美国FDA指南-中文版

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美国FDA生产过程(工艺)验证总则指南中英文版

GUIDELINEON GENERAL PRINCIPLES OFPROCESS VALIDATIONMay, 1987Prepared by: Center for Drugs and Biologics andCenter for Devices and Radiological HealthFood and Drug AdministrationMaintained by: Division of Manufacturing and Product Quality (HFN-320)Office of ComplianceCenter for Drugs and BiologicsFood and Drug Administration5600 Fishers LaneRockville, Maryland 20857General Principles of Process Validation May 1987GENERAL PRINCIPLES OF PROCESS VALIDATIONI. PURPOSEThis guideline outlines general principles that FDA considers to beacceptable elements of process validation for the preparation ofhuman and animal drug products and medical devices.II. SCOPEThis guideline is issued under Section 10.90 (21 CFR 10.90) and isapplicable to the manufacture of pharmaceuticals and medicaldevices. It states principles and practices of generalapplicability that are not legal requirements but are acceptable tothe FDA. A person may rely upon this guideline with the assurance of its acceptability to FDA, or may follow different procedures.When different procedures are used, a person may, but is notrequired to, discuss the matter in advance with FDA to prevent theexpenditure of money and effort on activities that may later bedetermined to be unacceptable. In short, this guideline listsprinciples and practices which are acceptable to the FDA for theprocess validation of drug products and medical devices; it doesnot list the principles and practices that must, in all instances,be used to comply with law.-1-This guideline may be amended from time to time. Interestedpersons are invited to submit comments on this document and anysubsequent revisions. Written comments should be submitted to the Dockets Management Branch (HFA-305), Food and Drug Administration,Room 4-62, 5600 Fishers Lane, Rockville, Maryland 20857. Receivedcomments may be seen in that office between 9\a.m. and 4\p.m.,Monday through Friday.III. INTRODUCTIONProcess validation is a requirement of the Current GoodManufacturing Practices Regulations for Finished Pharmaceuticals,21 CFR Parts 210 and 211, and of the Good Manufacturing PracticeRegulations for Medical Devices, 21 CFR Part 820, and therefore, isapplicable to the manufacture of pharamaceuticals and medicaldevices.Several firms have asked FDA for specific guidance on what FDAexpects firms to do to assure compliance with the requirements forprocess validation. This guideline discusses process validationelements and concepts that are considered by FDA as acceptableparts of a validation program. The constituents of validationpresented in this document are not intended to be all-inclusive.FDA recognizes that, because of the great variety of medicalproducts (drug products and medical devices), processes and-2-manufacturing facilities, it is not possible to state in onedocument all of the specific validation elements that areapplicable. Several broad concepts, however, have generalapplicability which manufacturers can use successfully as a guidein validating a manufacturing process. Although the particular requirements of process validation will vary according to such factors as the nature of the medical product (e.g., sterile vsnon-sterile) and the complexity of the process, the broad concepts stated in this document have general applicability and provide an acceptable framework for building a comprehensive approach to process validation.DefinitionsInstallation qualification - Establishing confidence that process equipment and ancillary systems are capable of consistently operating within established limits and tolerances.Process performance qualification - Establishing confidence thatthe process is effective and reproducible.Product performance qualification - Establishing confidence through appropriate testing that the finished product produced by aspecified process meets all release requirements for functionalityand safety.-3-Prospective validation - Validation conducted prior to thedistribution of either a new product, or product made under arevised manufacturing process, where the revisions may affect the product's characteristics.Retrospective validation - Validation of a process for a product already in distribution based upon accumulated production, testing and control data.Validation - Establishing documented evidence which provides a high degree of assurance that a specific process will consistentlyproduce a product meeting its pre-determined specifications and quality attributes.Validation protocol - A written plan stating how validation will be conducted, including test parameters, product characteristics, production equipment, and decision points on what constitutes acceptable test results.Worst case - A set of conditions encompassing upper and lowerprocessing limits and circumstances, including those withinstandard operating procedures, which pose the greatest chance ofprocess or product failure when compared to ideal conditions. Such conditions do not necessarily induce product or process failure.-4-IV. GENERAL CONCEPTSAssurance of product quality is derived from careful attention to anumber of factors including selection of quality parts andmaterials, adequate product and process design, control of theprocess, and in-process and end-product testing. Due to thecomplexity of today's medical products, routine end-product testingalone often is not sufficient to assure product quality for severalreasons. Some end-product tests have limited sensitivity.1 Insome cases, destructive testing would be required to show that themanufacturing process was adequate, and in other situationsend-product testing does not reveal all variations that may occurin the product that may impact on safety and effectiveness.2The basic principles of quality assurance have as their goal theproduction of articles that are fit for their intended use. These1 For example, USP XXI states: "No sampling plan for applyingsterility tests to a specified proportion of discrete unitsselected from a sterilization load is capable of demonstrating withcomplete assurance that all of the untested units are in factsterile."2 As an example, in one instance a visual inspection failed to detecta defective structural weld which resulted in the failure of aninfant warmer. The defect could only have been detected by usingdestructive testing or expensive test equipment.-5-principles may be stated as follows: (1) quality, safety, and effectiveness must be designed and built into the product; (2) quality cannot be inspected or tested into the finished product;and (3) each step of the manufacturing process must be controlled to maximize the probability that the finished product meets all quality and design specifications. Process validation is a key element in assuring that these quality assurance goals are met.It is through careful design and validation of both the process and process controls that a manufacturer can establish a high degree of confidence that all manufactured units from successive lots will be acceptable. Successfully validating a process may reduce the dependence upon intensive in-process and finished product testing. It should be noted that in most all cases, end-product testingplays a major role in assuring that quality assurance goals are met; i.e., validation and end-product testing are not mutually exclusive.The FDA defines process validation as follows:Process validation is establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determinedspecifications and quality characteristics.-6-It is important that the manufacturer prepare a written validation protocol which specifies the procedures (and tests) to be conducted and the data to be collected. The purpose for which data are collected must be clear, the data must reflect facts and becollected carefully and accurately. The protocol should specify a sufficient number of replicate process runs to demonstrate reproducibility and provide an accurate measure of variability among successive runs. The test conditions for these runs should encompass upper and lower processing limits and circumstances, including those within standard operating procedures, which pose the greatest chance of process or product failure compared to ideal conditions; such conditions have become widely known as "worst case" conditions. (They are sometimes called "most appropriate challenge" conditions.) Validation documentation should include evidence of the suitability of materials and the performance and reliability of equipment and systems.Key process variables should be monitored and documented. Analysisof the data collected from monitoring will establish thevariability of process parameters for individual runs and willestablish whether or not the equipment and process controls areadequate to assure that product specifications are met.-7-Finished product and in-process test data can be of value inprocess validation, particularly in those situations where qualityattributes and variabilities can be readily measured. Wherefinished (or in-process) testing cannot adequately measure certainattributes, process validation should be derived primarily fromqualification of each system used in production and fromconsideration of the interaction of the various systems.V. CGMP REGULATIONS FOR FINISHED PHARMACEUTICALS Process validation is required, in both general and specific terms,by the Current Good Manufacturing Practice Regulations for FinishedPharmaceuticals, 21 CFR Parts 210 and 211. Examples of suchrequirements are listed below for informational purposes, and arenot all-inclusive.A requirement for process validation is set forth in general termsin section\211.100 -- Written procedures; deviations -- whichstates, in part:"There shall be written procedures for production and processcontrol designed to assure that the drug products have theidentity, strength, quality, and purity they purport or arerepresented to possess."-8-Several sections of the CGMP regulations state validationrequirements in more specific terms. Excerpts from some ofthese sections are:Section 211.110, Sampling and testing of in-processmaterials and drug products.(a) "....control procedures shall be established to monitor theoutput and VALIDATE the performance of those manufacturingprocesses that may be responsible for causing variability in thecharacteristics of in-process material and the drug product."(emphasis added)Section 211.113, Control of Microbiological Contamination.(b) "Appropriate written procedures, designed to preventmicrobiological contamination of drug products purporting to besterile, shall be established and followed. Such proceduresshall include VALIDATION of any sterilization process."(emphasis added)VI. GMP REGULATION FOR MEDICAL DEVICESProcess validation is required by the medical device GMPRegulations, 21 CFR Part\820. Section 820.5 requires everyfinished device manufacturer to:"...prepare and implement a quality assurance program that isappropriate to the specific device manufactured..."-9-Section 820.3(n) defines quality assurance as:"...all activities necessary to verify confidence in the qualityof the process used to manufacture a finished device."When applicable to a specific process, process validation is anessential element in establishing confidence that a process willconsistently produce a product meeting the designed qualitycharacteristics.A generally stated requirement for process validation is containedin section\820.100:"Written manufacturing specifications and processing proceduresshall be established, implemented, and controlled to assure thatthe device conforms to its original design or any approvedchanges in that design."Validation is an essential element in the establishment andimplementation of a process procedure, as well as in determiningwhat process controls are required in order to assure conformanceto specifications.Section 820.100(a)(1) states:"...control measures shall be established to assure that thedesign basis for the device, components and packaging iscorrectly translated into approved specifications."-10-Validation is an essential control for assuring that thespecifications for the device and manufacturing process areadequate to produce a device that will conform to the approveddesign characteristics.VII. PRELIMINARY CONSIDERATIONSA manufacturer should evaluate all factors that affect productquality when designing and undertaking a process validation study.These factors may vary considerably among different products andmanufacturing technologies and could include, for example,component specifications, air and water handling systems,environmental controls, equipment functions, and process controloperations. No single approach to process validation will beappropriate and complete in all cases; however, the followingquality activities should be undertaken in most situations.During the research and development (R&D) phase, the desiredproduct should be carefully defined in terms of itscharacteristics, such as physical, chemical, electrical and-11-performance characteristics.3 It is important to translate theproduct characteristics into specifications as a basis fordescription and control of the product.Documentation of changes made during development providetraceability which can later be used to pinpoint solutions tofuture problems.The product's end use should be a determining factor in thedevelopment of product (and component) characteristics andspecifications. All pertinent aspects of the product which impacton safety and effectiveness should be considered. These aspects3 For example, in the case of a compressed tablet, physicalcharacteristics would include size, weight, hardness, and freedomfrom defects, such as capping and splitting. Chemicalcharacteristics would include quantitative formulation/potency;performance characteristics may include bioavailability (reflectedby disintegration and dissolution). In the case of blood tubing,physical attributes would include internal and external diameters,length and color. Chemical characteristics would include rawmaterial formulation. Mechanical properties would include hardness and tensile strength; performance characteristics would includebiocompatibility and durability.-12-include performance, reliability and stability. Acceptable rangesor limits should be established for each characteristic to set upallowable variations.4 These ranges should be expressed inreadily measurable terms.The validity of acceptance specifications should be verifiedthrough testing and challenge of the product on a sound scientificbasis during the initial development and production phase.Once a specification is demonstrated as acceptable it is importantthat any changes to the specification be made in accordance withdocumented change control procedures.VIII. ELEMENTS OF PROCESS VALIDATIONA. Prospective ValidationProspective validation includes those considerations that should bemade before an entirely new product is introduced by a firm or whenthere is a change in the manufacturing process which may affect theproduct's characteristics, such as uniformity and identity. Thefollowing are considered as key elements of prospective validation.4 For example, in order to assure that an oral, ophthalmic, orparenteral solution has an acceptable pH, a specification may beestablished by which a lot is released only if it has been shown tohave a pH within a narrow established range. For a device, aspecification for the electrical resistance of a pacemaker leadwould be established so that the lead would be acceptable only ifthe resistance was within a specified range.-13-1. Equipment and ProcessThe equipment and process(es) should be designed and/or selectedso that product specifications are consistently achieved. Thisshould be done with the participation of all appropriate groupsthat are concerned with assuring a quality product, e.g.,engineering design, production operations, and quality assurancepersonnel.a. Equipment: Installation QualificationInstallation qualification studies establish confidence thatthe process equipment and ancillary systems are capable ofconsistently operating within established limits andtolerances. After process equipment is designed orselected, it should be evaluated and tested to verify thatit is capable of operating satisfactorily within theoperating limits required by the process.5 This phase ofvalidation includes examination of equipment design;determination of calibration, maintenance, and adjustmentrequirements; and identifying critical equipment featuresthat could affect the process and product. Informationobtained from these studies should be used to establishwritten procedures covering equipment calibration,maintenance, monitoring, and control.5 Examples of equipment performance characteristics which maybe measured include temperature and pressure of injectionmolding machines, uniformity of speed for mixers,temperature, speed and pressure for packaging machines, andtemperature and pressure of sterilization chambers.-14-In assessing the suitability of a given piece of equipment,it is usually insufficient to rely solely upon therepresentations of the equipment supplier, or uponexperience in producing some other product.6 Soundtheoretical and practical engineering principles andconsiderations are a first step in the assessment.It is important that equipment qualification simulate actualproduction conditions, including those which are "worstcase" situations.6 The importance of assessing equipment suitability based uponhow it will be used to attain desired product attributes isillustrated in the case of deionizers used to producePurified Water, USP. In one case, a firm used such water tomake a topical drug product solution which, in view of itsintended use, should have been free from objectionablemicroorganisms. However, the product was found to becontaminated with a pathogenic microorganism. The apparentcause of the problem was failure to assess the performanceof the deionizer from a microbiological standpoint. It isfairly well recognized that the deionizers are prone tobuild-up of microorganisms--especially if the flow rates arelow and the deionizers are not recharged and sanitized atsuitable intervals. Therefore, these factors should havebeen considered. In this case, however, the firm reliedupon the representations of the equipment itself, namely the"recharge" (i.e., conductivity) indicator, to signal thetime for regeneration and cleaning. Considering the desiredproduct characteristics, the firm should have determined theneed for such procedures based upon pre-use testing, takinginto account such factors as the length of time theequipment could produce deionized water of acceptablequality, flow rate, temperature, raw water quality,frequency of use, and surface area of deionizing resins.-15-Tests and challenges should be repeated a sufficient numberof times to assure reliable and meaningful results. Allacceptance criteria must be met during the test orchallenge. If any test or challenge shows that theequipment does not perform within its specifications, anevaluation should be performed to identify the cause of thefailure. Corrections should be made and additional testruns performed, as needed, to verify that the equipmentperforms within specifications. The observed variability ofthe equipment between and within runs can be used as a basisfor determining the total number of trials selected for thesubsequent performance qualification studies of theprocess.7Once the equipment configuration and performancecharacteristics are established and qualified, they shouldbe documented. The installation qualification shouldinclude a review of pertinent maintenance procedures, repairparts lists, and calibration methods for each piece ofequipment. The objective is to assure that all repairs canbe performed in such a way that will not affect the7 For example, the AAMI Guideline for Industrial EthyleneOxide Sterilization of Medical Devices approved 2 December 1981, states: "The performance qualification should includea minimum of 3 successful, planned qualification runs, inwhich all of the acceptance criteria are met.....(5.3.1.2.).-16-characteristics of material processed after the repair. Inaddition, special post-repair cleaning and calibrationrequirements should be developed to prevent inadvertentmanufacture a of non-conforming product. Planning during the qualification phase can prevent confusion duringemergency repairs which could lead to use of the wrongreplacement part.b. Process: Performance QualificationThe purpose of performance qualification is to providerigorous testing to demonstrate the effectiveness andreproducibility of the process. In entering the performance qualification phase of validation, it is understood that theprocess specifications have been established and essentially proven acceptable through laboratory or other trial methods and that the equipment has been judged acceptable on thebasis of suitable installation studies.Each process should be defined and described with sufficient specificity so that employees understand what is required.-17-Parts of the process which may vary so as to affectimportant product quality should be challenged.8In challenging a process to assess its adequacy, it isimportant that challenge conditions simulate those that willbe encountered during actual production, including "worstcase" conditions. The challenges should be repeated enoughtimes to assure that the results are meaningful andconsistent.8 For example, in electroplating the metal case of animplantable pacemaker, the significant process steps todefine, describe, and challenge include establishment andcontrol of current density and temperature values forassuring adequate composition of electrolyte and forassuring cleanliness of the metal to be plated. In theproduction of parenteral solutions by aseptic filling, thesignificant aseptic filling process steps to define andchallenge should include the sterilization anddepyrogenation of containers/closures, sterilization ofsolutions, filling equipment and product contact surfaces,and the filling and closing of containers.-18-Each specific manufacturing process should be appropriatelyqualified and validated. There is an inherent danger inrelying on what are perceived to be similarities betweenproducts, processes, and equipment without appropriatechallenge.9c. Product: Performance QualificationFor purposes of this guideline, product performancequalification activities apply only to medical devices.These steps should be viewed as pre-production qualityassurance activities.9 For example, in the production of a compressed tablet, afirm may switch from one type of granulation blender toanother with the erroneous assumption that both types have similar performance characteristics, and, therefore,granulation mixing times and procedures need not bealtered. However, if the blenders are substantiallydifferent, use of the new blender with procedures used forthe previous blender may result in a granulation with poorcontent uniformity. This, in turn, may lead to tabletshaving significantly differing potencies. This situationmay be averted if the quality assurance system detects theequipment change in the first place, challenges the blender performance, precipitates a revalidation of the process, and initiates appropriate changes. In this example,revalidation comprises installation qualification of the newequipment and performance qualification of the processintended for use in the new blender.-19-Before reaching the conclusion that a process has beensuccessfully validated, it is necessary to demonstrate thatthe specified process has not adversely affected thefinished product. Where possible, product performancequalification testing should include performance testingunder conditions that simulate actual use. Productperformance qualification testing should be conducted usingproduct manufactured from the same type of productionequipment, methods and procedures that will be used forroutine production. Otherwise, the qualified product maynot be representative of production units and cannot be usedas evidence that the manufacturing process will produce aproduct that meets the pre-determined specifications andquality attributes.1010 For example, a manufacturer of heart valves receivedcomplaints that the valve-support structure was fracturingunder use. Investigation by the manufacturer revealed thatall material and dimensional specifications had been met butthe production machining process created microscopicscratches on the valve supporting wireform. These scratchescaused metal fatigue and subsequent fracture. Comprehensivefatigue testing of production units under simulated useconditions could have detected the process deficiency.In another example, a manufacturer recalled insulin syringesbecause of complaints that the needles were clogged.Investigation revealed that the needles were clogged bysilicone oil which was employed as a lubricant duringmanufacturing. Investigation further revealed that themethod used to extract the silicone oil was only partiallyeffective. Although visual inspection of the syringesseemed to support that the cleaning method was effective,actual use proved otherwise.-20-After actual production units have sucessfully passed product performance qualification, a formal technical review should be conducted and should include:o Comparison of the approved product specifications and the actual qualified product.o Determination of the validity of test methods used to determine compliance with the approved specifications.o Determination of the adequacy of the specification change control program.2. System to Assure Timely RevalidationThere should be a quality assurance system in place which requires revalidation whenever there are changes in packaging, formulation, equipment, or processes which could impact on product effectiveness or product characteristics, and whenever there are changes in product characteristics. Furthermore, when a change is made in raw material supplier, the manufacturer should consider subtle, potentially adverse differences in theraw material characteristics. A determination of adverse differences in raw material indicates a need to revalidate the process.-21-One way of detecting the kind of changes that should initiate revalidation is the use of tests and methods of analysis whichare capable of measuring characteristics which may vary. Such tests and methods usually yield specific results which go beyond the mere pass/fail basis, thereby detecting variations within product and process specifications and allowing determination of whether a process is slipping out of control.The quality assurance procedures should establish the circumstances under which revalidation is required. These may be based upon equipment, process, and product performance observed during the initial validation challenge studies. It is desirable to designate individuals who have the responsibilityto review product, process, equipment and personnel changes to determine if and when revalidation is warranted.。

FDA现场检查行业指南(中英文对照)

FDA行业指南-药品现场检查中被认为是延迟、否认、限制或拒绝的情形一、介绍2012年7月9日，《美国食品和药物管理局安全及创新法案》（FDASIA）被签署成为法律。

FDASIA章节707添加了501（j）到《食品、药品和化妆品法令》（FD&C Act），认为“任何从事生产、加工、包装或持有的生产企业、库房造成现场检查的延迟、否认、限制或拒绝的情况均被认为该产品为假劣药品”。

该指南的目的是对“延迟、否认、限制或拒绝”的情形进行定义。

二、定义1、延迟A、检查计划安排的延迟FDA将会根据当地的情况对检查计划进行适当的调整，例如天气、安保、节假日、其他非工作日、企业的生产计划等。

以下延迟的情况将会被认为产品是假劣药品，包括但不仅限于：●企业不同意建议的检查日期，但没有合理的解释。

●在检查安排后，企业要求延迟检查日期，但没有合理的解释。

●企业不能回答为什么FDA联系不上企业指定的联系人。

下面给出了将不会被认为是假劣药品的潜在合理解释的一个例子，但不仅限于：●企业没有正在生产，例如每个月只生产一次，企业要求检查日期另定，以便FDA检查时生产正在进行中。

B、检查期间的延迟以下检查期间的延迟情况将会被认为产品是假劣药品，包括但不仅限于：●企业不允许FDA检查官进入某个区域直至一段时间过去之后，即使这个区域是正在进行操作的并且是FDA有权检查的区域，对于这种行为没有合理的解释。

●企业长时间把FDA检查官单独撂在会议室，没有相应的文件或责任人供审查和询问，从而干扰检查官完成其相应的检查。

下面给出了将不会被认为是假劣药品的潜在合理解释的一个例子，但不仅限于：●企业不允许FDA检查官进入无菌工艺区域，直至检查官能满足企业的无菌更衣程序要求。

C、记录提供延迟以下记录提供延迟的情况将会被认为产品是假劣药品，包括但不仅限于：●在检查期间，FDA检查官要求在合理的时间内提供其有权查看的文件和记录，但是企业不能按时提供，且没有合理的解释。

美国FDA分析方法验证指南中文译稿[1]

1II. 背景 (2)III. 分析方法的类型 (3)A. 法定分析方法 (3)B. 可选择分析方法 (3)3 C. 稳定性指示分析 (3)IV. 对照品……………………………………………………………………………4A. 对照品的类型 (4)B. 分析报告单 (4)C. 对照品的界定 (4)V. IND 中的分析方法验证 (6)VI. NDA, ANDA, BLA 和PLA 中分析方法验证的内容和格式 (6)A. 原则 (6)B. 取样 (7)C. 仪器和仪器参数 (7)D. 试剂 (7)E. 系统适应性实验 (7)F. 对照品的制备 (7)G. 样品的制备 (8)H. 分析方法 (8)L. 计算 (8)J. 结果报告 (8)VII. NDA，ANDA,BLA 和PLA 中的分析方法验证 (9)A．非法定分析方法 (9)1．验证项目 (9)2. 其它分析方法验证信息 (10)a. 耐用性 (11)b. 强降解实验 (11)c. 仪器输出/原始资料 (11)3．各类检测的建议验证项目 (13)B．法定分析方法 (15)VIII. 统计分析…………………………………………………………………………15A. 总则 (15)C. 统计 (16)IX. 再验证 (16)X. 分析方法验证技术包：内容和过程……………………………………………17A. 分析方法验证技术包 (17)B. 样品的选择和运输 (18)C. 各方责任 (19)XI. 方法………………………………………………………………………………20A. 高效液相色谱(HPLC) (20)B. 气相色谱(GC) (22)C. 分光光度法，光谱学，光谱法和相关的物理方法 (23)D. 毛细管电泳 (23)E. 旋光度 (24)F. 粒径相关的分析方法 (25)G. 溶出度 (26)H. 其它仪器分析方法 (27)附件A：NDA，ANDA，BLA 和PLA 申请的内容 (28)附件B：分析方法验证的问题和延误 (29)参考文献……………………………………………………………………………………30术语表………………………………………………………………………………………32This 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。

FDA指南中文版

目录表I. 导言 (1)II. 背景 (2)III. 分析方法的类型 (3)A. 法定分析方法 (3)B. 可选择分析方法 (3)3 C. 稳定性指示分析 (3)IV. 对照品 (4)A. 对照品的类型 (4)B. 分析报告单 (4)C. 对照品的界定 (4)V. IND中的分析方法验证 (6)VI. NDA, ANDA, BLA 和PLA中分析方法验证的内容和格式 (6)A. 原则 (6)B. 取样 (7)C. 仪器和仪器参数 (7)D. 试剂 (7)E. 系统适应性实验 (7)F. 对照品的制备 (7)G. 样品的制备 (8)H. 分析方法 (8)L. 计算 (8)J. 结果报告 (8)VII. NDA，ANDA,BLA和PLA中的分析方法验证 (9)A．非法定分析方法 (9)1．验证项目 (9)2. 其它分析方法验证信息 (10)a. 耐用性 (11)b. 强降解实验 (11)c. 仪器输出/原始资料 (11)3．各类检测的建议验证项目 (13)B．法定分析方法 (15)VIII. 统计分析 (15)A. 总则 (15)B. 比较研究 (16)C. 统计 (16)IX. 再验证 (16)X. 分析方法验证技术包：内容和过程 (17)A. 分析方法验证技术包 (17)B. 样品的选择和运输 (18)C. 各方责任 (19)XI. 方法 (20)A. 高效液相色谱(HPLC) (20)B. 气相色谱(GC) (22)C. 分光光度法，光谱学，光谱法和相关的物理方法 (23)D. 毛细管电泳 (23)E. 旋光度 (24)F. 粒径相关的分析方法 (25)G. 溶出度 (26)H. 其它仪器分析方法 (27)附件 A：NDA，ANDA，BLA和PLA申请的内容 (28)附件 B：分析方法验证的问题和延误 (29)参考文献 (30)术语表 (32)I. INTRODUCTIONThis guidance provides recommendations to applicants on submitting analyticalprocedures, 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。

美国FDA指南-中文版

《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。

美国FDA分析方法验证指南中文译稿

美国FDA分析方法验证指南中文译稿引言：分析方法的验证在确定该方法是否适合特定用途以及是否能够产生准确和可靠结果方面起着关键作用。

准确和可靠的分析结果对于药品和食品行业是至关重要的。

本指南旨在提供制药和食品行业关于分析方法验证的指导，以满足FDA的法规要求。

验证目标：分析方法的验证需要进行一系列的实验以确定其精确性、精密度、特异性、线性范围和灵敏度等参数。

验证的目标是确保分析方法能够产生准确、可重复和可靠的结果，以支持产品的质量控制和合规性。

验证过程：验证过程可以分为三个主要阶段：方法开发、验证实验和验证报告。

方法开发阶段包括确定分析参数、选择仪器和试剂、制定实验方案等。

验证实验阶段涵盖了一系列实验，如准确度实验、精确度实验、特异性实验等。

验证报告阶段需要详细记录所有实验结果，以便后续复查和审查。

实验设计：验证实验需要进行大量的实验设计，以覆盖所有可能的情况和变化。

例如，准确度实验应包括加标回收率实验和Spiked样品测试等。

精确度实验应包括系统反应的重复性和运行时间的稳定性等。

数据分析：验证实验收集到的数据需要进行统计分析，以确定分析方法的可信度。

数据分析应包括数学计算、图表绘制和合规性评估等。

分析结果应该足够准确和可靠，以支持产品的质量控制和合规性。

验证报告：验证报告是验证过程的最终产物，它需要详细记录实验设计、数据分析和结论等信息。

验证报告应包括验证实验的目的、方法、结果和结论等内容。

验证报告需要通过内部审查和外部审查，确保其准确性和可靠性。

结论：美国FDA的《分析方法验证指南》为制药和食品行业提供了详细的指导，以确保分析方法的有效性和可靠性。

通过正确进行方法的验证，可以保证分析结果的准确性，从而支持产品的质量控制和合规性。

制药和食品企业应密切遵循该指南，以便符合FDA的法规要求。

FDA 行业指南中英对照待完成

FDA 行业指南中英对照待完成Guidance for IndustryContainer Closure Systems for Packaging Human Drugs and BiologicsChemistry, Manufacturing and Controls Documentation行业指南人用药品及生物制品的包装容器和封装系统：化学，生产和控制文件指南发布者：美国FDA下属的CDER及CBER 发布日期：May 1999TABLE OF CONTENTS目录I. II.INTRODUCTION 介绍 BACKGROUND 背景 A. B. C.III.Definitions 定义CGMP, CPSC and USP Requirements on Containers and Closures. CGMP, CPSC和USP对容器和密封的要求Additional Considerations 其他需要考虑的事项QUALIFICATION AND QUALITY CONTROL OF PACKAGING COMPONENTS 包装组件的合格要求以及质量控制 A. B. C. D. E. F. G. H.IV. V.Introduction 介绍General Considerations 通常要求Information That Should Be Submitted in Support of an Original Application for Any Drug Product 为支持任何药品的原始申请所必须提供的信息 Inhalation Drug Products 吸入性药品Drug Products for Injection and Ophthalmic Drug Products 注射剂和眼科用药Liquid-Based Oral and Topical Drug Products and Topical Delivery Systems 液体口服和外用药品和外用给药系统Solid Oral Dosage Forms and Powders for Reconstitution 口服固体剂型和待重新溶解的粉末Other Dosage Forms 其他剂型POSTAPPROVAL PACKAGING CHANGES 批准后的包装变更 TYPE III DRUG MASTER FILES 药品主文件第III类 A. B.VI.A. B.General Comments 总体评述Information in a Type III DMF 第III类DMF中包括的信息 Containers for Bulk Drug Substances 用于原料药的容器 Containers for Bulk Drug Products 用于散装药品的容器BULK CONTAINERS 大包装容器ATTACHMENT A 附件AREGULATORY REQUIREMENTS 药政要求ATTACHMENT B 附件BCOMPLIANCE POLICY GUIDES THAT CONCERN PACKAGING 关于包装，所适用的政策指南ATTACHMENT C 附件CEXTRACTION STUDIES “提取性”研究 ATTACHMENT D 附件DABBREVIATIONS 缩略语ATTACHMENT E 附件EREFERENCES 参考文献GUIDANCE FOR INDUSTRY1Container Closure Systems for Packaging Human Drugs and BiologicsChemistry, Manufacturing and Controls DocumentationThis guidance document represents the Agency's current thinking on container closure systems for the packaging of human drugs and biological products. It does not create or confer any rights for or on any person anddoes not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statute, regulations, or both.本指南代表了FDA目前对于人用药品和生物制品包装的容器/封装系统方面的看法。

《美国FDA化妆品良好操作规范（FDA-CGMP）》中文版

美国食品和药品管理局Cosmetic Good Manufacturing Practice Guidelines化妆品良好生产规范指南联邦食品、药品和化妆品法案（The Federal Food, Drug and Cosmetic Act, 以下简称FD&C 法案）禁止在州际直接贸易的化妆品是掺杂的或贴假标签的情况。

(Sec. 301)以下4种情况下，化妆品被认为是可能掺杂的：1．在用户使用过程中，由于化妆品本身含有或在包装容器中有潜在的、对人体有害的成分而使用户受到伤害的；2．本身含有不洁成分的；3．本身含有禁用成分，例如：未认可的色素添加剂；4．在不卫生条件下生产的、或保留的，可导致产品伤害用户有害或被不洁成分所污染。

以下几种情况下，化妆品被认为可能会认为贴假标签(Sec. 602)：1.虚假的标签或存在误导信息的标签2.显著违反了联邦食品、药品和化妆品法案的要求在标签上声明的信息要求3.在容器上有误导的信息为了确定化妆品生产厂家是否保留或发货了掺杂的、或是贴假标签的化妆品，和防止这些违反了FD&C 法案生产的化妆品流入市场，法律给了FDA进入这些化妆品工厂检查的权利，包括检查相关工厂的设备，成品，原料，容器和标签。

（见Sec. 704(a) of the FD&C Act.）如果工厂严格的根据良好的操作规范（GMP）的要求生产，将最低限度的减少掺杂的，或贴假标签的情况。

随后的化妆品指导，引用于FDA检查操作手册（FDA's Inspection Operations Manual），可以作为指南，用来有效的进行自我检查除。

良好的检查得分则意味着工厂执行了良好的操作规范（GMP）的要求。

指南1．建筑物和设施：检查是否a.用于生产或存放化妆品的建筑物应大小合适，设计和结构应保证设备进出不受阻碍，材料存放整洁，操作卫生以及正确的清洁和维护；b.地面，墙壁和天花板结构表面应光滑，易于清洁，并保持干净和良好状况；c.安装的固定装置，管道的滴水或者冷凝水不会污染化妆品原料，器具，以及与化妆品原料，散装产品或成品接触的设备的表面；d.照明和排风系统应满足预期员工操作和舒适的要求；e.供水，清洗和卫生设施，地面排水和废水系统应充分满足清洁操作的要求，和设备、器具的清洁要求，以及满足员工的需要并易于让员工保持个人清洁2．设备：检查是否a.加工、盛放、中转和灌装过程使用的设备和器具应设计合理，使用的材料和工艺能防止腐蚀、污垢的堆积、以及被润滑油、灰尘或者消毒剂污染；b.器具，运送管道以及和化妆品接触的设备表面应维护良好，并定期清洁和消毒；c.清洁和消毒后的便携式设备和器具应妥善放置，与化妆品接触的设备表面应罩住，以防止飞溅，灰尘或其他污染物3．员工: 检查是否a.监督化妆品的生产或者控制的员工应具有一定的教育背景，培训和/或经验来执行指定的监督工作；b.为防止化妆品掺杂，与化妆品原料，散装成品或化妆品接触表面直接接触的员工，应穿戴适合的工作服，手套，头套等，并保持良好的个人清洁；c.吃东西，喝水，或者抽烟都应严格限制在制定的区域。

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因此，客户务必依照规定提供尽可能详细的内容。

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 normally not needed to describe domestic facilities, except in special cases, such as when a person is not registered and not routinely inspected.3、场地的描述应包括面积、实际地址以及表明该场地与最近的城市的距离的地图。

提供该场地的鸟瞰图和平面图。

The description of the site should include acreage, actual site address, and a map showing its location with respect to the nearest city. An aerial photograph and a diagram of the site may be helpful.4、主要生产和加工区域的平面图对于理解整个生产布局会有帮助。

应当描述主要设备的生产能力、用途和位置。

通常不用描述设备的制造商和型号，除非特别新或独特的设备。

A diagram of major production and processing areas is helpful for understanding the operational layout. Major equipment should be described in terms of capabilities, application, and location. Make and model would not normally be needed unless the equipment is new or unique.5、公司主要的组成部门结构图，包括总公司和生产场地的关键生产、质量控制、质量保证岗位，A diagram of major corporate organizational elements, with key manufacturing, quality control, and quality assurance positions highlighted, at both the manufacturing site and corporate headquarters, is also helpful.二、原料药的物理和化学特征1、特性Properties相关法规要求对原料药的物理和化学特征做出详细描述。

该要求可以通过提供下述信息来满足：名称（通用名、化学名、编码等）、化学摘要服务(CAS)编码、性状描述（如：外观、颜色、物理状态）、分子式和分子重量、结构式（包括离子状态）、立体化学（找出手性中心、顺式反式异性等）、对映结构体比率（如：外消旋物、规定的异构体、对映异构物和固态形式的混合物）、溶解度概况（水溶性的或非水溶性的）、分配系数、溶液pH值、解离常数、熔点或沸点、折射率、比重。

对于蛋白质原料药，参见：“CRC生物化学和分子生物学手册”“酶学方法”和有关描述蛋白质特性的专论。

The regulations require a full description of the physical and chemical characteristics of the drug substance. This requirement may be satisfied by the submission of information such as the following: name (generic name, chemical name, code number); Chemical Abstracts Service (CAS) number if available; description (e.g., appearance, color, physical state); molecular formula and molecular weight; structural formula (including ionic state if applicable); stereochemistry (identifying chiral centers, cis-trans isomerism, etc.); enantiomer or solid-state form ratios (e.g., for racemates, and for defined admixtures of isomers or enantiomers or solid-state forms); solubility profile (aqueous and nonaqueous as applicable); partition coefficients; solution pH; dissociation constant(s); melting or boiling point; refractive index; specific gravity. For drug substances that are proteins, see the "CRC Handbook of Biochemistry and Molecular Biology," "Methods in Enzymology," and related monographs for how protein properties may be described.并非所有的递交都要求上述信息，额外的信息也可能需要，特别是随着生产工艺的复杂性的增加。

The items above are not necessary or appropriate for all submissions. Additional information may be required, particularly as the state of the art progresses.2、结构Structure对于结构的说明（如：相关数据和其解释）应当基于一个合适的物理和化学检测结果。

这包括以下内容：元素分析；质谱分析(MS)；核磁共振(NMR)；紫外(UV)和红外(IR)光谱学；分子量测定；立体化学和构象分析（如：光学和几何学异构体）；X光分析；降解分析（如：氨基酸排序和分析）；色析图谱；其它检验（如：功能团分析，衍生作用，络合形式等）The elucidation of structure (e.g., the data and its interpretation) should be based on appropriate physical and chemical test results. These may include the following: elemental analysis; mass spectrometry (MS); nuclear magnetic resonance (NMR), ultraviolet (UV), and infrared (IR) spectroscopy; molecularweight determination; stereochemistry and configurational or conformational analysis (e.g., optical and geometric isomers); X-ray analysis; degradative analysis (e.g., amino acid sequencing and/or analysis); chromatographic profile; other tests (e.g., functional group analysis, derivatization, complex formation).同样，并非所有以上条目都是必须的或适用于所有情况，所列条目也不是完全的（工艺过程更加复杂和新原料药需要时，也许需要做出更多的分析）。

实际数据及其解释的细节应当放在“参考标准”章节（参见II.F.2, 和 3）。

Again, not all items are necessary or appropriate in all cases, and the listing should not be considered limiting (i.e., more analysis may be required as the state of the art progresses and the nature of the new drug substance demands). The actual data and the details of its interpretation should be placed in the section for Reference Standard (see II.F.2, and 3.).三、原料药的稳定性相关法规要求对原料药的稳定性做全面的描述。

美国FDA指南-中文版

美国FDA生产过程(工艺)验证总则指南中英文版

FDA现场检查行业指南(中英文对照)

美国FDA分析方法验证指南中文译稿[1]

FDA指南中文版

美国FDA指南-中文版

美国FDA分析方法验证指南中文译稿

FDA 行业指南 中英对照 待完成

《美国FDA化妆品良好操作规范（FDA-CGMP）》中文版

FDA 行业指南中英对照待完成