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FDA检验方法验证指南中英文

美国FDA分析方法验证指南中英文对照Guide to the U.S. FDA method validation Chinese and English目录ContentsI. INTRODUCTION (3)II. BACKGROUND (4)III. TYPES OF ANALYTICAL PROCEDURES (6)IV. REFERENCE STANDARDS (7)V. METHODS VALIDATION FOR INDs (10)VI. CONTENT AND FORMAT OF ANALYTICAL PROCEDURES FOR NDAs, 230ANDAs, BLAs, AND PLAs (11)VII. METHODS VALIDATION FOR NDAs, ANDAs, BLAs, AND PLAs (15)VIII. STATISTICAL ANALYSIS (23)IX. REVALIDATION (24)X. METHODS VALIDATION PACKAGE: CONTENTS AND PROCESSING (25)XI. METHODOLOGY (30)ATTACHMENT ANDA, ANDA, BLA, AND PLA SUBMISSION CONTENTS (40)ATTACHMENT BMETHODS VALIDATION PROBLEMS AND DELAY (41)GLOSSARY (42)美国FDA分析方法验证指南中英文对照I. INTRODUCTIONThis guidance provides recommendations to applicants on submittinganalytical procedures, validation data, and samples to support thedocumentation of the identity, strength, quality, purity, and potencyof 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.。

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药物分析程序及方法验证指导原则(中文版)

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。

FDA最新工艺验证指南(XXXX1版)(中文版)

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@/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htmand/orOffice of Communication, Outreach and Development, HFM-40Center for Biologics Evaluation and ResearchFood and Drug Administration1401 Rockville Pike, Rockville, MD 20852-1448(Tel) 800-835-4709 or 301-827-1800/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm and/orCommunications Staff, HFV-12Center for Veterinary MedicineFood and Drug Administration7519 Standish Place,Rockville, MD 20855(Tel) 240-276-9300/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/default.htm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@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@/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm和/或马里兰州洛克维尔市洛克维尔大道1401号HFM-40 FDA生物制品评价和研究中心对外信息、外联与发展办公室邮政编码：20852-1448电话：800-835-4709 或301-827-1800/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm和/或马里兰州洛克维尔市Standish Place 7519号食品药品管理局兽药中心HFV-12通讯处，邮政编码：20885电话：240-276-9300/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/default.htmU.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估和研究中心（CDER）生物制品评估和研究中心（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@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 thinking on this topic. It does not 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 andregulations. If you want to discuss an alternative approach, contact the FDA staff responsible forimplementing 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--6

美国FDA分析⽅法验证指南中英⽂对照--6XI. METHODOLOGYSections II through IX provide general information on the submission of analytical procedures and methods validation information, including validation characteristics. Additional information on certain methodologies is provided below.XI．⽅法学II章到第IX章提供了分析⽅法和分析⽅法验证资料⽅⾯的基本信息，包括验证项⽬。

下⽂就⼀些具体的⽅法给出了说明：A. High-Pressure Liquid Chromatography (HPLC)The widespread use of HPLC analytical procedures and the multitude of commercial sources of columns and packings frequently have created problems in assessing comparability. Many of the following points may also apply to other chromatographic analytical procedures.⾊谱(HPLC)⾼效液相⾊谱A．⾼效液相HPLC分析⽅法的⼴泛应⽤及⾊谱柱和柱填充的众多来源都经常会给可⽐性评估带来很多问题。

如下这些要点中，很多都适⽤于其它⾊谱分析⽅法。

1. ColumnThe following characteristics are useful for defining a particular column and, if known, should be included in the analytical procedure description. If method development has indicated that columns from only one commercial source are suitable, this information should be included as part of the analytical procedure. If more than one column is suitable, a listing of columns found to be equivalent should be included.1.⾊谱柱在定义某⼀⾊谱柱时，如下这些性质是很有⽤的，也应当要包括在分析⽅法描述中。

FDA清洁验证审计指南

Validation of Cleaning Processes(7/93)SHARETWEETLINKEDINPIN ITMORE SHARING OPTIONSLINKEDINPIN ITEMAILPRINTGUIDE TO INSPECTIONS VALIDATION OF CLEANINGPROCESSESNote: This document is reference material for investigators and other FDApersonnel. The document does not bind FDA, and does no confer any rights, privileges, benefits, or immunities for or on any person(s).I. INTRODUCTIONValidation of cleaning procedures has generated considerable discussionsince agency documents, including the Inspection Guide for BulkPharmaceutical Chemicals and the Biotechnology Inspection Guide, havebriefly addressed this issue. These Agency documents clearly establish the expectation that cleaning procedures (processes) be validated.This guide is designed to establish inspection consistency and uniformity by discussing practices that have been found acceptable (or unacceptable).Simultaneously, one must recognize that for cleaning validation, as withvalidation of other processes, there may be more than one way to validate a process. In the end, the test of any validation process is whether scientificdata shows that the system consistently does as expected and produces a result that consistently meets predetermined specifications.This guide is intended to cover equipment cleaning for chemical residuesonly.II. BACKGROUNDFor FDA to require that equipment be clean prior to use is nothing new, the 1963 GMP Regulations (Part 133.4) stated as follows "Equipment *** shallbe maintained in a clean and orderly manner ***." A very similar section on equipment cleaning (211.67) was included in the 1978 CGMP regulations. Of course, the main rationale for requiring clean equipment is to preventcontamination or adulteration of drug products. Historically, FDAinvestigators have looked for gross insanitation due to inadequate cleaning and maintenance of equipme nt an d/or poor dust con trol systems. Also,historically speak ing, FDA was more concerned about the con tam in ati onof nonpenicillin drug products with penicillins or the cross-contamination ofdrug products with pote nt steroids or horm on es. A nu mber of productshave bee n recalled over the past decade due to actual or pote ntial peni cilli n cross-c on tam in ati on.One eve nt which in creased FDA aware ness of the pote ntial for cross con tam in ati on due to in adequate procedures was the 1988 recall of afinished drug product, Cholestyramine Resin USP. The bulk pharmaceutical chemical used to produce the product had become con tam in ated with low levels of in termediates and degrada nts from the producti on of agricultural pesticides. The cross-c on tam in ati on in that case is believed to have bee n due to the reuse of recovered solve nts. The recovered solve nts had bee n con tam in ated because of a lack of con trol over the reuse of solve ntdrums. Drums that had bee n used to store recovered solve nts from apesticide producti on process were later used to store recovered solve ntsused for the res in manu facturi ng process. The firm did not have adequate con trols over these solve nt drums, did not do adequate testi ng ofdrummed solve nts, and did not have validated clea ning procedures for the drums.Some shipme nts of this pesticide con tam in ated bulk pharmaceutical were supplied to a second facility at a different location for finishing. This resulted in the contamination of the bags used in that facility's fluid bed dryers withpesticide contamination. This in turn led to cross contamination of lotsproduced at that site, a site where no pesticides were no rmally produced.FDA instituted an import alert in 1992 on a foreign bulk pharmaceuticalmanu facturer which manu factured pote nt steroid products as well as non-steroidal products using com mon equipme nt. This firm was a multi-usebulk pharmaceutical facility. FDA con sidered the pote ntial for cross-contamination to be significant and to pose a serious health risk to thepublic. The firm had only recently started a cleaning validation program atthe time of the in spect ion and it was con sidered in adequate by FDA. One of the reas ons it was con sidered in adequate was that the firm was onlylook ing for evide nee of the abse nee of the previous compo und. The firm had evidenee, from TLC tests on the rinse water, of the presence ofresidues of react ion byproducts and degrada nts from the previous process. III. GENERAL REQUIREMENTSFDA expects firms to have writte n procedures (SOP's) detaili ng the cleaning processes used for various pieces of equipme nt. If firms have one clea ning process for clea ning betwee n differe nt batches of the same productand use a differe nt process for clea ning betwee n product cha nges, weexpect the written procedures to address these different scenario. Similarly, if firms have one process for rem oving water soluble residues and ano ther process for non-water soluble residues, the writte n procedure shouldaddress both sce narios and make it clear whe n a give n procedure is to be followed. Bulkpharmaceutical firms may decide to dedicate certa in equipme nt for certa in chemical manu facturi ng process steps that produce tarry or gummyresidues that are difficult to remove from the equipment. Fluid bed dryerbags are ano ther example of equipme nt that is difficult to clea n and is ofte n dedicated to a specific product. Any residues from the clea ning processitself (detergents, solvents, etc.) also have to be removed from the equipme nt.FDA expects firms to have writte n gen eral procedures on how clea ningprocesses will be validated.FDA expects the gen eral validati on procedures to address who is resp onsible for perform ing and appro ving the validati on study, the acceptancecriteria, and when revalidation will be required.FDA expects firms to prepare specific writte n validati on protocols in advance for the studies to be performed on each manu facturi ng system or piece of equipme nt which should address such issues as sampli ng procedures,and an alytical methods to be used in clud ing the sen sitivity of thosemethods. FDA expects firms to con duct the validati on studies in accordance with the protocols and to docume nt the results of studies.FDA expects a final validati on report which is approved by man ageme ntand which states whether or not the clea ning process is valid. The datashould support a con clusi on that residues have bee n reduced to an"acceptable level."IV.EVALUATION OF CLEANING VALIDATIONThe first step is to focus on the objective of the validation process, and wehave see n that some compa nies have failed to develop such objectives. It is not unu sual to see manu facturers use exte nsive sampli ng and testi ngprograms follow ing the clea ning process without ever really evaluati ng the effective ness of the steps used to clea n the equipme nt. Several questi ons n eed to be addressed whe n evaluat ing the clea ning process. Forexample, at what point does a piece of equipme nt or system become clean? Does it have to be scrubbed by hand? What is accomplished by handscrubb ing rather tha n just a solve nt wash? How variable are manual cleaning processes from batch to batch and product to product? The an swers to these questions are obviously important to the inspection and evaluation ofthe clea ning process since one must determ ine the overall effective ness of the process. An swers to these questi ons may also ide ntify steps that canbe elimi nated for more effective measures and result in resource sav ingsfor the compa ny.Determ ine the nu mber of clea ning processes for each piece of equipme nt.Ideally, a piece of equipment or system will have one process for cleaning,however this will depe nd on the products being produced and whether theclea nup occurs betwee n batches of the same product (as in a largecampaig n) or betwee n batches of differe nt products. Whe n the clea ningprocess is used only betwee n batches of the same product (or differe nt lotsof the same in termediate in a bulk process) the firm n eed only meet a criteria of, "visibly clea n" for the equipme nt. Such betwee n batch clea ning processes do not require validati on.1. Equipme nt Desig nExam ine the desig n of equipme nt, particularly in those large systems that may employ semi-automatic or fully automatic clean-in-place (CIP) systems since they represe nt sig nifica nt concern. For example, sanitary type pip ing without ball valves should be used. Whe n suchnonsan itary ball valves are used, as is com mon in the bulk drug industry, the clea ning process is more difficult.When such systems are ide ntified, it is importa nt that operatorsperform ing clea ning operatio ns be aware of problems and havespecial trai ning in clea ning these systems and valves. Determ inewhether the clea ning operators have kno wledge of these systems and the level of training and experie nee in clea ning these systems. Alsocheck the writte n and validated clea ning process to determ ine if these systems have been properly identified and validated.In larger systems, such as those employi ng long tran sfer lines or pipi ng, check the flow charts and pip ing diagrams for the ide ntificati on of valves and writte n clea ning procedures. Pip ing and valves should be tagged and easily identifiable by the operator performing the cleaningfunction. Sometimes, in adequately ide ntified valves, both on prints and physically, have led to in correct clea ning practices.Always check for the prese nee of an ofte n critical eleme nt in thedocume ntati on of the clea ning processes; ide ntify ing and con troll ing the len gth of time betwee n the end of process ing and each clea ning step. This is especially importa nt for topicals, suspe nsions, and bulkdrug operations. In such operations, the drying of residues will directly affect the efficie ncy of a clea ning process.Whether or not CIP systems are used for clea ning of process ingequipme nt, microbiological aspects of equipme nt clea ning should be con sidered. This con sists largely of preve ntive measures rather tha n removal of con tam in ati on once it has occurred. There should besome evide nee that rout ine clea ning and storage of equipme nt does not allow microbial proliferation. For example, equipment should bedried before storage, and un der no circumsta nces should stag nantwater be allowed to rema in in equipme nt subseque nt to clea ningoperati ons.Subseque nt to the clea ning process, equipme nt may be subjected to sterilizati on or san itizati on procedures where such equipme nt is used for sterile process ing, or for non sterile process ing where the products may support microbial growth. While such sterilizatio n or san itizati on procedures are bey ond the scope of this guide, it is importa nt to note that con trol of the bioburde n through adequate clea ning and storageof equipme nt is importa nt to en sure that subseque nt sterilizati on orsanitization procedures achieve the necessary assuranee of sterility.This is also particularly important from the standpoint of the control ofpyroge ns in sterile process ing since equipme nt sterilizati on processes may not be adequate to achieve sig nifica nt in activati on or removal of pyroge ns.2. Clea ning Process Writte nProcedure and Docume ntati onExam ine the detail and specificity of the procedure for the (clea ning)process being validated, and the amount of docume ntati on required.We have see n gen eral SOPs, while others use a batch record or logsheet system that requires some type of specific docume ntati on forperform ing each step. Depe nding upon the complexity of the systemand cleaning process and the ability and training of operators, theamount of docume ntati on n ecessary for executi ng various clea ningsteps or procedures will vary.When more complex clea ning procedures are required, it is importa nt to docume nt the critical clea ning steps (for example certa in bulk drug syn thesis processes). I n this regard, specific docume ntati on on theequipme nt itself which in cludes in formati on about who clea ned it and when is valuable. However, for relatively simple cleaning operations, the mere docume ntati on that the overall clea ning process was performed might be sufficie nt.Other factors such as history of clea nin g, residue levels found aftercleaning, and variability of test results may also dictate the amount ofdocume ntati on required. For example, whe n variable residue levelsare detected follow ing clea ning, particularly for a process that isbelieved to be acceptable, one must establish the effective ness of the process and operator performa nee. Appropriate evaluati ons must bemade and whe n operator performa nee is deemed a problem, moreexte nsive docume ntati on (guida nee) and training may be required. 3. Analytical MethodsDetermine the specificity and sensitivity of the analytical method used to detect residuals or con tam inan ts. With adva nces in an alytical tech no logy, residues from the manu facturi ng and clea ning processes can be detected at very low levels. If levels of contamination or residual are not detected, it does not mean that there is no residual con tam inant prese nt after clea nin g. It only means that levels of con tam inant greaterthan the sensitivity or detection limit of the analytical method are notpresent in the sample. The firm should challenge the analytical method in comb in ati on with the sampli ng method(s) used to show that contam inants can be recovered from the equipme nt surface and at whatlevel, i.e. 50% recovery, 90%, etc. This is n ecessary before any conclusi ons can be made based on the sample results. A n egative testmay also be the result of poor sampli ng tech nique (see below).4. Sampli ngThere are two gen eral types of sampli ng that have bee n foundacceptable. The most desirable is the direct method of sampling thesurface of the equipme nt. Ano ther method is the use of rinse soluti ons.a. Direct Surface Sampli ng - Determi ne the type of samplingmaterial used and its impact on the test data since the sampli ngmaterial may in terfere with the test. For example, the adhesiveused in swabs has been found to interfere with the analysis ofsamples. Therefore, early in the validation program, it is importantto assure that the sampli ng medium and solve nt (used for extraction from the medium) are satisfactory and can be readily used.Advantages of direct sampling are that areas hardest to clean andwhich are reas on ably accessible can be evaluated, lead ing toestablish ing a level of con tam in ati on or residue per give nsurface area. Additi on ally, residues that are "dried out" or are insoluble can be sampled by physical removal.b.systems or ones that cannot be routi nely disassembled can besampled and evaluated.A disadva ntage of rinse samples is that the residue or con tam inantmay not be soluble or may be physically occluded in the equipme nt. An an alogy that can be used is the "dirty pot." In the evaluatio n of cleaning of a dirty pot, particularly with dried out residue, one does no t look at the rinse water to see that it is clea n; one looks at the pot.Check to see that a direct measureme nt of the residue or con tam inant has bee n made for the rinse water whe n it is used to validate the cleaning process. For example, it is not acceptable to simply test rinse water for water quality (does it meet the compendia tests) rather than test it for potential contaminates.c. Rout ine Producti on In-Process Con trolMon itori ng - In direct test ing, such as con ductivity testi ng, may be of some value for rout ine mon itori ng once a clea ning process has bee n validated. This would be particularly true for the bulk drug substa neemanu facturer where reactors and cen trifuges and pip ing betwee nsuch large equipme nt can be sampled only using rinse soluti onsamples. Any in direct test method must have bee n show n to correlate with the condition of the equipment. During validation,the firm should docume nt that test ing the un clea ned equipme nt givesa not acceptable result for the in direct test.ESTABLISHMENT OF LIMITSFDA does not intend to set accepta nee specificati ons or methods for determining whether a cleaning process is validated. It is impractical for FDA to do so due to the wide variati on in equipme nt and products used throughout the bulk and fini shed dosage form in dustries. The firm's rati on ale for the residue limitsestablished should be logical based on the manu facturer's kno wledge of the materials invo Ived and be practical, achievable, and verifiable. It is important to define the sensitivity of the an alytical methods in order to set reas on able limits. Some limits that have bee n men tio ned by in dustry represe ntatives in the literature or in presentations include analytical detection levels such as 10 PPM, biological activity levels such as 1/1000 of the normal therapeutic dose, and orga no leptic levels such as no visible residue.Check the manner in which limits are established. Uni ike fini shedpharmaceuticals where the chemical ide ntity of residuals are known (i.e., from actives, in actives, deterge nts) bulk processes may have partial reacta nts and unwan ted by-products which may n ever have bee n chemically identified. In establishing residual limits, it may not be adequate to focus only on the prin cipal reacta nt since other chemical variati ons may be more difficult to remove. There are circumsta nces where TLC scree ning, in additi on to chemical an alyses, may be n eeded. In a bulk process, particularly for very potent chemicals such as some steroids, the issue of by-products n eeds to be con sidered if equipme nt is not dedicated. The objective of the inspection is to ensure that the basis for any limits is scie ntifically justifiable.OTHER ISSUESa. Placebo ProductIn order to evaluate and validate clea ning processes some manu facturers have processed a placebo batch in the equipme nt un der esse ntially the same operat ing parameters used for process ing product. A sample of the placebo batch is then tested for residual contamination. However, we have docume nted several sig nifica nt issues that n eed to be addressed whe n using placebo product to validate clea ning processes.One cannot assure that the con tam in ate will be uniformly distributedthroughout the system. For example, if the discharge valve or chute of a ble nder are con tam in ated, the con tam inant would probably not be uni formly dispersed in the placebo; it would most likely be concen trated in the in itial discharge portion of the batch. Additi on ally, if the con tam inant or residue is of a larger particle size, it may not be uniformly dispersed in the placebo. V. VI.Some firms have made the assumpti on that a residual con tam inant would be worn off the equipme nt surface uniformly; this is also an inv alid con clusi on.Fin ally, the an alytical power may be greatly reduced by diluti on of the contam in ate. Because of such problems, rinse an d/or swab samples should beused in conj un cti on with the placebo method.b. Deterge ntIf a deterge nt or soap is used for clea ning, determ ine and con sider thedifficulty that may arise whe n attempti ng to test for residues. A com monproblem associated with deterge nt use is its compositi on. Many deterge ntsuppliers will not provide specific compositi on, which makes it difficult for theuser to evaluate residues. As with product residues, it is importa nt and it isexpected that the manu facturer evaluate the efficie ncy of the clea ningprocess for the removal of residues. However, un like product residues, it isexpected that no (or for ultra sen sitive an alytical test methods - very low)deterge nt levels remai n after clea ning. Deterge nts are not part of the manufacturi ng process and are only added to facilitate clea ning duri ng the cleaning process. Thus, they should be easily removable. Otherwise, a differe ntdeterge nt should be selected.c. Test Until CleanExamine and evaluate the level of testing and the retest results since testinguntil clean is a concept utilized by some manufacturers. They test, resample,and retest equipme nt or systems un til an "acceptable" residue level isattained. For the system or equipment with a validated clea ning process, thispractice of resampli ng should not be utilized and is acceptable only in rarecases. Constant retesting and resampling can show that the clea ning processis not validated since these retests actually docume nt the prese nee of unacceptable residue and con tam inants from an in effective clea ning process.REFERENCES0. J. Rodehamel, "Cleaning and Maintenance," Pgs 82-87, University of Wisc VII.onsin's Con trol Procedures in Drug Productio n Sem inar, July 17-22, 1966,William Blockstein, Editor, Published by the University of Wisco nsi n,L.O.C.#66-64234.1. J.A. Constanee, "Why Some Dust Control Exhaust Systems Don't Work,"Pharm. Eng., January-February, 24-26 (1983).2. S.W. Harder, "The Validation of Cleaning Procedures," Pharm. Technol. 8 (5),29-34 (1984)3. W.J. Mead, "Maintenance: Its Interrelationship with Drug Quality," Pharm. Eng.7(3), 29-33 (1987).4. J.A. Smith, "A Modified Swabb ing Tech ni que for Validati on of Deterge ntResidues in Clean-in-Place Systems," Pharm. Technol. 16(1), 60-66 (1992).5. Fourman, G.L. and Mullen, M.V., "Determining Cleaning Validation Acceptanee Limits for Pharmaceutical Manu facturi ng Operati on s," Pharm. Tech nol.17(4), 54-60 (1993).6. McCormick, P.Y. and Cullen, L.F., in Pharmaceutical Process Validation, 2ndEd., edited by I.R. Berry and R.A. Nash, 319-349 (1993)。

FDA指南草案(中文)

基于下一代测序技术的传染病诊断设备：微生物鉴定及抗生素抗性和毒力标志物的检测工业和食品药品管理局工作人员指南草案Document issued on: May 13, 2016U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Devices and Radiological HealthOffice of In Vitro Diagnostics and Radiological HealthDivision of Microbiology Devices目录I.简介 (1)II.背景 (1)A.传染病NGS Dx设备的系统方法 (2)B.FDA-ARGOS: FDA监管级微生物序列数据库 (2)III.范围 (3)IV.利弊分析 (5)V.设备描述 (5)A.预期用途 (5)B.测试方法学 (6)C.辅助试剂 (7)D.控制 (8)(1)阴性对照 (8)(2)阳性对照 (9)(3)内部对照 (9)E.试验结果和报告的解释 (10)VI.设备验证 (10)A.预分析因素 (11)(1)样本收集和处理 (11)(2)样本准备和测序 (12)(3)测序、化学过程和数据收集 (12)(4)数据储存 (13)(5)临床决策要求 (13)B.感染性疾病NGS Dx设备性能指标 (13)(1)感染性疾病NGS Dx设备数据集 (14)(2)测序策略 (14)(3)用于靶向鉴定的参考序列和所选的靶标 (14)(4)临床识别信息学工序流程 (15)(5)减法原理 (15)(6)质量控制 (15)(7)测序及序列比对 (15)(8)污染分析 (15)(9)感染性疾病NGS Dx设备应当提供从样本到结果的周期 (16)(10)数据存储 (16)C.分析性能 (17)(1)检测极限 (17)(2)包容性 (17)(3)干扰物质 (18)(4)精确（可重现性及可重复性） (19)(5)携带及交叉污染 (19)(6)稳定性 (19)(7)其他分析性实验 (19)D.仪器和软件 (19)E.临床评估 (21)(1)阴性百分比一致性评价 (21)(2)阳性百分比一致性评价 (22)(3)数据展示 (23)(4)样本研究和样本类型 (23)Ⅶ设备调试 (24)基于下一代测序技术的传染病诊断设备：微生物鉴定及抗生素抗性和毒力标志物的检测工业和食品药品管理局工作人员指南草案I.简介美国食品药品监督管理局（FDA）发布该指南草案是为工业和机构工作人员提供建议，以研究建立基于下一代测序的用于分析传染病临床表现特征的微生物鉴定及抗生素耐药性和毒力标志的检测设备（以下简称“传染病NGS Dx设备”）。

FDA最新工艺验证指南(2011.1版)(中文版)

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************** 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: 301-847-8714****************.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htmand/orOffice of Communication, Outreach and Development, HFM-40Center for Biologics Evaluation and ResearchFood and Drug Administration1401 Rockville Pike, Rockville, MD 20852-1448(Tel) 800-835-4709 or 301-827-1800/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm and/orCommunications Staff, HFV-12Center for Veterinary MedicineFood and Drug Administration7519 Standish Place,Rockville, MD 20855(Tel) 240-276-9300/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/default.htm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**************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：301-847-8714****************.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm和/或马里兰州洛克维尔市洛克维尔大道1401号HFM-40 FDA生物制品评价和研究中心对外信息、外联与发展办公室邮政编码：20852-1448电话：800-835-4709 或301-827-1800/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm和/或马里兰州洛克维尔市Standish Place 7519号食品药品管理局兽药中心HFV-12通讯处，邮政编码：20885电话：240-276-9300/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/default.htmU.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估和研究中心（CDER）生物制品评估和研究中心（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**************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**************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 does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use 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 number listed 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。

FDA工艺验证指南(2023年.1版)(中文版)

FDA最新工艺验证指南(2011.1版)(中文版)1000字食品药品监管局(FDA)发布了2011年1月的最新工艺验证指南(中文版)，该指南包含了关于工艺验证的详细信息和建议。

工艺验证是一个验证过程，旨在确保产品的性能符合特定的规格要求。

以下是指南中重要的一些提要：工艺验证的定义工艺验证是一种验证过程，它通过控制和监测生产过程的关键要素(如温度、时间和物料)来证明产品性能的一致性，并确定任何很少出现的过程偏差的控制方法和监测程序。

此外，工艺验证有助于识别和消除潜在的质量问题，并确保产品的质量和安全性。

工艺验证的类型指南中提到了三种类型的工艺验证：安装资格验证、功能性验证和进程验证。

1.安装资格验证安装资格验证是确保关键设备和系统的安装、操作和性能符合要求的过程。

2.功能性验证功能性验证是证明产品在链接到现实的生产环境中，能够满足性能要求的过程。

3.进程验证进程验证是确保每次生产批次的过程参数符合规格要求的过程。

工艺验证的步骤指南中提到了四个主要的工艺验证步骤。

1.设计验证方案首先，必须设计一个包括验证示例、过程和程序检查和监测方法的验证方案。

2.执行验证执行验证时必须记录和监测所有的步骤和数据，特别是关键参数。

3.收集和分析数据通过收集和分析数据以确认生产过程的稳定性和一致性。

4.确定验证完成和维护验证状态一旦数据收集和分析完成，并验证的结果可以证明产品的一致性，就可以确定验证工作已经完成。

验证后，工厂必须确保维护验证状态，并定期进行监测。

总之，食品药品监管局(FDA)最新工艺验证指南(2011.1版)(中文版)提供了在生产过程中进行工艺验证的详细说明，这有助于确保生产的产品质量达到极高的水平，同时也有利于确保产品的安全性。

FDA清洁验证检查指南(中英文对照)

FDA清洁验证检查指南（中英文对照）清洗过程验证检查指南GUIDE TOINSPECTIONS VALIDATION OF CLEANINGPROCESSES请注意：本指南是检查官和其他FDA人员的参考材料。

本指南不受FDA约束，并没有赋予任何人任何权利、特权、收益或豁免权。

I．介绍I. INTRODUCTION自从机构文件，包括原料药化学制剂检查指南和生物制剂检查指南，大体上提到该清洗问题以来，就出现了关于清洗过程验证的大量讨论。

这些机构文件清晰的建立了要验证的清洗过程需要达到的要求。

本指南是为了通过讨论实际操作是可接受的(或不可接受的)，来建立检查要求的一致性和统一性。

同时，对清洗验证需要了解的是，像其他过程验证一样，可能有不止一种方法来对过程进行验证。

最后，任何验证过程的测试就是指科学数据是否显示出系统与要求相符和产生的结果是否符合预先定义的参数指标。

本指南只适用于化学残留物的设备清洗。

II．背景对于FDA来说，要求设备在使用前进行清洗并不新奇。

1963GMP 法规(部分133.4)中指出“设备***应该按照清洁和有序的方式进行维护***。

”在1978 CGMP法规中也包含了非常相似的有关设备清洗的章节(211.67)。

当然，清洁设备的主要理由是防止药品被污染或掺假。

在历史上，FDA检查官寻找由于对设备不当的清洗和维护和/或不良的灰尘控制系统而带来的总体不卫生情况。

而且，从历史上来说，FDA对非青霉素药品中的青霉素污染或药品中的活性激素或荷尔蒙交叉污染更加关注。

有很多药品在过去十年中被撤回就是因为实际的或潜在的青霉素的交叉污染。

导致FDA对由于不满足要求的过程导致交叉污染的可能性的进一步关注的案例是，1988年对成品药消胆胺树脂USP的撤回。

用于生产成品的原料药被生产农用杀虫剂中产生的中间体和降解物污染。

本案例中的交叉污染被认为是由于回收溶剂的重新使用。

回收溶剂由于缺乏对溶剂桶的重新使用的控制而被污染。

FDA清洁验证指南

FDA清洁验证指南
FDA（美国食品药品监督管理局）的清洁验证指南（Cleaning Validation Guidance for FDA）是一份详细说明如何进行清洁验证的指南，以确保在药品和医疗器械生产中使用的设备得到有效清洁的文件。

该
指南包含了清洁验证的定义、原则、程序和要求，以及检验设备清洁性能
的方法和技术。

清洁验证是制药行业中的一个关键步骤，旨在确保设备在使用前不含
有任何的残留物。

残留物可能会对产品质量和安全性产生负面影响，因此
清洁验证是产品质量保证和合规性的重要部分。

该指南中提到了一些重要的原则，如总体清洁验证策略、验证程序的
不同阶段、适当的样本大小和技术要求。

它强调了验证过程应该是科学、
系统和可重复的，并应基于理解和评估风险。

指南还描述了清洁验证程序的各个阶段，例如验证计划的编制、击中
关键因素的确定、清洁程序和剂量的开发、样本收集和分析等。

它还提供
了相关文件的要求，如验证报告和标准操作程序（SOPs），以确保验证结
果的准确性和追溯性。

此外，该指南还提供了一些实施清洁验证时应考虑的额外要求，如定
期审核验证程序、定义验证周期、报告异常结果、记录过程参数和审核活
动等。

总之，FDA清洁验证指南是一份重要的文件，为制药和医疗器械行业
提供了进行清洁验证的详细指导。

它对于确保设备在使用前得到有效清洁，并遵守相关法规和要求起到了重要的作用。

制药公司和设备制造商应该遵
循该指南的要求，并根据需要进行相应的验证程序，以保证产品质量和安全性。

美国FDA指南-中文版

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。

FDA清洁工艺验证指南中英文对照

FDA清洁工艺验证指南中英文对照FDA（Food and Drug Administration）是美国食品药品监督管理局的简称。

FDA的清洁工艺验证指南提供了有关如何验证食品加工设备和工艺的清洁性的指导，确保产品的安全。

下面是FDA清洁工艺验证指南的英文全文对照。

FDA Cleaning Process Validation GuideIntroduction简介This document provides guidance on how to validate the cleaning processes used in food processing equipment to ensure their cleanliness. Cleaning validation is an essential step in preventing cross-contamination and ensuring the production of safe products.本文提供了关于如何验证食品加工设备中使用的清洁程序以确保其清洁度的指导。

清洁工艺验证是防止交叉污染和确保生产安全产品的关键步骤。

General Principles基本原则1. Validation should be based on a scientific and risk-based approach, taking into account the specific characteristics of the equipment and the product being manufactured.验证应基于科学和风险评估的方法，考虑到设备和正在生产的产品的特殊特性。

2. The validation process should be well-documented and include clear objectives, acceptance criteria, and a description of the methods used.验证过程应有良好的记录，并包括明确的目标、准入标准和方法描述。

01APIC清洗验证指南(APIC,中文)

活性药物成分清洁验证指南APIC(Active Pharmaceutical Ingredients Committee)2000.12目录1.0 前言......................................................... .12.0 目标......................................................... .13.0 范围......................................................... .14.0 可接受标准................................................... .14.1 简介......................................................... .14.2 可接受标准的计算方法.......................................... .14.2.1 基于治疗日剂量............................................... .14.2.2 基于毒性数据................................................. .34.2.3 一般限度..................................................... .44.2.4 擦拭限度..................................................... ..54.2.5 淋洗限度 (11)5.0 清洁水平 (12)5.1 简介.......................................................... .125.2 程序.......................................................... .126.0 分类和最坏情况评估〔WCR 〕 (14)6.1 简介.......................................................... .14 6.2 分类程序......................................................... ..15 6.3 清洁程序......................................................... ..17 6.4 调查及最坏情况评估.............................................. ..186.5 最坏情况评估.................................................... ..217.0 残留量确定....................................................... ..24简介 ...................................................... .24验证要求 ...................................................... ..24取样方法 ...................................................... ..29 分析方法清洁验证方案背景目的.......................................................... ..33 范围 ...................................................... ..33 职责 ...................................................... ..34 取样程序 .................................................. ..34 检测程序 ..................................................... ...34 可接受标准 ...................................................... 35 与方案的偏差 ..................................................... 37 验证相关的冋题 .. (37)参考书目 ................................................... ...40 术语 ........................................................ ..40版权和声明 .................................................. ..437.17.2 7.3 7.4 8.0 8.18.2 8.3 8.4 8.5 8.6 8.7 8.8 9.0 10.011.012.0..31 ..32 ..331.0前言本指南由CEFIC的原料药委员会〔APIC〕清洁验证特别工作组所编写。

FDA清洁验证指南(中英文对照)

Validation of Cleaning Processes清洁工艺验证GUIDE TO INSPECTIONS VALIDATION OF CLEANING PROCESSES清洁工艺验证检查指南Mike Ma Sort outXiao GangNote: This document is reference material for investigators and other FDA personnel. The document does not bind FDA, and does no confer any rights, privileges, benefits, or immunities for or on any person(s).注意：本指南是审计官和其他FDA人员的参考资料。

FDA不受本指南的约束，也没有授予任何人任何权利、特权、收益或豁免权。

1 of 14ContentI. INTRODUCTION 简介 (3)II. BACKGROUND 背景 (3)III. GENERAL REQUIREMENTS 常规要求 (5)IV. EVALUATION OF CLEANING VALIDATION清洁验证的评估 (6)V. ESTABLISHMENT OF LIMITS 确定限度 (11)VI. OTHER ISSUES 其他问题 (12)VII. REFERENCES 参考资料 (13)2 of 14Validation of cleaning procedures has generated considerable discussion since agency documents, including the Inspection Guide for Bulk Pharmaceutical Chemicals and the Biotechnology Inspection Guide, have briefly addressed this issue. These Agency documents clearly establish the expectation that cleaning procedures (processes) be validated.自从机构文件，包括化学原料药制剂检查指南和生物技术制剂检查指南简明的提及清洁验证规程以来，就对清洁规程验证产生了大量的讨论。

美国FDA清洗验证检查指南

美国FDA清洗验证检查指南注释：这份文件是检查员和其他FDA人员的参考资料。

这份文件不约束FDA，不授予任何人任何权力、特权、利益或豁免权。

Ⅰ. 简介对于清洗程序的验证的讨论，已经在FDA原料药检查指南和生物制品检查指南中有了简要地解释。

这些官方文件明确表达了清洗验证的期望。

本指南通过讨论一些可接受（或不可接受）的实例来建立检查的连贯性和一致性。

同时我们必须意识到清洗验证同其他过程的验证一样，都有不止一种的方法进行验证。

最后验证证明，是否有科学数据表明系统确实如预期稳定，并满足预设规定的结果。

这个指南仅涉及对设备化学残留物的清洗。

Ⅱ. 背景FDA对于设备使用前的清洗没有什么新要求，1963GMP规范中（133.4部分）有以下陈述“设备***应保持清洁和有序的状态***”。

在1978cGMP规范的设备清洁中有非常类似的章节。

当然，设备清洗的主要目的是为了防止药品的污染和混淆。

历史上，FDA 检查员发现由于设备的清洗和维护的不充分及不良的灰尘控制系统带来总体上的不卫生。

历史上来说，FDA更关注非青霉素类受青霉素类的污染和高活性的类固醇或激素对药物的交叉污染。

过去的几十年里，许多产品由于实际存在或潜在的青霉素交叉污染而召回。

1998年消胆胺树脂USP制剂的召回事件使FDA对由于不充分的清洗程序造成的潜在交叉污染更为重视。

产品生产中用到的化学原料药有低量的中间体和农业杀虫剂的降解物污染。

那个事件中交叉污染被认为来自回收溶剂的套用过程。

回收溶剂的污染是由于缺少对溶剂罐重复使用的控制。

杀虫剂生产过程中存放回收溶剂的罐子随后用于存放树脂生产过程中的回收溶剂。

公司对这些溶剂罐未严格管理，对存放的溶剂未充分检测，对罐子的清洗程序未验证。

杀虫剂污染了的原料药运到另一个地方提供给第二个工厂最后加工。

这对后一个工厂流化床干燥器上用到的捕尘袋造成杀虫剂污染。

这反过来导致在这里生产的多个批次交叉污染，而这里正常情况下没有杀虫剂生产。