FDA工艺验证指南(中文)
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.。
FDA工艺验证指南
FDA工艺验证指南GUIDELINEON GENERAL PRINCIPLES OF ROCESS V ALIDATIONMay, 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 be acceptable elements of process validation for the preparation of human and animal drug products and medical devices.II. SCOPEThis guideline is issued under Section 10.90 (21 CFR 10.90) and is applicable to the manufacture of pharmaceuticals and medical devices. It states principles and practices of general applicability that are not legal requirements but are acceptable to the 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 not required to, discuss the matter in advance with FDA to prevent the expenditure of money and effort on activities that may later be determined to be unacceptable. In short, this guideline lists principles and practices which are acceptable to the FDA for the process validation of drug products and medical devices; it does not list the principles and practices that must, in all instances, be used to comply withlaw.This guideline may be amended from time to time. Interested persons are invited to submit comments on this document and any subsequent 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. Received comments 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 Good Manufacturing Practices Regulations for Finished Pharmaceuticals, 21 CFR Parts 210 and 211, and of the Good Manufacturing Practice Regulations for Medical Devices, 21 CFR Part 820, and therefore, is applicable to the manufacture of pharamaceuticals and medical devices.Several firms have asked FDA for specific guidance on what FDA expects firms to do to assure compliance with the requirements for process validation. This guideline discusses process validation elements and concepts that are considered by FDA as acceptable parts of a validation program. The constituents of validation presented in this document are not intended to be all-inclusive. FDA recognizes that, because of the great variety of medical products (drug products and medical devices), processes and manufacturing facilities, it is not possible to state in one document all of the specific validation elements that are applicable. Several broad concepts, however, have general applicability which manufacturers can use successfully as a guide in 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 vs non-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 that the process is effective and reproducible.Product performance qualification - Establishing confidence through appropriate testing that the finished product produced by a specified process meets all release requirements for functionality and safety.Prospective validation - Validation conducted prior to the distribution of either a new product, or product made under a revised 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 consistently produce a product meeting its pre-determined specifications andquality 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 lower processing limits and circumstances, including those within standard operating procedures, which pose the greatest chance of process or product failure when compared to ideal conditions. Such conditions do not necessarily induce product or process failure.IV. GENERAL CONCEPTSAssurance of product quality is derived from careful attention to a number of factors including selection of quality parts and materials, adequate product and process design, control of the process, and in-process and end-product testing. Due to the complexity of today's medical products, routine end-product testing alone often is not sufficient to assure product quality for several reasons. Some end-product tests have limited sensitivity.1 In some cases, destructive testing would be required to show that the manufacturing process was adequate, and in other situations end-product testing does not reveal all variations that may occur in the product that may impact on safety and effectiveness.2The basic principles of quality assurance have as their goal the production of articles that are fit for their intended use. These1 For example, USP XXI states: "No sampling plan for applying sterility tests to a specified proportion of discrete units selected from a sterilization load is capable of demonstrating with complete assurance that all of the untested units are in fact sterile."2 As an example, in one instance a visual inspection failed to detect a defective structural weld which resulted in the failure of an infant warmer. The defect could only have been detected by using destructive testing or expensive test equipment.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;(3)and (3) each step of the manufacturing process must be controlled to maximize the probability thatthe finished product meets all quality and design specifications. Process validation is a keyelement 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 testing plays 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-determined specifications and qualitycharacteristics.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 be collected 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. Analysis of the data collected from monitoring will establish the variability of process parameters for individual runs and will establish whether or not the equipment and process controls are adequate to assure that product specifications are met.Finished product and in-process test data can be of value in process validation, particularly in those situations where quality attributes and variabilities can be readily measured. Where finished (or in-process) testing cannot adequately measure certain attributes, process validation should be derived primarily from qualification of each system used in production and from consideration of the interaction of the various systems.V. CGMP REGULATIONS FOR FINISHED PHARMACEUTICALSProcess validation is required, in both general and specific terms, by the Current Good Manufacturing Practice Regulations for Finished Pharmaceuticals, 21 CFR Parts 210 and 211. Examples of such requirements are listed below for informational purposes, and are not all-inclusive.A requirement for process validation is set forth in general terms in section\211.100 -- Written procedures; deviations -- which states, in part:"There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess."Several sections of the CGMP regulations state validation requirements in more specific terms. Excerpts from some of these sections are:Section 211.110, Sampling and testing of in-process materials and drug products.(a) "....control procedures shall be established to monitor the output and V ALIDATE the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product." (emphasis added) Section 211.113, Control of Microbiological Contamination.(b) "Appropriate written procedures, designed to prevent microbiological contamination of drug products purporting to besterile, shall be established and followed. Such proceduresshall include V ALIDATION of any sterilization process."(emphasis added)VI. GMP REGULATION FOR MEDICAL DEVICESProcess validation is required by the medical device GMP Regulations, 21 CFR Part\820. Section 820.5 requires every finished device manufacturer to:"...prepare and implement a quality assurance program that is appropriate to the specific device manufactured..."Section 820.3(n) defines quality assurance as:"...all activities necessary to verify confidence in the quality of the process used to manufacture a finished device."When applicable to a specific process, process validation is an essential element in establishing confidence that a process will consistently produce a product meeting the designed quality characteristics.A generally stated requirement for process validation is contained in section\820.100:"Written manufacturing specifications and processing procedures shall be established, implemented, and controlled to assure that the device conforms to its original design or any approved changes in that design."Validation is an essential element in the establishment and implementation of a process procedure, as well as in determining what process controls are required in order to assure conformance to specifications.Section 820.100(a)(1) states:"...control measures shall be established to assure that the design basis for the device, components and packaging is correctly translated into approved specifications."Validation is an essential control for assuring that the specifications for the device and manufacturing process are adequate to produce a device that will conform to the approveddesign characteristics.VII. PRELIMINARY CONSIDERA TIONSA manufacturer should evaluate all factors that affect product quality when designing and undertaking a process validation study. These factors may vary considerably among different products and manufacturing technologies and could include, for example, component specifications, air and water handling systems, environmental controls, equipment functions, and process control operations. No single approach to process validation will be appropriate and complete in all cases; however, the following quality activities should be undertaken in most situations.During the research and development (R&D) phase, the desired product should be carefully defined in terms of its characteristics, such as physical, chemical, electrical and performance characteristics.3 It is important to translate the product characteristics into specifications as a basis for description and control of the product.Documentation of changes made during development provide traceability which can later be used to pinpoint solutions to future problems.The product's end use should be a determining factor in the development of product (and component) characteristics and specifications. All pertinent aspects of the product which impact on safety andeffectiveness should be considered. These aspectsFor example, in the case of a compressed tablet, physical characteristics would include size, weight, hardness, and freedom from defects, such as capping and splitting. Chemical characteristics would include quantitative formulation/potency; performance characteristics may include bioavailability (reflected by disintegration and dissolution). In the case of blood tubing, physical attributes would include internal and external diameters, length and color. Chemical characteristics would include raw material formulation. Mechanical properties would include hardness and tensile strength; performance characteristics would include biocompatibility and durability.include performance, reliability and stability. Acceptable ranges or limits should be established for each characteristic to set up allowable variations.4 These ranges should be expressed in readily measurable terms.The validity of acceptance specifications should be verified through testing and challenge of the product on a sound scientific basis during the initial development and production phase.Once a specification is demonstrated as acceptable it is important that any changes to the specification be made in accordance with documented change control procedures.VIII. ELEMENTS OF PROCESS V ALIDATIONA. Prospective ValidationProspective validation includes those considerations that should be made before an entirely new product is introduced by a firm or when there is a change in the manufacturing process which may affect the product's characteristics, such as uniformity and identity. The following are considered as key elements of prospective validation.4 For example, in order to assure that an oral, ophthalmic, or parenteral solution has an acceptable pH, a specification may be established by which a lot is released only if it has been shown to have a pH within a narrow established range. For a device, a specification for the electrical resistance of a pacemaker lead would be established so that the lead would be acceptable only if the resistance was within a specified range.1. Equipment and ProcessThe equipment and process(es) should be designed and/or selected so that product specifications are consistently achieved. This should be done with the participation of all appropriate groups that are concerned with assuring a quality product, e.g., engineering design, production operations, and quality assurance personnel.a. Equipment: Installation Qualification Installation qualification studies establish confidence that the process equipment and ancillary systems are capable of consistently operating within established limits and tolerances. After process equipment is designed or selected, it should be evaluated and tested to verify that it is capable of operating satisfactorily within the operating limits required by the process.5 This phase of validation includes examination of equipment design; determination of calibration, maintenance, and adjustment requirements; and identifying critical equipment features that could affect the process and product. Information obtained from these studies should be used to establish written procedures covering equipment calibration, maintenance, monitoring, and control.5 Examples of equipment performance characteristics which may be measured include temperature and pressure of injection molding machines, uniformity of speed for mixers, temperature, speed and pressure for packaging machines, and temperature and pressure of sterilization chambers.In assessing the suitability of a given piece of equipment, it is usually insufficient to rely solely upon the representations of the equipment supplier, or upon experience in producing some other product.6 Sound theoretical and practical engineering principles and considerations are a first step in the assessment.It is important that equipment qualification simulate actual production conditions, including those which are "worst case" situations.6 The importance of assessing equipment suitability based upon how it will be used to attain desired product attributes is illustrated in the case of deionizers used to produce Purified Water, USP. In one case, a firm used such water to make a topical drug product solution which, in view of its intended use, should have been free from objectionable microorganisms. However, the product was found to be contaminated with a pathogenic microorganism. The apparent cause of the problem was failure to assess the performance of the deionizer from a microbiological standpoint. It is fairly well recognized that the deionizers are prone to build-up of microorganisms--especially if the flow rates are low and the deionizers are not recharged and sanitized at suitable intervals. Therefore, these factors should have been considered. In this case, however, the firm relied upon the representations of the equipment itself, namely the "recharge" (i.e., conductivity) indicator, to signal the time for regeneration and cleaning. Considering the desired product characteristics, the firm should have determined the need for such procedures based upon pre-use testing, taking into account such factors as the length of time the equipment could produce deionized water of acceptable quality, flow rate, temperature, raw water quality, frequency of use, and surface area of deionizing resins.Tests and challenges should be repeated a sufficient number of times to assure reliable and meaningful results. All acceptance criteria must be met during the test or challenge. If any test or challenge shows that the equipment does not perform within its specifications, an evaluation should be performed to identify the cause of the failure. Corrections should be made and additional test runs performed, as needed, to verify that the equipment performs within specifications. The observed variability of the equipment between and within runs can be used as a basis for determining the total number of trials selected for the subsequent performance qualification studies of the process.7Once the equipment configuration and performance characteristics are established and qualified, they should be documented. The installation qualification should include a review of pertinent maintenance procedures, repair parts lists, and calibration methods for each piece of equipment. The objective is to assure that all repairs can be performed in such a way that will not affect the7 For example, the AAMI Guideline for Industrial Ethylene Oxide Sterilization of Medical Devices approved 2 December 1981, states: "The performance qualification should include a minimum of 3 successful, planned qualification runs, in which all of the acceptance criteria are met.....(5.3.1.2.).characteristics of material processed after the repair. In addition, special post-repair cleaning and calibration requirements should be developed to prevent inadvertent manufacture a of non-conforming product. Planning during the qualification phase can prevent confusion during emergency repairs which could lead touse of the wrong replacement part.b. Process: Performance Qualification The purpose of performance qualification is to provide rigorous testing to demonstrate the effectiveness and reproducibility of the process. In entering the performance qualification phase of validation, it is understood that the process specifications have been established and essentially proven acceptable through laboratory or other trial methods and that the equipment has been judged acceptable on the basis of suitable installation studies.Each process should be defined and described with sufficient specificity so that employees understand what is required.Parts of the process which may vary so as to affect important product quality should be challenged.8In challenging a process to assess its adequacy, it is important that challenge conditions simulate those that will be encountered during actual production, including "worst case" conditions. The challenges should be repeated enough times to assure that the results are meaningful and consistent.8 For example, in electroplating the metal case of an implantable pacemaker, the significant process steps to define, describe, and challenge include establishment and control of current density and temperature values for assuring adequate composition of electrolyte and for assuring cleanliness of the metal to be plated. In the production of parenteral solutions by aseptic filling, the significant aseptic filling process steps to define and challenge should include the sterilization and depyrogenation of containers/closures, sterilization of solutions, filling equipment and product contact surfaces, and the filling and closing of containers.Each specific manufacturing process should be appropriately qualified and validated. There is an inherent danger in relying on what are perceived to be similarities between products, processes, and equipment without appropriate challenge.9c. Product: Performance Qualification For purposes of this guideline, product performance qualification activities apply only to medical devices. These steps should be viewed as pre-production quality assurance activities.9 For example, in the production of a compressed tablet, a firm may switch from one type of granulation blender to another with the erroneous assumption that both types have similar performance characteristics, and, therefore, granulation mixing times and procedures need not be altered. However, if the blenders are substantially different, use of the new blender with procedures used for the previous blender may result in a granulation with poor content uniformity. This, in turn, may lead to tablets having significantly differing potencies. This situation may be averted if the quality assurance system detects the equipment 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 new equipment and performance qualification of the process intended for use in the new blender.Before reaching the conclusion that a process has been successfully validated, it is necessary to demonstrate that the specified process has not adversely affected the finished product. Where possible, product performance qualification testing should include performance testing under conditions that simulate actual use.Product performance qualification testing should be conducted using product manufactured from the same type of production equipment, methods and procedures that will be used for routine production. Otherwise, the qualified product may not be representative of production units and cannot be used as evidence that the manufacturing process will produce a product that meets the pre-determined specifications and quality attributes.10 For example, a manufacturer of heart valves received complaints that the valve-support structure was fracturing under use. Investigation by the manufacturer revealed that all material and dimensional specifications had been met but the production machining process created microscopic scratches on the valve supporting wireform. These scratches caused metal fatigue and subsequent fracture. Comprehensive fatigue testing of production units under simulated use conditions could have detected the process deficiency.In another example, a manufacturer recalled insulin syringes because of complaints that the needles were clogged. Investigation revealed that the needles were clogged by silicone oil which was employed as a lubricant during manufacturing. Investigation further revealed that the method used to extract the silicone oil was only partially effective. Although visual inspection of the syringes seemed to support that the cleaning method was effective, actual use proved otherwise.After actual production units have sucessfully passed product performance qualification, a formal technical review should be conducted and should include:Comparison of the approved product specifications and the actual qualified product.Determination of the validity of test methods used to determine compliance with the approved specifications.Determination of the adequacy of the specification change control program.2. System to Assure Timely Revalidation There 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 the raw material characteristics. A determination of adverse differences in raw material indicates a need to revalidate the process.One way of detecting the kind of changes that should initiate revalidation is the use of tests and methods of analysis which are 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 responsibility to review product, process, equipment and personnel changes to determine if and when revalidation is warranted.The extent of revalidation will depend upon the nature of the changes and how they impact upon。
FDA工艺验证指南（中文）
工艺验证：通则和实践本指南代表FDA对这一话题的当前观点，它不会创造或授予任何人任何权利，并不会对FDA或公众起约束作用，你可以使用另外的能够满足法律法规的替代方法，如果你要讨论替代方法，联系FDA负责该指南实施的人员。
如果你不认识特定的FDA 工作人员，请拨打本指南标题页的电话号码。
Ⅰ序言本指南概括了FDA认为的制造人用药和兽用药和生物制品的工艺验证通则和方法，包括APIs和药品。
在本指南中被称为药物或产品。
所有生产企业都可将这些原理和方法用于制造过程的工艺验证。
本指南结合产品生命周期观点和FDA现行的指南，包括FDA/ICH的工业指南，Q8(R2)制药开发，Q9风险管理，和QQ10制药质量体系。
尽管本指南没有重复上述指南中的观点和原理，但FDA鼓励在产品生命周期的所有阶段使用现在的药物开发理念，质量风险管理，和质量体系管理。
1、本指南由药品评估和研究中心（CDER）的生产和产品质量部起草，在FDA下属的药品评价和研究中心的药学办公室(PS)，生物制品评估和研究中心(CBER)，法规事务办公室(ORA)，兽药中心(CVM)的协助下完成。
2、确认你有的指南是最新版的，在CDER指南浏览页查找（网址省略）：生命周期观点和产品和工艺开发过程，商业化生产确认，如何在日常商业化生产过程确保工艺处于受控制的状态相关联，本指南支持用合理的技术和方法对工艺进行改进和创新。
本指南适用于以下类别的药品●人用药●兽用药●生物和生物技术产品●制剂和API（API’s或药用物质）●组合药物（药物和医疗器械）中的药物成分本指南不适用于以下类型的产品●含A型药物的产品和含药饲料●医疗器械●膳食补充剂●公共卫生法令361章节用于移植手术的人体组织本指南没有指定哪些信息为注册资料的一部分。
利害关系人可参考适当的指南或联系有关中心决定那些信息应注册时提交。
本指南也没有特别的讨论自动化过程控制系统的验证（比如，计算机硬件和软件界面），通常它们整合在新的制造设备中，本指南存在相关性，不论如何，在加工过程验证中应包括自动化设备的验证。
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。
2011-FDA行业指南_工艺验证(中英文对照)：一般原则与规范
Guidance for Industry行业指南Process Validation: GeneralPrinciples 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 1Guidance for Industry行业指南Process Validation: GeneralPrinciples 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.htmand/orCommunications Staff, HFV-12Center for Veterinary MedicineFood and Drug Administration7519 Standish Place,Rockville, MD 20855(Tel) 240-276-9300/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/default.htm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 1Table 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)Guidance 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 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
美国FDA生产过程(工艺)验证总则指南I．目的本指南概述了人用和兽用药品和医疗器械的生产过程(工艺)验证的总则，其验证的基本原理是得到fdA认可的。
II．范围本指南是根据21CFR10-90颁布的，适用于药品和医疗器械的生产。
本指南阐述了一般适用范围的原则和方法，这些原则和方法在法律上未做规定要求，但是得到了fdA认可。
本指南可以作为依据，并保证可以得到FDA的批准，但也可以按照其他方法进行验证。
在使用不同方法进行验证时，可事前与(但也可以不与)fdA讨论所要进行的验证工作，以避免在以后被FDA认为不合格而浪费了财力和精力。
总而言之，本指南列述的有关药品和医疗器械的生产过程验证原则和方法，是得到FdA认可的。
但不是在所有情况下都必须使用本指南所列述的原则和方法以符合法律。
本指南是要经常进行修订的。
对此有兴趣的人士可对本文件及随后的任一版本提出意见。
书面意见应向FDA的Dockets Maragement Branch(HFA—305)上报。
地址为：Room 462，5600FishersLane，Rockville，Maryland20847。
在星期—至星期五，上午9：00到下午4：00可在该办公处查阅所收到的意见，III．序言生产过程验证是药品生产管理规范法规21CFR210·211和医疗器械生产管理规范法规21CFR820的规定要求，所以适用于药品和医疗器械的生产。
有些生产厂商曾向FDA要求提供具体的指导：关寸FDA要求生产商做些什么工作，以保证生产过程验证符合规定的要求。
本指南讨沦了生产过程验证的原理和概念，FDA认为这些原理和概念是符合验证方案要求的。
本指南所陈述的验证组成部分并不打算把所有内容都包括在内。
FDA认为，由于医药产品(药品和医疗器械)的生产过程和厂房设施种类繁多，所以不可能把所有适用于验证的具体原理一在本指南内述及。
然而，有些广义的概念有普遍的适用性，生产厂商在生产过程验证时可以用作验证的指南。
FDA清洁工艺验证指南中英文对照
Validation of Cleaning Processes (7/93)清洁工艺验证GUIDE TO INSPECTIONS VALIDATION OF CLEANING PROCESSES清洁工艺验证检查指南Note: 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：此指南是FDA检查官和其他人员的参考资料，此文件不约束FDA，也不赋予任何人任何权利、特权、利益或豁免权I. INTRODUCTION一、介绍Validation 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FDA的各文件，包括化学原料药检查指南和生物技术检查指南，简单的提出了清洁验证的这个话题后，关于清洁工艺的验证已经引发了相当多的讨论，这些官方的文件，都清楚的确定了对清洁工艺需要被验证的期望。
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FDA工艺验证指南指引在 ROCESS 确认的一般原则上准备被: 对于药物是中央的和生物的和对于装置和放射线学的健康是中央的食物药品管制局维护被: 制造业和产品质量的区分 (HFN-320)服从的办公室对于药物是中央的和生物的食物药品管制局5600 渔人小路Rockville, 马里兰 20857程序确认 1987 年五月的一般原则程序确认的一般原则1 目的食品药物管理局考虑是人类的准备和动物的程序确认的可接受元素的这一个指引大纲一般的原则下药产品和医学的装置。
2. 范围这一个指引在第 10.90 节 (21 CFR 10.90) 之下被发行和适用于药学的和医学装置的产品。
它不是合法的需求的一般适用性说原则而且练习但是对食品药物管理局是可接受的。
一个人可能以保证仰赖这一个指引对食品药物管理局的它的可接受, 或可能依照不同的程序。
当不同的程序被用的时候, 一个人可能, 但是不被需要到, 预先和食品药物管理局讨论物质在稍后可能决定是无法接受的活动上避免钱的开支和努力。
简而言之, 这一本指引目录对于药物产品和医学的装置程序确认对食品药物管理局是可接受的原则和练习; 它不列出原则和练习在所有的例证必须用来遵从法律。
这一个指引可能被修正时常。
感兴趣的人被邀请委托在这一份文件和任何的后来校订方面的意见。
书面的意见应该交付给诉讼案件一览表管理部门(HFA-305) ，食物药品管制局，房间 4-62,5600 渔人小路， Rockville ，马里兰20857 。
被一般承认的意见可能在 9\ a.m. 和 4\ p.m. 之间的那一个办公室被调查,星期一整个星期五。
3. 介绍程序确认是练习规则的现在好制造业的一个需求为完成的药学,21 CFR 部份210 和 211, 和好制造业的练习为医学的装置规则,21 CFR 部份 820, 因此, 适用于 pharamaceuticals 和医学的装置产品。
一些公司已经在什么食品药物管理局期待公司之上为特定的指导问食品药物管理局做保证符合程序确认的需求作法。
这一个指引讨论程序确认被如确认计画的可接受部份的食品药物管理局考虑的元素和观念。
在这一份文件被呈现的确认的成份不被想要到是所有的-包含在内的。
食品药物管理局因为医学产品(药物产品和医学的装置) 的棒多样性认识程序和生产设备, 在一份文件可适用的所有的特定确认元素说是不可能的。
然而, 一些宽广的观念已经能成功地在确认一个制造业的程序方面使用如一个引导者的一般的适用性。
虽然程序确认的特别需求依照如医学产品的性质的因素将会改变 (举例来说, 不毛的相对非不毛的) 和程序的复杂, 在这一份文件被陈述的宽广的观念有一般的适用性而且提供建筑包罗万象的方式处理确认可接受的架构。
定义安装资格 - 建立处理设备和补助的系统的信心一致地能够在确定的极限和宽容里面操作。
处理表现资格 - 建立信心程序是有效的和可再生的。
产品表现资格 -建立被一个指定程序生产的完成的产品为功能性和安全符合所有的释放需求的信心完成的适当测试。
预期的确认 - 确认在分配之前引导了或一种新的产品, 或产品在一个被校订的制造业的程序,校订可能影响产品的特性之下制造了。
回顾的确认 - 给已经在分配的一种产品的程序确认基于了累积的生产，测试和控制数据。
建立确认的证明了提供一个保证，一个特定的程序将会一致地生产遇见它的前坚决的规格的一种产品的高程度的证据和质量归于。
确认记录 - 一个书面的计划说确认将会如何被引导, 在什么组成可接受的测验结果之上包括测试叁数，产品特性，生产设备和决定点。
最坏的情形 - 一系列情况包含上面的和比较低的处理极限和环境, 在操作程序的标准里面包括那些, 这造成程序的最好的机会或者产品失败当与理想的情况相较了。
如此的情况不必然地引诱产品或者处理失败。
4. 一般的观念产品质量的保证从小心的注意到包括质量的选择部份和材料, 适当的产品和程序设计，程序的控制的一些因素被源自, 和在-程序和结束-产品的测试。
由于今天的医学产品的复杂, 常式结束-尝试的产品独自地时常不足以为一些理由保证产品质量。
一些结束-产品的测试已经限制敏感。
1 在一些情形，破坏力测试会是表示所必要者那制造业程序是适当的，而且在其他的情形中结束-产品的测试不揭露可能在可能在安全和效力上挤入的产品中发生的所有的变化.2质量保证的基本原则有如他们的目标适合他们的有意使用的文章的生产。
这些1 举例来说, USP XXI 州: "应用不毛测试到从一个消毒负荷被选择的不连续单位的指定比例的没有抽取样品计划能够以完全的保证示范所有的没受过考验的单位是事实上不毛的 ."2 为例, 在一次视觉的检验没有发现造成了婴儿使热的人的失败的有缺陷的结构焊接处的一个例证中。
缺点可以藉由使用只已经被发现破坏力测试或贵的测试设备。
原则可能依下列各项被陈述:(1) 质量，安全和效力一定进入产品之内被设计而且建造;(2) 质量不能够被进入完成的产品之内检查或测试;(3) 而且 (3) 制造业程序的每个步骤一定被控制取可能性最大值完成的产品遇见所有的质量和设计规格。
程序确认是一支钥匙元素在保证的这些质量保证目标被符合。
它是完成的小心设计和一个制造业者能建立一个信心的高程度来自连续的运气的所有的被制造的单位将会是的程序和程序控制的确认可接受的。
成功地确认一个程序可能减少依赖在强烈的之上在-程序和完成的产品测试。
它应该被注意大多数的所有情形的那, 结束-产品的测试作傻事; 也就是, 确认和结束-产品的测试不是互斥的。
食品药物管理局依下列各项定义程序确认:程序确认正在建立证明提供一个保证，一个特定的程序将会一致地生产遇见它的前坚决的规格和质量特性的一种产品的高程度的证据。
很重要的是，制造业者准备叙述要引导的程序 (和测试) 和数据被收集的一个书面的确认记录。
目的为哪些数据被收集一定很清楚,数据一定反映事实和小心地而且正确地被收集。
记录应该叙述一被跑向的统计实验程序的充份数字示范重制度而且提供在连续的奔跑之中的对易变的正确衡量。
对于这些奔跑的测试情况应该包含上面的和比较低的处理极限和环境, 在操作程序的标准里面包括那些, 姿势程序的最好的机会或产品失败与理想的情况相较了; 如此的情况已经广泛地变得知道当做 " 最坏的情形 " 情况。
(他们有时被称为 " 大多数的适当挑战 " 情况.) 确认文件应该包括材料的适合和表现的证据和设备和系统的可信度。
主要程序变数应该被检测而且证明。
数据的分析从监听收集了将会为个别的奔跑建立程序叁数的易变和将会建立是否设备和程序控制适当保证产品规格被遇见。
完成的产品和在-程序测试数据可能是程序确认的价值, 特别地在质量归于的那些情形和易变可能是不迟疑地测量的地方中。
在完成的 (或在-程序) 测试不能够足够地测量特定的属性的地方, 程序确认应该主要地起源于被用于生产的每个系统的资格和从各种不同系统的交互作用的考虑。
V。
CGMP 规则为完成的药学的在上将和特性期限中，程序确认被需要, 被现在好制造业练习规则为完成的药学,21 CFR 部份 210 和 211. 例子如此的需求对于信息的目的在下面被列出, 而且不是所有的-包含。
在内的程序确认的需求在 section\211.100 中是往前大体上组期限 -- 书面的程序; 偏离 -- 哪一个说, 部份地 :"为生产将有书面的程序，而且程序控制设计保证药物产品有他们意味着的身份，力量，质量和纯净或者被表现持有 ."CGMP 规则的一些区段以比较特定的角度说确认需求。
来自一些区段的摘录是:第 211.110 节, 抽取样品和测试在-程序材料和药物产品。
(一) "....控制程序将被建立检测输出而且使可能负责引起特性的易变的那些制造业的程序的表现有效在-程序材料和药物产品."(强调补述) 第 211.113 节， Microbiological 污染的控制。
(b) "适当的书面程序,设计阻止药物产品的 microbiological 污染跟besterile 意味着, 将被建立而且跟随。
如此的 proceduresshall 包括任何消毒程序的确认。
"(强调补述)6. 为医学的装置 GMP 规则程序确认被医学装置 GMP 规则需要,21 CFR 部份\820. 第 820.5 节需要每一完成的装置制造业者:".。
准备而且实现对被制造的特定的装置很适当的一个质量保证计画。
"第 820.3 节 (n) 定义质量保证当做:".。
查证所需的所有活动对程序的质量的信心过去一直制造一个完成的装置。
"当适用于一种特性处理, 程序确认是在建立信心一个程序将会一致地生产遇见被设计的质量特性的一种产品方面一种必要的元素。
通常决定了的程序确认的需求被包含在 section\820.100:"书面的制造规格而且处理程序将被建立,实现, 而且控制保证装置遵照它最初设计或者任何的方面经核准改变设计 ."确认在程序程序的建立和落实方面是一种必要的元素, 连同在决定控制被需要为了要跟规格保证顺应什么程序方面。
第 820.100 节 (一)(1) 州:".。
控制措施将被建立保证设计基础为装置, 成份和包装正确地被转变为经核准规格。
"确认是必要的控制为保证的给装置和制造业程序的规格适当生产将会遵照approveddesign 特性的一个装置。
7. 初步行动考虑当设计的时候，一个制造业者应该评估影响产品质量的所有的因素和事业程序确认学习。
这些因素可能非常地在不同的产品和制造业的技术之中改变和举例来说可以包括成份规格, 空气和水处理系统,环境的控制，设备功能和程序控制操作。
没有独身者接近处理确认将会在所有的情况很适当的和完全; 然而，下列的质量活动应该在大多数的情形被接手。
在研究和发展 (R&D) 状态期间，被需要的产品应该小心地根据它的特性被定义, 像是实际的，化学的，和电的和表现特性。
3 为描述和产品的控制将产品特性翻译成规格如一种基础是重要的。
变化的文件在发展期间制造了提供稍后能用来精确地找见对将来的问题解决办法的可描绘。
产品的结束使用应该是产品 (和成份) 特性和规格的发展的一个决定因素。
在安全和效力上挤入的产品的所有相关方面应该被考虑。
这些方面举例来说，在一个被压缩的平板情况，身体检查特性会包括大小，重量，坚硬 , 和没有缺点,像是加帽于而且分离。
化学的特性会包括数量的形成/效力; 表现特性可能包括 bioavailability 。