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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。

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。

附录15和FDA工艺验证指南英文

GMP News28/10/2015Annex 15 and FDA Process Validation Guideline: Similarities/differences from the FDA perspective附录15和FDA工艺验证指南：与FDA预期的异同The "new" FDA Process Validation Guidance has been in force since January 2011. The revised Annex 15 has been valid since 1 October 2015. At a Conference in September 2015 which was co-sponsored by the FDA, Grace McNally, Senior FDA Official reported about similarities and differences between the two documents from the perspective of the FDA.“新”的FDA工艺验证已于2011年1月实施。

修订后的附录15在2015年10月1日生效。

在2015年9月的会议上，FDA提出了倡议，GRACE MCNALLY, FDA的资深官员报告了FDA角度所诠释的这两份文件的异同。

First to the similarities: both documents address a process validation life cycle and quality risk management across all stages of the life cycle. For Grace McNally there is also comparability with regard to a science-based process development and to the development of process understanding as the basis for stage 2 in accordance with the FDA Process Validation Guideline, resp. with the actual process validation in the sense of Annex 15. Prospective validation is favoured in both documents. Only in special cases one concurrent validation is possible, but is never favoured as a routine procedure. The FDA also sees similarities between the Annex 15 and the FDA Process Validation Guidelinerelative to the need for a rationale for determining the number of samples for PPQ/process validation, as well as in determining the number of PPQ - / validation runs. And this rationale should include, for example, the process variables and the complexity and experience with the process. For the FDA there are further similarities with regard to statistical methods and analyses as part of the process validation: mentioned are PAT, multivariate SPC, statistical methods regarding variability and process capabilities, trend analyses and methods for measuring/evaluating process stabilities and capabilities. Moreover, the authority considers stage 3 in the process validation life cycle (continued/ongoing process verification) as comparable. An exception is mentioned below in the differences. Finally, the requirements for change control in both FDA Process Validation Guideline and the revised Annex 15 are also similar from the perspective of the FDA.首先是相同的地方：两份文件均强调了工艺验证的生命周期和各阶段的质量风险管理。

FDA最新版-药物分析程序及方法验证指导原则-中文翻译版

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 (3)A.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。

它不会创造或赋予或任何人的任何权利，不约束FDA 或公众。

您可以使用另一种方法，如果该方法符合适用的法律和法规的要求。

如果你想讨论一个替代方法，请与FDA 工作人员负责实施本指南。

如果你不能确定适当的FDA 工作人员，请拨打本指南的标题页上所列的电话号码。

介绍：该修订指南草案将取代行业2000 年的指导分析方法和方法验证草案，并最终确定后，也将取代1987 年美国FDA 行业指南《提交的样品和分析数据的方法验证》。

该草案提供了有关申请人如何提交分析程序和方法验证数据来支持说明原料药和制剂具有强度、质量、纯度和效用的文件。

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工业指南--CGMP的质量体系(中文译稿)

Guidance for IndustryQuality Systems Approach to Pharmaceutical CGMP Regulations业界指南——制药企业CGMP规范的质量体系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)Office of Regulatory Affairs (ORA)September 2006Pharmaceutical CGMPs目录Ⅰ简介Ⅱ背景和目的A 背景B 指南的目标C 指南适用范围D 指南的组织结构Ⅲ CGMP和现代质量系统的概念A 质量B 质量设计和产品开发C 质量风险管理D CAPA（纠偏和预防措施）E 变更控制F 质量部门G 六系统检查模式IV 质量系统模型A 管理责任1 授予领导权2 构建组织3 建立符合要求的质量系统4 建立方针政策、目标和计划5 系统审核B资源1 授予领导权2人员提高3厂房和设备4对外包工作的控制C生产制造1产品和生产工艺的设计、开发和文件化2检查输入3运作的执行和监控4 非一致性D 评估活动1 数据的趋势分析2 内部审核3 质量风险管理4 纠偏措施5 预防措施6 推动改善V 结论术语表（本指南代表了FDA对质量体系当前的思考。

它既没有为任何人也不是为赋予任何人利益而制定。

并且其操作也不对FDA或公众形成约束。

只要能够满足对现行法规和规范的要求你可以采用其它方法。

如果你有兴趣讨论其它方法，可以联系负责执行本指南的FDA人员。

如果你无法确认恰当的FDA人员，可以拨打本指南公布的电话。

美国FDA生产过程(工艺)验证总则指南1 9 8 7年.doc

美国FDA生产过程(工艺)验证总则指南1 9 8 7年I．目的 (3)II．范围 (3)III．序言 (3)Ⅳ. 总概念 (4)V．现行药品生产质量管理规范(CGMP)法规 (6)Ⅵ．医疗器械的生产质量管理规范法规 (7)Ⅶ．验证预备阶段所需考虑的事情 (7)Ⅷ．生产过程验证的内容 (8)Ⅸ．产品检验的可接受性 (11)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 Management 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。

FDA工艺验证总则指南

FDA工艺验证总则指南GUIDELINE ON GENERALPRINCIPLESOF PROCESS V ALIDATION工艺验证总则指南MAY, 19871987年5月Prepared by: Center for Drug Evaluation and Research, Center for BiologicsEvaluation and Research, andCenter for Devices and Radiological HealthFood and Drug Administration起草：药物审评与研究中心，生物学评估与研究中心器械及放射学卫生中心食品药品管理局Maintained by: Division of Manufacturing and Product Quality (HFD-320)Office of ComplianceCenter for Drug Evaluation and ResearchFood and Drug Administration保存：制造与产品质量（HFD-320）部门法规管理办公室药物审评与研究中心食品药品管理局5600 Fishers LaneRockville, Maryland 20857Reprinted February, 1993byThe Division of Field InvestigationsOffice of Regional OperationsOffice of Regulatory AffairsU.S.Food and Drug Administration马里兰州，罗克维尔，渔夫巷5600号，邮编：20857美国食品药品管理局现场调查部门区域业务办公室日常事务办公室1993年2月再版Center for Devices and Radiological HealthFood and Drug AdministrationNote: This printed form of the Guideline was prepared by Dr. Arthur Shaw, Food and Drug Administration, for a Course offered by the Center for Professional Advancement in March of 1994. There have been no changes in the text from the original printed version of the Guideline.However the text has been reformatted to reduce the number of pages. The T able of Contents reflects the new pagination. The old pagination is noted in the Guideline.备注：该指南印刷版本由专业促进中心于1994年3月提供方案，由食品药品管理局阿瑟·肖博士起草完成。

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。

FDA 2011工艺验证指南培训

FDA 2011 工艺验证指南简介
前言概述范围生命周期法规要求
前言
• 验证工作是实施 GMP 规范的基础，而工艺验证又是验证工作中的关键性环节。1987年FDA发布了关于工艺验证的指南文件，FDA关于工艺验证的要求和理解深深地影响着世界各国药政当局和制药行业。2008年 11月，FDA再次发布最新的工艺验证指南（草案），对工艺验证的概念和文件要求进行了大幅度修改和更新。经过2年多的收集制药行业的意见和激烈争论,2011年1月24日,FDA发布了工艺验证指南的正式版指南文件《Process Validation: General Principles and Practices》。修订后的指南文件更加明确和具体 , 毫无疑问 , 这个指南文件将对GMP实施产生巨大影响,尤其对于以国际市场为主的外向型制药企业,影响必将是深远的。新指南对原来的观念有了颠覆性的转变，尤其是将验证概念延伸到了研发阶段，这对中国企业是个很有难度的课题。最大的变化是将整个验证过程分成3个阶段，制药企业需要在目前验证管理的基础上，将前期在研发和中试阶段的数据进行分析整理，作为验证的第一部分。与上一版本不同的是，没有针对具体的工艺验证进行规范，而是将ICH-Q8,Q9和Q10的理念整合到了新的指南中。不再从技术指南文件上提出具体措施，而是鼓励制药企业在原则范围内进行技术革新。
概述
• 此版指南将产品生命周期概念和工艺验证活动结合起来，将工艺验证分为工艺设计、工艺确认、持续的工艺核实三个阶段。 • 工艺验证是指从工艺设计阶段到商业生产的整个过程中，对数据进行收集和评价，建立能够使工艺始终如一的传递到优质产品中的科学证据。 • 对已经上市的产品则直接执行持续工艺核实这一阶段的工作。制作商应该保持持续的信息收集和对工艺的定期评价，以发现常见的工艺变异情况，进而增加对工艺和变异的理解，评价和控制工艺参数，并建立科学的参数评价方法，在商品生产这一阶段内做到对工艺的逐步改进（如缩小参数范围等）。在此阶段如发现有重大变异或工艺有较大改动，而现有数据不足以进行分析时，可以回到工艺设计或工艺确认阶段。

制药设备与工艺验证

制药设备与工艺验证制药工艺验证是实施药品GMP的重要基础，也是制药企业贯彻采用质量管理体系的重要组成部分。

特別是近些年来，我国制药行业快速发展，各种制药相关法规、指南相继发布，国内的验证标准逐渐和国际接轨，呈现趋同化。

为了提高我国制药行业的发展水平，满足《国家中长期教育改革和发展规划纲要（2010—2020）》和《国家中长期人才发展规划纲要（2010—2020）》中“强调要培养一大批创新能力强、适应经济社会发展需要的高质量各类型工程技术人才，为国家走新型工业化发展道路、建设创新型国家和人才强国战略服务”的需求，本书编者团队基于多年从事验证工作的丰富经验，为帮助普通高等院校和国内制药企业快速而高效地培养一批验证工程技术人员，秉承“推动行业进步”的发展使命，依据中国、欧盟、WHO和美国等国家和组织的GMP和监管要求，参考ICH、ISO、ISPE、PIC/S等有关实践指南，基于以下重要原则编写本书：•强调“生命周期”概念；•强调“质量源于设计”（Quality by Design，QbD）；•强调对产品和工艺需求的理解；•强调产品保护；•强调关键质量属性（Critical Quality Attribute，CQA）和关键工艺参数（Critical Process Parameter，CPP）的重要性；•采用基于风险评估的方法；•综合国际现行GMP法规对确认与验证的要求；•包含良好工程管理规范（Good Engineering Practice，GEP）概念；•贯穿全书的最新验证案例分析。

本书内容涉及制药行业中原料药、固体制剂、无菌制剂、生物制剂和中药生产的工艺设备、公用设施、辅助设备、计算机化系统的验证工作；同吋涵盖了风险管理、实验室系统、数据可靠性、清洁验证及工艺验证等国内制药行业重点关注的主题。

从理论和实际两个方面，以验证对象特性和验证原理作为起始，将前沿的验证理念与具体的验证实践相结合，归纳总结为以下7章内容：验证概述；设备/设施/系统确认与验证；计算机化系统验证与数据可靠性；QC实验室确认与验证；工艺程序验证；制药工艺验证；制药工艺验证支持活动。

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。

药品确认与验证

二、再确认或再验证
• 3、强制性再确认或再验证 • 1、附录1：无菌药品第四十七条无菌生产工艺的验证应当包括培养基模拟灌装试验。……培养基模拟灌装试验通常应当按照生产工艺每班次半年进行1次，每次至少一批。 • 2、附录1：无菌药品第六十四条应当定期对灭菌工艺的有效性进行再验证（每年至少一次）。
空调净化系统验证的检查要点
• 检查HVAC验证的URS、DQ、IQ、OQ、PQ验证方案. • 检查HVAC验证报告中以下数据是否符合要求（可依据施工单位提供的洁净厂房竣工验收报告的数据）：温湿度、换气次数、压差、气流组织形式等以及环境监控计划及实施。 • 检查HVAC送风机组故障的报警系统。 • 最终或非最终灭菌药品生产的生产间歇期HVAC 系统控制措施及验证情况。 • 非无菌药品生产间歇期对中间站采取的防止污染的措施。
二、再确认或再验证
• 4、回顾性确认或回顾性验证 • 附录2：原料药第二十二条验证的方式：原料药生产工艺的验证方法（二）如没有发生因原料、设备、系统、设施或生产工艺改变而对原料药质量有影响的重大变更时，可例外进行回顾性验证。
二、再确认或再验证
• 5、同步确认或同步验证 • 附录2：原料药第二十二条验证的方式：（一）……因原料药不经常生产、批数不多或生产工艺已有变更等原因，难以从原料药的重复性生产获得现成的数据时，可进行同步验证。
• 2、2010 版GMP 对验证和确认的要求
• 3、验证和确认的新思路 • 4、验证和确认的检查
行业指南（FDA）
• 《药品质量生产管理规范》 2011年1月修订版（FDA）
• 工艺验证：一般原则与规范
工艺验证指南的原则
•
指南体现了食品药品管理局（FDA）关于这一主题的最新见解。

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