

１．８可能的化学相互作用一个药物可能化学修饰另一个药物（如一个药物可能氧化、甲基化、乙酰化另一个药物），这可能会产生新化合物（可能产生新的毒性）。

１．９一个药物可能影响另一个治疗急症药物的有效性。

２非临床研究建议某些情况下，复方制剂中单药及联合用药均有足够的临床用药信息，此时再要求进行非临床研究可能是不必要的。

例如，治疗人类免疫缺陷病毒（ＨＩＶ）的药物研究指导原则中指出，以前已被批准用于治疗ＨＩＶ病人的药物用于复方制剂时可不要求进行体外的实验研究，因为联合用药的有效性和安全性已经在临床得到评价，或在药品说明书中介绍过，或已有研究文献报道。

２个或２个以上药物联合用药时，若复方制剂具有足够的临床用药信息，对此类复方制剂进行申报，建议注册申请人与审评相关部门讨论是否需要进行其他的非临床安全性评价。

41Journal of China Prescription Drug 2009.3 No.84——美国FDA CDER新药质量审评部简介Meheb Nasr 博士 汤玉冰 博士ONDQA持续不断的致力于寻求多种方式以进一步推动科学与风险综合评估举措进入审评规范，改进审评效率，应用最先进的科学手段应对突发事件，以及鼓励药厂运用质量源于设计的原理进行药品质量管理。

除非处方药典药（O T C monograph drugs）及临床试验药（Investigational New Drugs，IND）以外，在美国上市的所有新药都必须遵守美国相关新药申请（New Drug Application）法规，事先接受美国食品药品管理局（US Food and Drug Administration，FDA）的审理并取得其批准。

FDA 下属的化学类药物评价与研究中心（Center for Drug Evaluation and Research，CDER）是其属下的五个中心之一。

此中心的职责为审评并批准申请在美上市的化学类药品及某些生物类药品的安全性、有效性及质量可控性。

新药申请材料中相当一部分涉及药品的药物化学、药品生产以及生产和质量监控（Chemistry，Manufacture and Control，CMC）。

而这部分的审评则为CDER 下属的新药质量评审部（Office of New Drug Quality Assessment，ONDQA）的主要职责，生物药品的这部分则属于生物科技产品部的职责。

需要补充说明的是国际会议协调组织（International Conference Harmonization，I C H ）将C M C 部分统称为质量CMC 审评：科学加风险的综合评估专家简介Moheb Nasr博士为本文英文作者，现为美国FDA药物评审与研究中心（CDER）新药质量评审办公室主任。

负责审查药品的化学、生产与控制(CMC)的属性。

FDA对原料药的检查流程一、概述“FDA”是美国食品药物管理局（Food and Drug Administration)的英文缩写，它是国际医疗审核权威机构,由美国国会即联邦政府授权,专门从事食品与药品管理的最高执法机关。

FDA 是一个由医生、律师、微生物学家、药理学家、化学家和统计学家等专业人事组成的致力于保护、促进和提高国民健康的政府卫生管制的监控机构。

就原料药而言，FDA检查目的是为了保证从国外进口的原料药的质量充分符合USP的要求，美国政府规定外国的药物生产商向美国出口药物产品，除了要对该产品的样品进行质量检查之外,还要对药物制造企业的相关设施进行检查才能做出批准与否的决定，FDA现场检查由此而生。

FDA检查主要分为三类：一是批准前的现场检查(Pre-approval Inspection)，即我们通常说的“FDA检查"，对新药和仿制药品的生产采取的检查行动;二是定期检查(Biennial）,对批准后的药品进行定期的合规性检查,通常两年进行一次；三是基于投诉、召回或不良反应FDA临时决定进行专门的检查或监督。

FDA检查的依据起源于是美国国会1938年颁发的联邦食品、药品和化妆品法案（常缩写为FFDCA，FDCA，或FD＆C），该法案赋予美国食品药品监督管理局（FDA）监督监管食品安全、药品、及化妆品的权力。

关于药品方面，主要是受“食品、药物及化妆品法案”第501款（a）(2)(b）的管制，即所有药物的制造、加工和包装，均要严格符合cGMP的要求。

GMP制度在联邦法规(code 0f Federal Regulations）中的第210和第211条款中有具体规定。

不过，自发布以来的GMP主要是为制剂药而制定的。

在它的前言中说明：虽然它不是用于原料药，但有许多实例说明对原料药的GMP要求是与第211条款中所制定的要求很近似.因此，FDA就采用第2ll条款作为规范来对原料药厂进行检查。

药品及生物制品的分析方法和方法验证指导原则目录1.介绍...................... (1)2.背景..................... .. (2)3.分析方法开发. ..................... . (3)4.分析程序内容.............................................. ......... ..................................... .. 3A.原则/范围 (4)B.仪器/设备............................................. . (4)C.操作参数.............................................. .. (4)D.试剂/标准............................................. . (4)E.样品制备.............................................. .. (4)F.标准对照品溶液的制备............................................ .. (5)G.步骤......... ....................................... (5)H.系统适应性..... (5)I.计算 (5)J.数据报告 (5)5.参考标准和教材............................................ (6)6分析方法验证用于新药，仿制药，生物制品和DMF (6)A.非药典分析方法............................................. (6)B.验证特征 (7)C.药典分析方法............................................. .. (8)7.统计分析和模型 (8)A.统计 (8)B.模型 (8)8.生命周期管理分析程序 (9)A.重新验证 (9)B.分析方法的可比性研究............................................ . (10)1.另一种分析方法............................................... .. (10)2.分析方法转移的研究 (11)C.报告上市后变更已批准的新药，仿制药，或生物制品 (11)9.美国FDA方法验证............................................... . (12)10.参考文献前言本指导原则草案，定稿后，将代表美国食品和药物管理局（FDA）目前关于这个话题目前的想法。

Guidance for IndustryImmediate Release Solid Oral Dosage FormsScale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence DocumentationSUPAC-IR指导原则：速释口服固体制剂放大生产和批准后变更：化学、生产和控制，体外溶出试验、体内生物等效性文件Center for Drug Evaluation and Research (CDER)November 1995CMC 5药品评价与研究中心1995年11月CMC 5TABLE OF CONTENTS目录I. PURPOSE OF GUIDANCE （本指导原则的目的）. . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . 1 II. DEFINITION OF TERMS（术语定义）. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 3 PONENTS AND COMPOSITION（辅料成分或组成的变更）. . . . . . . . . . . . . . . . . . . . . . . . .. 6 IV. SITE CHANGES（地点变更）. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 13 V. CHANGES IN BATCH SIZE (SCALE-UP/SCALE-DOWN)（批量大小（放大/缩小）的变更）. .. . . . 16 VI. MANUFACTURING（生产变更）. . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 VII. IN VITRO DISSOLUTION （体外溶出试验）. . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 VIII. IN VIVO BIOEQUIVALENCE STUDIES （体内生物等效性）. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 IX. REFERENCES（参考文献）. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 APPENDIX A: NARROW THERAPEUTIC RANGE DRUGS（附录A：治疗窗狭窄药物）. . . . . . . . . A-1GUIDANCE FOR INDUSTRY 1IMMEDIATE RELEASE SOLID ORAL DOSAGE FORMS SCALE-UP AND POSTAPPROVAL CHANGES: CHEMISTRY, MANUFACTURING, AND CONTROLS, IN VITRO DISSOLUTION TESTING, AND IN VIVO BIOEQUIVALENCE DOCUMENTATION速释口服固体制剂放大生产和批准后变更：化学、生产和控制，体外溶出试验、体内生物等效性文件I. PURPOSE OF GUIDANCE（本指导原则的目的）This guidance provides recommendations to sponsors of new drug applications (NDA's), abbreviated new drug applications (ANDA's), and abbreviated antibiotic applications (AADA's) who intend, during the postapproval period, to change: 1) the components or composition; 2) the site of manufacture; 3) the scale-up/scale-down of manufacture; and/or 4) the manufacturing (process and equipment) of an immediate release oral formulation.本指导原则所提供的的建议适用于新药申请（NDA's）、仿制药申请（ANDA's）和抗生素仿制药申请（AANA’S）的企业的批准后变更，内容包括：1）成分或组分的变更；2）生产地点的变更；3）放大/缩小生产规模的变更；和/或4）生产过程（工艺和设备）的变更This guidance is the result of: 1) a workshop on the scale-up of immediate release drug products conducted by the American Association of Pharmaceutical Scientists in conjunction with the United States Pharmacopoeial Convention and the Food and Drug Administration (FDA); 2) research conducted by the University of Maryland at Baltimore on the chemistry, manufacturing and controls of immediate release drug products under the FDA/University of Maryland Manufacturing Research Contract; 3) the drug categorization research conducted at the University of Michigan and the University of Uppsala on the permeability of drug substances; and 4) the Scale-Up and Post Approval Changes (SUPAC) Task Force which was established by the Center for Drug Evaluation and Research (CDER) Chemistry, Manufacturing and Controls Coordinating Committee to develop guidance on scale-up and other postapproval changes.本指导原则是以下工作的成果：1）在美国药学科学家协会与美国药典委员会和FDA的指导下，进行速释药品放大生产的车间；2）在位于巴尔的摩的马里兰大学指导下，并在FDA/马里兰大学生产研究合同下的速释药品的化学、生产和控制的研究；3）在密歇根大学和乌普萨拉大学指导下的药品分类学研究中关于药物渗透性的研究；4）由药品评价和研究中心（CDER）化学、生产和控制协调委员会成立的放大生产和批准后变更（SUPAC）特别小组，来制定关于放大生产和其它的批准后变更的指导原则。

Analytical Procedures and Methods Validation for Drugsand BiologicsDRAFT GUIDANCEThis 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 electronic comments to . Submit written comments to the Division of Dockets Management (HFA-305), Food and 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 Registe r.For questions regarding this draft document contact (CDER) Lucinda Buhse 314-539-2134, or (CBER) Office of Communication, Outreach and Development at 800-835-4709 or 301-827-1800.U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Research (CBER)February 2014CMCAnalytical Procedures and Methods Validation for Drugsand BiologicsAdditional copies are available from:Office of CommunicationsDivision of Drug Information, WO51, Room 2201Center for Drug Evaluation and ResearchFood and Drug Administration10903 New Hampshire Ave., Silver Spring, MD 20993Phone: 301-796-3400; Fax: 301-847-8714druginfo@/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htmand/orOffice of Communication, Outreach andDevelopment, HFM-40Center for Biologics Evaluation and ResearchFood and Drug Administration1401 Rockville Pike, Rockville, MD 20852-1448ocod@/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm(Tel) 800-835-4709 or 301-827-1800U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Research (CBER)Febr uary 2014CMCTABLE OF CONTENTSI.INTRODUCTION (1)II.BACKGROUND (2)III.ANALYTICAL METHODS DEVELOPMENT (3)IV.CONTENT OF ANALYTICAL PROCEDURES (3)A.Principle/Scope (4)B.Apparatus/Equipment (4)C.Operating Parameters (4)D.Reagents/Standards (4)E.Sample Preparation (4)F.Standards Control Solution Preparation (5)G.Procedure (5)H.System Suitability (5)I.Calculations (5)J.Data Reporting (5)V.REFERENCE STANDARDS AND MATERIALS (6)VI.ANALYTICAL METHOD VALIDATION FOR NDA, ANDAs, BLAs, AND DMFs (6)A.Noncompendial Analytical Procedures (6)B.Validation Characteristics (7)pendial Analytical Procedures (8)VII.STATISTICAL ANALYSIS AND MODELS (8)A.Statistics (8)B.Models (8)VIII.LIFE CYCLE MANAGEMENT OF ANALYTICAL PROCEDURES (9)A.Revalidation (9)B.Analytical Method Comparability Studies (10)1.Alternative Analytical Procedures (10)2.Analytical Methods Transfer Studies (11)C.Reporting Postmarketing Changes to an Approved NDA, ANDA, or BLA (11)IX.FDA METHODS VERIFICATION (12)X.REFERENCES (12)Guidance for Industry11Analytical Procedures and Methods Validation for Drugs and2Biologics345This draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA’s) current 6thinking on this topic. It does not create or confer any rights for or on any person and does not operate to 7bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of 8the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA9staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call 10the appropriate number listed on the title page of this guidance.11121314I. INTRODUCTION1516This revised draft guidance supersedes the 2000 draft guidance for industry on Analytical17Procedures and Methods Validation2,3 and, when finalized, will also replace the 1987 FDA18guidance for industry on Submitting Samples and Analytical Data for Methods Validation. It19provides recommendations on how you, the applicant, can submit analytical procedures4 and20methods validation data to support the documentation of the identity, strength, quality, purity,21and potency of drug substances and drug products.5It will help you assemble information and 22present data to support your analytical methodologies. The recommendations apply to drug23substances and drug products covered in new drug applications (NDAs), abbreviated new drug 24applications (ANDAs), biologics license applications (BLAs), and supplements to these25applications. The principles in this revised draft guidance also apply to drug substances and drug 26products covered in Type II drug master files (DMFs).2728This revised draft guidance complements the International Conference on Harmonisation (ICH) 29guidance Q2(R1)Validation of Analytical Procedures: Text and Methodology(Q2(R1)) for30developing and validating analytical methods.3132This revised draft guidance does not address investigational new drug application (IND) methods 33validation, but sponsors preparing INDs should consider the recommendations in this guidance.34For INDs, sufficient information is required at each phase of an investigation to ensure proper35identity, quality, purity, strength, and/or potency. The amount of information on analytical36procedures and methods validation will vary with the phase of the investigation.6 For general371 This guidance has been prepared by the Office of Pharmaceutical Science, in the Center for Drug Evaluation andResearch (CDER) and the Center for Biologics Evaluation and Research (CBER) at the Food and DrugAdministration.2 Sample submission is described in section IX, FDA Methods Verification.3 We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDADrugs guidance Web page at/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.4Analytical procedure is interchangeable with a method or test procedure.5The terms drug substance and drug product, as used in this guidance, refer to human drugs and biologics.6 See 21 CFR 312.23(a)(7).guidance on analytical procedures and methods validation information to be submitted for phase 38one studies, sponsors should refer to the FDA guidance for industry on Content and Format of39Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including40Well-Characterized, Therapeutic, Biotechnology-Derived Products. General considerations for 41analytical procedures and method validation (e.g., bioassay) before conduct of phase three42studies are discussed in the FDA guidance for industry on IND Meetings for Human Drugs and 43Biologics, Chemistry, Manufacturing, and Controls Information.4445This revised draft guidance does not address specific method validation recommendations for46biological and immunochemical assays for characterization and quality control of many drug47substances and drug products. For example, some bioassays are based on animal challenge48models, and immunogenicity assessments or other immunoassays have unique features that49should be considered during development and validation.5051In addition, the need for revalidation of existing analytical methods may need to be considered 52when the manufacturing process changes during the product’s life cycle. For questions on53appropriate validation approaches for analytical procedures or submission of information not54addressed in this guidance, you should consult with the appropriate FDA product quality review 55staff.5657If you choose a different approach than those recommended in this revised draft guidance, we58encourage you to discuss the matter with the appropriate FDA product quality review staff before 59you submit your application.6061FDA’s guidance documents, including this guidance, do not establish legally enforceable62responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should 63be viewed only as recommendations, unless specific regulatory or statutory requirements are64cited. The use of the word should in Agency guidances means that something is suggested or65recommended, but not required.666768II.BACKGROUND6970Each NDA and ANDA must include the analytical procedures necessary to ensure the identity, 71strength, quality, purity, and potency of the drug substance and drug product.7 Each BLA must 72include a full description of the manufacturing methods, including analytical procedures that73demonstrate the manufactured product meets prescribed standards of identity, quality, safety,74purity, and potency.8 Data must be available to establish that the analytical procedures used in 75testing meet proper standards of accuracy and reliability and are suitable for their intended76purpose.9 For BLAs and their supplements, the analytical procedures and their validation are77submitted as part of license applications or supplements and are evaluated by FDA quality78review groups.79807 See 21 CFR 314.50(d)(1) and 314.94(a)(9)(i).8 See 21 CFR 601.2(a) and 601.2(c).9 See 21 CFR 211.165(e) and 211.194(a)(2).Analytical procedures and validation data should be submitted in the corresponding sections of 81the application in the ICH M2 eCTD: Electronic Common Technical Document Specification.108283When an analytical procedure is approved/licensed as part of the NDA, ANDA, or BLA, it84becomes the FDA approved analytical procedure for the approved product. This analytical85procedure may originate from FDA recognized sources (e.g., a compendial procedure from the 86United States Pharmacopeia/National Formulary (USP/NF)) or a validated procedure you87submitted that was determined to be acceptable by FDA. To apply an analytical method to a88different product, appropriate validation studies with the matrix of the new product should be89considered.909192III.ANALYTICAL METHODS DEVELOPMENT9394An analytical procedure is developed to test a defined characteristic of the drug substance or95drug product against established acceptance criteria for that characteristic. Early in the96development of a new analytical procedure, the choice of analytical instrumentation and97methodology should be selected based on the intended purpose and scope of the analytical98method. Parameters that may be evaluated during method development are specificity, linearity, 99limits of detection (LOD) and quantitation limits (LOQ), range, accuracy, and precision.100101During early stages of method development, the robustness of methods should be evaluated102because this characteristic can help you decide which method you will submit for approval.103Analytical procedures in the early stages of development are initially developed based on a104combination of mechanistic understanding of the basic methodology and prior experience.105Experimental data from early procedures can be used to guide further development. You should 106submit development data within the method validation section if they support the validation of 107the method.108109To fully understand the effect of changes in method parameters on an analytical procedure, you 110should adopt a systematic approach for method robustness study (e.g., a design of experiments 111with method parameters). You should begin with an initial risk assessment and follow with112multivariate experiments. Such approaches allow you to understand factorial parameter effects 113on method performance. Evaluation of a method’s performance may include analyses of114samples obtained from in-process manufacturing stages to the finished product. Knowledge115gained during these studies on the sources of method variation can help you assess the method 116performance.117118119IV.CONTENT OF ANALYTICAL PROCEDURES120121You should describe analytical procedures in sufficient detail to allow a competent analyst to 122reproduce the necessary conditions and obtain results within the proposed acceptance criteria. 123You should also describe aspects of the analytical procedures that require special attention. An 124analytical procedure may be referenced from FDA recognized sources (e.g., USP/NF,12510 See sections 3.2.S.4 Control of Drug Substance, 3.2.P.4 Control of Excipients, and 3.2.P.5 Control of DrugProduct.Association of Analytical Communities (AOAC) International)11 if the referenced analytical126procedure is not modified beyond what is allowed in the published method. You should provide 127in detail the procedures from other published sources. The following is a list of essential128information you should include for an analytical procedure:129130A.Principle/Scope131132A description of the basic principles of the analytical test/technology (separation, detection, etc.); 133target analyte(s) and sample(s) type (e.g., drug substance, drug product, impurities or compounds 134in biological fluids, etc.).135136B.Apparatus/Equipment137138All required qualified equipment and components (e.g., instrument type, detector, column type, 139dimensions, and alternative column, filter type, etc.).140141C.Operating Parameters142143Qualified optimal settings and ranges (allowed adjustments) critical to the analysis (e.g., flow144rate, components temperatures, run time, detector settings, gradient, head space sampler). A145drawing with experimental configuration and integration parameters may be used, as applicable. 146147D.Reagents/Standards148149The following should be listed:150151•Grade of chemical (e.g., USP/NF, American Chemical Society, High152Performance or Pressure Liquid Chromatography, or Gas153Chromatography and preservative free).154•Source (e.g., USP reference standard or qualified in-house reference material). 155•State (e.g., dried, undried, etc.) and concentration.156•Standard potencies (purity correction factors).157•Storage controls.158•Directions for safe use (as per current Safety Data Sheet).159•Validated or useable shelf life.160161New batches of biological reagents, such as monoclonal antibodies, polyclonal antisera, or cells, 162may need extensive qualification procedures included as part of the analytical procedure.163164E.Sample Preparation165166Procedures (e.g., extraction method, dilution or concentration, desalting procedures and mixing 167by sonication, shaking or sonication time, etc.) for the preparations for individual sample tests. 168A single preparation for qualitative and replicate preparations for quantitative tests with16911 See 21 CFR 211.194(a)(2).appropriate units of concentrations for working solutions (e.g., µg/ml or mg/ml) and information 170on stability of solutions and storage conditions.171172F.Standards Control Solution Preparation173174Procedures for the preparation and use of all standard and control solutions with appropriate175units of concentration and information on stability of standards and storage conditions,176including calibration standards, internal standards, system suitability standards, etc.177178G.Procedure179180A step-by-step description of the method (e.g., equilibration times, and scan/injection sequence 181with blanks, placeboes, samples, controls, sensitivity solution (for impurity method) and182standards to maintain validity of the system suitability during the span of analysis) and allowable 183operating ranges and adjustments if applicable.184185H.System Suitability186187Confirmatory test(s) procedures and parameters to ensure that the system (equipment,188electronics, and analytical operations and controls to be analyzed) will function correctly as an 189integrated system at the time of use. The system suitability acceptance criteria applied to190standards and controls, such as peak tailing, precision and resolution acceptance criteria, may be 191required as applicable. For system suitability of chromatographic systems, refer to CDER192reviewer guidance on Validation of Chromatographic Methods and USP General Chapter <621> 193Chromatography.194195I.Calculations196197The integration method and representative calculation formulas for data analysis (standards,198controls, samples) for tests based on label claim and specification (e.g., assay, specified and199unspecified impurities and relative response factors). This includes a description of any200mathematical transformations or formulas used in data analysis, along with a scientific201justification for any correction factors used.202203J.Data Reporting204205A presentation of numeric data that is consistent with instrumental capabilities and acceptance 206criteria. The method should indicate what format to use to report results (e.g., percentage label 207claim, weight/weight, and weight/volume etc.) with the specific number of significant figures 208needed. The American Society for Testing and Materials (ASTM) E29 describes a standard209practice for using significant digits in test data to determine conformance with specifications. For 210chromatographic methods, you should include retention times (RTs) for identification with211reference standard comparison basis, relative retention times (RRTs) (known and unknown212impurities) acceptable ranges and sample results reporting criteria.213214215V.REFERENCE STANDARDS AND MATERIALS216217Primary and secondary reference standards and materials are defined and discussed in the218following ICH guidances: Q6A Specifications: Test Procedures and Acceptance Criteria for 219New Drug Substances and New Drug Products: Chemical Substances (ICH Q6A), Q6B220Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological221Products, and Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical222Ingredients. For all standards, you should ensure the suitability for use. Reference standards for 223drug substances are particularly critical in validating specificity for an identity test. You should 224strictly follow storage, usage conditions, and handling instructions for reference standards to225avoid added impurities and inaccurate analysis. For biological products, you should include226information supporting any reference standards and materials that you intend to use in the BLA 227and in subsequent annual reports for subsequent reference standard qualifications. Information 228supporting reference standards and materials include qualification test protocols, reports, and 229certificates of analysis (including stability protocols and relevant known impurity profile230information, as applicable).231232Reference standards can often be obtained from USP and may also be available through the233European Pharmacopoeia, Japanese Pharmacopoeia, World Health Organization, or National 234Institute of Standards and Technology. Reference standards for a number of biological products 235are also available from CBER. For certain biological products marketed in the U.S., reference 236standards authorized by CBER must be used before the product can be released to the market.12 237Reference materials from other sources should be characterized by procedures including routine 238and beyond routine release testing as described in ICH Q6A. You should consider orthogonal 239methods. Additional testing could include attributes to determine the suitability of the reference 240material not necessarily captured by the drug substance or product release tests (e.g., more241extensive structural identity and orthogonal techniques for purity and impurities, biological242activity).243244For biological reference standards and materials, we recommend that you follow a two-tiered 245approach when qualifying new reference standards to help prevent drift in the quality attributes 246and provide a long-term link to clinical trial material. A two-tiered approach involves a247comparison of each new working reference standard with a primary reference standard so that it 248is linked to clinical trial material and the current manufacturing process.249250251VI.ANALYTICAL METHOD VALIDATION FOR NDA, ANDAs, BLAs, AND 252DMFs253254A.Noncompendial Analytical Procedures255256Analytical method validation is the process of demonstrating that an analytical procedure is257suitable for its intended purpose. The methodology and objective of the analytical procedures 258should be clearly defined and understood before initiating validation studies. This understanding 25912 See 21 CFR 610.20.is obtained from scientifically-based method development and optimization studies. Validation 260data must be generated under an protocol approved by the sponsor following current good261manufacturing practices with the description of methodology of each characteristic test and262predetermined and justified acceptance criteria, using qualified instrumentation operated under 263current good manufacturing practices conditions.13 Protocols for both drug substance and264product analytes or mixture of analytes in respective matrices should be developed and executed. 265266ICH Q2(R1) is considered the primary reference for recommendations and definitions on267validation characteristics for analytical procedures. The FDA Reviewer Guidance: Validation of 268Chromatographic Methods is available as well.269270B.Validation Characteristics271272Although not all of the validation characteristics are applicable for all types of tests, typical273validation characteristics are:274275•Specificity276•Linearity277•Accuracy278•Precision (repeatability, intermediate precision, and reproducibility)279•Range280•Quantitation limit281•Detection limit282283If a procedure is a validated quantitative analytical procedure that can detect changes in a quality 284attribute(s) of the drug substance and drug product during storage, it is considered a stability285indicating assay. To demonstrate specificity of a stability-indicating assay, a combination of286challenges should be performed. Some challenges include the use of samples spiked with target 287analytes and all known interferences; samples that have undergone various laboratory stress288conditions; and actual product samples (produced by the final manufacturing process) that are289either aged or have been stored under accelerated temperature and humidity conditions.290291As the holder of the NDA, ANDA, or BLA, you must:14 (1) submit the data used to establish292that the analytical procedures used in testing meet proper standards of accuracy and reliability, 293and (2) notify the FDA about each change in each condition established in an approved294application beyond the variations already provided for in the application, including changes to 295analytical procedures and other established controls.296297The submitted data should include the results from the robustness evaluation of the method,298which is typically conducted during method development or as part of a planned validation299study.1530013 See 21 CFR 211.165(e); 21 CFR 314.50 (d), and for biologics see 21 CFR 601.2(a), 601.2(c), and 601.12(a).14 For drugs see 21 CFR 314.50 (d), 314.70(d), and for biologics see 21 CFR 601.2(a), 601.2(c), and 601.12(a). For aBLA, as discussed below, you must obtain prior approval from FDA before implementing a change in analyticalmethods if those methods are specified in FDA regulations15 See section III and ICH Q2(R1).pendial Analytical Procedures302303The suitability of an analytical procedure (e.g., USP/NF, the AOAC International Book of304Methods, or other recognized standard references) should be verified under actual conditions of 305use.16 Compendial general chapters, which are complex and mention multiple steps and/or306address multiple techniques, should be rationalized for the intended use and verified. Information 307to demonstrate that USP/NF analytical procedures are suitable for the drug product or drug308substance should be included in the submission and generated under a verification protocol.309310The verification protocol should include, but is not limited to: (1) compendial methodology to 311be verified with predetermined acceptance criteria, and (2) details of the methodology (e.g.,312suitability of reagent(s), equipment, component(s), chromatographic conditions, column, detector 313type(s), sensitivity of detector signal response, system suitability, sample preparation and314stability). The procedure and extent of verification should dictate which validation characteristic 315tests should be included in the protocol (e.g., specificity, LOD, LOQ, precision, accuracy, etc.). 316Considerations that may influence what characteristic tests should be in the protocol may depend 317on situations such as whether specification limits are set tighter than compendial acceptance318criteria, or RT or RRT profiles are changing in chromatographic methods because of the319synthetic route of drug substance or differences in manufacturing process or matrix of drug320product. Robustness studies of compendial assays do not need to be included, if methods are 321followed without deviations.322323324VII.STATISTICAL ANALYSIS AND MODELS325326A.Statistics327328Statistical analysis of validation data can be used to evaluate validation characteristics against 329predetermined acceptance criteria. All statistical procedures and parameters used in the analysis 330of the data should be based on sound principles and appropriate for the intended evaluation.331Reportable statistics of linear regression analysis R (correlation coefficient), R square332(coefficient of determination), slope, least square, analysis of variance (ANOVA), confidence 333intervals, etc., should be provided with justification.For information on statistical techniques 334used in making comparisons, as well as other general information on the interpretation and335treatment of analytical data, appropriate literature or texts should be consulted.17336337B.Models338339Some analytical methods might use chemometric and/or multivariate models. When developing 340these models, you should include a statistically adequate number and range of samples for model 341development and comparable samples for model validation. Suitable software should be used for 342data analysis. Model parameters should be deliberately varied to test model robustness.34334416 See 21 CFR 211.194(a)(2) and USP General Chapter <1226> Verification of Compendial Procedures.17 See References section for examples including USP <1010> Analytical Data – Interpretation and Treatment.。

【审评规范】FDA发布的“改变剂型和改变给药途径药品非临床安全性评价指导原则”介绍萧惠来国家食品药品监督管理总局药品审评中心，北京 100038摘 要：美国食品药品管理局于2015年10月发布了“改变剂型和改变给药途径药品非临床安全性评价指导原则”，包括前言、背景、一般原则、对全身毒性的建议和对给药途径的建议5个部分，并且分别描述了15种不同给药途径的药品在改变剂型时应增加的非临床毒性研究内容。

我国目前尚无这类指导原则，了解该指导原则对我国完善相应法规和制定相应的指导原则及其对这类药物的审评有所启迪，也对改变剂型类药物的开发有所帮助，所以介绍该指导原则的主要内容。

关键词：美国食品药品管理局；改变剂型药品；改变给药途径药品；非临床安全性评价；指导原则中图分类号：R282.710.5 文献标志码：A 文章编号：1674-6376 (2016) 02-0171-04DOI: 10.7501/j.issn.1674-6376.2016.02.003Introduction of “Nonclinical Safety Evaluation of Reformulated Drug Products and Products Intended for Administration by an Alternate Route Guidance” issued by FDA recentlyXIAO Hui-laiCenter for Drug Evaluation, China Food and Drug Administration, Beijing 100038, ChinaAbstract: FDA issued “Nonclinical Safety Evaluation of Reformulated Drug Products and Products Intended for Administration by an Alternate Route Guidance” in October 2015, including introduction, background, general considerations, systemic toxicity consideration, route of administration considerations, and describing the additional nonclinical toxicity studies for reformulated drug products used in 15 different routes respectively. And there is no such guidance in our country at present. Because understanding the guidance for our country to improve the relevant regulations, to formulate corresponding guidance and to review these drug products are helpful, and for the development of these drug products also is helpful, therefore the main content is introduced.Key words: FDA; reformulated drug product; product with changed administration route; nonclinical safety evaluation; guidance美国食品药品管理局（FDA）于2015年10月发布了“改变剂型和改变给药途径药品非临床安全性评价指导原则”[1]。

药品检验结果超标调查工业指南草案本指南颁布的目的只是为了提供建议。

此指南的草案将在联邦注册通知上宣布生效，若有关于此草案的评论和提议，应在宣布生效后60天内提交。

提议应提交到……地址（5230 Fishers Lane., rm. 1061. Rockville, MD 20852）的FDA 诉讼事件管理部。

所有的评论均应与列于联邦注册发布的生效通知上的事件编号相一致。

此文件在HFD-210,5600 Fishers Lane. Rockville, MD 20857，（Tel）301-827-4573通信管理司的药物信息部和网址/cder/guidance/index.htm.上均有副本。

对草案内容如有疑问，请联系C. Russ Rutledge (301)594-2455美国健康与人服务部食品药品监督管理局药物评审中心1998年9月CP号目录表药品检验结果超标调查工业指南 (1)目录表 (2)1.前言 (3)2.背景 (3)3.检验结果鉴定与评估 (4)4.OOS 检验结果调查 (7)5.调查总结 (14)草案-不用于执行药品检验结果超标调查工业指南1.前言此工业指南提供评审部门目前在怎样评估可疑和超标检验结果上的看法，从此文档的目的出发，OOS 结果条款包含了所有的不符合新药申请、官方说明或者生产企业中制定的规范或可接收标准的可疑结果。

此指南适用于适应CGMP规范的原料药、赋形剂和其他成分生产期间的实验室检验和成品检验，特别是，指南论述了怎样调查可疑或OOS检验结果，包括实验室人员职责、调查的实验室阶段、必要的额外的检验，什么时候进行实验室外的扩展调查，和所有检验结果的最终评估。

2.背景FDA 关心在药品生产期间非常重要的实验室检验和文件记录的完整性。

CGMP法规必需的实验室检验对于确定成分、容器和密封件、进程物料和成品是否符合要求是非常重要的，包括稳定性试验在内。

检验也支持分析和工艺验证结果。

Guidance for Industry 行业指南Process Validation: General Principles and Practices工艺验证：一般原则与规范U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Research (CBER)Center for Veterinary Medicine (CVM)January 2011Current Good Manufacturing Practices (CGMP)Revision 1美国卫生与人类服务部食品药品管理局药物评价和研究中心（CDER）生物制品评价和研究中心（CBER）兽药中心（CVM）2011年1月现行药品质量生产管理规范（CGMP）修订版1包含不具约束力的建议中文译稿：北京大学药物信息与工程研究中心info@ Guidance for Industry 行业指南Process Validation: General Principles and Practices工艺验证：一般原则与规范Additional copies are available from:Office of CommunicationsDivision of Drug Information, WO51, Room 220110903 New Hampshire Ave.Silver Spring, MD 20993Phone: 301-796-3400; Fax: 301-847-8714druginfo@另外的副本可从以下部门得到：马里兰州银泉市新罕布什尔大道10193号2201室药品信息处，对外信息办公室，邮政编码：20993电话：301-796-3400; 传真：301-847-8714druginfo@Table of Contents目录I. INTRODUCTION (1)一. 简介 (1)II. BACKGROUND (3)二. 背景 (3)A. Process Validation and Drug Quality (4)A. 工艺验证与药品质量 (4)B. Approach to Process Validation (5)B. 工艺验证方法 (5)III. STATUTORY AND REGULATORY REQUIREMENTS FOR PROCESS VALIDATION (7)三. 对工艺验证的法规和监管要求 (7)IV. RECOMMENDATIONS (9)四. 建议 (9)A. General Considerations for Process Validation (9)A. 对工艺验证的总体考虑 (9)B. Stage 1 - Process Design (10)B. 第一阶段- 工艺设计 (10)1. Building and Capturing Process Knowledge and Understanding (11)1. 建立和捕获工艺知识与理解 (11)2. Establishing a Strategy for Process Control (12)2. 建立工艺控制策略 (12)C. Stage 2 - Process Qualification (14)C. 第二阶段- 工艺确认 (14)1. Design of a Facility and Qualification of Utilities and Equipment (14)1. 厂房设施设计以及公用设施与设备确认 (14)2. Process Performance Qualification (16)2. 工艺性能确认 (16)3. PPQ Protocol (17)3. 工艺性能确认方案 (17)4. PPQ Protocol Execution and Report (19)4. 工艺性能确认执行与报告 (19)D. Stage 3 - Continued Process Verification (20)D. 第三阶段- 持续工艺验证 (20)V. CONCURRENT RELEASE OF PPQ BATCHES (22)五. 工艺性能确认批次的同时放行 (22)VI. DOCUMENTATION (24)六. 文件记录 (24)VII. ANALYTICAL METHODOLOGY (24)七. 分析方法 (24)GLOSSARY (26)术语表 (26)REFERENCES (28)参考资料 (28)包含不具约束力的建议中文译稿：北京大学药物信息与工程研究中心info@1Guidance for Industry1行业指南1Process Validation: General Principles and Practices工艺验证：一般原则与实施This guidance represents the Food and Drug Administration’s (FDA’s) current thin king on this topic. It doesnot create or confer any rights for or on any person and does not operate to bind FDA or the public. You canuse an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate numberlisted on the title page of this guidance.本指南体现了食品药品管理局（FDA）关于这一主题的最新见解。

美国FDA分析方法验证指南中英文对照（二）上一篇/ 下一篇 2009-01-05 10:44:15 / 个人分类：GMP/GLP查看( 1076 ) / 评论( 2 ) / 评分( 0 / 0 ) III. TYPES OF ANALYTICAL PROCEDURESA. Regulatory A nalytical ProcedureA regulatory analy tical procedure is the analy tical procedure used to ev aluate a def ined characteristic of the drug substance or drug product. The analy tical 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 f or compendial items. For purpos es of determining compliance with 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. A lternative A nalytical ProcedureAn alternativ e analy tical procedure is an analytical procedure proposed by the applicant f or use instead of the regulatory analy tical procedure. A v alidated alternativ e analy tical procedure should be submitted only if it is shown to perf orm. equal to or better than the regulatory analy tical procedure.B. 替代分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。

I. INTRODUCTIONThis 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）， 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 covered in Type II drug master files （DMFs）。

FDA指导原则fda指导原则（中文）目录非专利药物晶型研究技术指南Pdf口服固体制剂溶出度试验技术指南Pdf口服缓释制剂体外和体内相关性研究技术指南Pdf改变制剂处方和变更药物给药途径的非临床安全性评价技术指导原则.pdf终端灭菌产品实施参数放行的相关申报资料要求.pdf制剂注册申请对所附原料药生产工艺资料的要求.pdf药用辅料的非临床安全性评价技术指导原则.pdf原料药、药用辅料和包装材料申请材料的内容和格式要求Pdf无菌制剂生产质量管理规范Pdf无菌工艺验证数据申请要求Pdf工艺验证的一般原则和方法Pdf药物临床安全性评价审评报告撰写指导原则.pdf药品审评质量管理规范.pdf生物利用度和生物等效性试验用生物样品的处理和保存要求Pdf群体药代动力学研究技术指南Pdf食物对生物利用度的影响以及餐后生物等效性研究技术指导原则.pdf临床试验中人种和种族数据收集的技术指导原则.pdf因临床研究者失职叫停临床试验的相关规定.pdf药物上市前风险评估的技术指导原则.pdf药物警戒管理规范和药物流行病学评估技术指南Pdf药物肝毒性评估技术指南Pdf药物代谢产物安全性试验技术指导原则.pdf现有治疗定义和新治疗评估的技术指南Pdf人体第一剂最大安全初始剂量的估计Pdf 新药临床试验样品制备的技术指南Pdf新药ⅱ期和ⅲ期临床试验药学申报资料的内容及格式要求.pdf新药ⅰ期临床试验申报资料的内容及格式要求.pdf临床研究进程中沟通交流会的药学资料准备要求.pdf临床试验中应用计算机系统的技术指导原则.pdf建立临床试验数据监测委员会和工作技术指南Pdf紧急临床研究豁免知情同意的相关规定Pdf风险最小化执行方案的制定和完善的技术指导原则.pdfⅱa期临床试验结束后沟通交流会的有关要求.pdfⅰ期临床试验用样品的生产质量管理规范.pdf获得药品临床研究有效性证据的技术指导原则.pdf上市药物和生物制品添加新抗肿瘤适应症的技术指南Pdf上市抗肿瘤药物新临床试验豁免申请的相关要求Pdf糖尿病药物研究和预防指南。

《美国FDA认证与申办指南》权威资讯系列《合成原料药DMF起草大纲》使用说明：1、本大纲是为了帮助我公司客户把握DMF的整体内容而准备的，由于DMF内容繁多，从整体上了解内容框架和组成部分，对于理解FDA对DMF的要求和意图非常有必要；2、根据FDA的要求，凡是本大纲提到的内容，原料药制造商均应该提供。

因此，客户务必依照规定提供尽可能详细的内容。

3、本大纲的内容和相关要求能够确保客户目前的运作达到FDA的cGMP标准，因此，准备DMF的过程，也使客户按照FDA的要求进行整改和提高的过程，这些都为FDA未来的现场检查打下良好基础；4、凡是本大纲中提到的非技术性具体内容要求，请参照本公司专有的与此大纲配套的相关DFM指导性文件，包括《FDA药物主文件指南》、《关于在药品递交中递交的有关原料药生产的支持文件的指南》、《药物申办中质量管理方面通用技术文件格式与内容要求》；5、凡是本大纲中提到的技术性具体内容要求，如杂质、稳定性、验证等具体技术要求，请参照本公司专有的FDA相关技术标准文件，包括《原料药认证指南》、《制剂认证指南》、《化学药物稳定性指南》、《化学药物杂质指南》、《化学药物化验与合格参数指南》、《化学药物验证指南》等；《合成原料药DMF起草大纲》一、公司和生产场地的基本描述1、第一类的DMF文件建议由位于美国之外的人提供，以帮助FDA对他们的生产设施进行现场检查。

DMF文件应描述生产场地、设备能力、生产流程图等。

A Type I DMF is recommended for a person outside of the United States to assist FDA in conducting on site inspections of their manufacturing facilities. The DMF should describe the manufacturing site, equipment capabilities, and operational layout.2、第一类的DMF文件对美国国内设施通常不需要，除非该设施没有登记并定期接受检查。

方法验证指导原则-《中国药典》2015年版第四部9101药品质量标准分析方法验证指导原则量。

③应注意固体制剂的晶型原料药含量应在标准曲线的线性范围内。

④应使用外标标准物质ai2o3对仪器及数据进行校正。

方法3差示扫描量热法（DSC)定置分析方法，获得供试品晶型含量数据。

采用DSC定量分析的晶型物质一般应具有不同的熔融吸热峰值，且晶型样品质量与吸热量呈正比关系。

(a)晶型原料药分析：精密称量不同质量晶型样品，建立质量与热量的热焓值的线性关系，绘制标准曲线，定量测定样品的晶型含量。

(b)混晶原料药分析：当不同晶型含量与热焓呈正比关系，采用精密称量配制不同晶型含量的混晶样品，建立晶型含量与热焓值的线性关系，绘制标准曲线，定量测定混晶样品中的晶型含量。

(c)方法说明：①仅适用于晶型原料药定量分析。

②对熔融吸热峰值相差大的混晶原料供试品，建立标准曲线时线性范围较宽；熔融吸热峰值相差小的混晶样品，建立标准曲线时线性范围较窄。

③有时DSC法仅能作为限量检测方法。

方法4红外光谱（IR)定量分析方法，获得供试品晶型含量数据。

采用IR法可以对晶型原料药或固体制剂进行定量分析，常用的方法为相对峰强度法。

晶型特征峰选取原则：①分别选取2种晶型特有的红外光谱吸收峰作为特征峰。

②2种晶型的特征峰应独立而不受对方干扰。

③特征峰强度应与晶型成分含量呈对应线性关系。

对压力可致晶型状态发生转变的晶型原料供试品，制样时应避免压片法。

(a)晶型原料药分析：采用相对峰强度法时分别选择2 种晶型成分的特征吸收峰位置匕与b2,在同一红外光谱图上读取2种晶型成分的特征吸收峰的吸光度值V1与42，计算二者特征吸收峰的吸光度比值r。

通过配制一系列不同晶型比例的混晶样品，建立特征吸收峰的吸光度比值的对数值与晶型含量间的线性关系，绘制标准曲线，实现对混晶样品的晶型含量进行定量分析。

(b)制剂中晶型原料药成分分析：采用相对峰强度法时分别选择晶型原料药特征吸收峰位置h与空白辅料的特征吸收峰位置b2，在同一红外光谱图上读取2种晶型成分的特征吸收峰的吸光度值八1与A2，计算二者特征吸收峰的吸光度比值~通过配制一系列含有不同质量晶型原料与空白辅料比例混合样品，建立特征吸收峰的吸光度比值的对数值与晶型原料药含量间的线性关系，绘制标准曲线，实现对固体制剂中晶型原料药含量进行定量分析。

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分析方法开发的四大要项[精华]大概在20年以前，美国化学学会出版的分析化学杂志刊登了一篇讨论分析方法开发的文章。

这个杂志一般都是学术界发表文章。

偶尔会刊登一些实用性的文章。

这篇文章我记得非常清楚。

讨论的就是分析方法开发的4S。

这4S就是Specificity（专属性），Sensitivity（灵敏度），Speed（速度）还有就是$（费用）。

其实任何分析方法开发，都需要考虑这4S。

当初那篇文章也不知跑到那里去了，我就把我这几年工作上的经验，一起与大家分享。

我相信很多大家一定都知道了。

看看我说的是不是有道理。

当然，还是希望大家加入讨论，分享大家的经验。

分析方法首先要注意的就是专属性。

所谓专属性就是我们分析某一个化合物，所得到的分析信号必须是完全来自於这一个化合物本身所产生的信号。

早年色谱不那么的盛行，我们就试图使用各种方法，取得这个化合物专属性的信号。

譬如光谱中的某一个波长只对这个化合物发生吸收。

我们也可以利用这个化合物氧化还原的特性而能够从电极上产生信号。

还有就是利用化合物本身在热化学产生吸热放热的信号。

慢慢的我们的色谱开展了。

因为色谱的开发，可以把要分析的化合物从一个混合物中分开，而取得这个化合物的专属性而进行定性定量。

目前在美国，色谱的应用已经排在天平，pH计成为第三位最常用的分析仪器了。

我相信主要的原因就是色谱很容易的就能够提供各个化合物的专属性。

简单的说，所谓取得专属性其实就是处理样品的基质(SampleMatrix)产生的效应。

如果把基质所造成的干扰除去，我们的分析物(Analyte)的专属性就自然出现了。

也就是说我们可以化合物的对照品来定量定性。

灵敏度就是借着调动仪器的组成(Components)使我们能够得到最大的信号。

或者借着化学反应使分析物能够产生柱前或柱后的衍生物，来增加灵敏度。

当然我们谈到信号就要考虑到基线，也就是Signal/Noise比例。

就拿色谱来说，如果灵敏度高，我们所进样的样品量就小。