FDA最新工艺验证指南(2011.1版)(中文版)
【课件共享】基于FDA工艺验证指南PDATR60的全生命周期工艺验证（二）
【课件共享】基于FDA工艺验证指南PDATR60的全生命周期工艺验证（二）致同仁ICH Q10颁布，FDA于2011年发布《工艺验证：一般原则与规范》以来，将对工艺验证的要求，从原先的3批，变化为了生命周期的方法，这些变化对整个制药企业在工艺从研究开发到确认，再到持续工艺确认都带来的巨大的挑战，使得企业在工艺控制方面，不再是生产企业独自承担的工作，而是扩增到了整个研发、生产、质量体系中。
为此我们特邀请验证与风险管理专家马义岭教授、资深GMP顾问李基老师联袂举办“基于FDA 工艺验证指南&PDA TR60的全生命周期工艺验证”专修班”。
了解详细课程信息请点击链接：升级版--（6月北京）“基于FDA 工艺验证指南&PDA TR60的全生命周期工艺验证”专修班本课件PPT为培训课程的概述版，欲了解课程详细内容，欢迎报名参加现场培训允咨简介上海允咨医药科技有限公司是一家服务于医药行业的GxP一站式培训服务中心，本中心旨在提供“基于对工艺的深度理解之上，服务于医药生产实践的系列化、专业化的高端专业技术培训服务，通过对国内外各类法规、技术指南、行业新技术的培训，帮助制药企业搭建起基于药品全生命周期的多维度的知识空间体系，为行业培训一批具有实战管理经验的高端制药技术与质量管理人才，最终实现制药强国的伟大梦想。
本培训中心目前拥有20多名的全职讲师和100多名的签约兼职讲师，授课教师主要为活跃在制药一线的国内外各类法规指南的编写专家、国际著名制药企业或咨询中本培训中心秉承“帮助企业构建专业化、系统化的法规符合性知识结构；培养学员具有跨部门、跨专业的的综合思考能力，助力企业建立“全员GMP”的学习型组织”心的技术总监、医药研发与科研机构的高级研究员等，培训讲师的从业经验全部在15年以上。
为办学理念。
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现场检查行业指南(中英文对照)
FDA行业指南-药品现场检查中被认为是延迟、否认、限制或拒绝的情形一、介绍2012年7月9日，《美国食品和药物管理局安全及创新法案》（FDASIA）被签署成为法律。
FDASIA章节707添加了501（j）到《食品、药品和化妆品法令》（FD&C Act），认为“任何从事生产、加工、包装或持有的生产企业、库房造成现场检查的延迟、否认、限制或拒绝的情况均被认为该产品为假劣药品”。
该指南的目的是对“延迟、否认、限制或拒绝”的情形进行定义。
二、定义1、延迟A、检查计划安排的延迟FDA将会根据当地的情况对检查计划进行适当的调整，例如天气、安保、节假日、其他非工作日、企业的生产计划等。
以下延迟的情况将会被认为产品是假劣药品，包括但不仅限于：●企业不同意建议的检查日期，但没有合理的解释。
●在检查安排后，企业要求延迟检查日期，但没有合理的解释。
●企业不能回答为什么FDA联系不上企业指定的联系人。
下面给出了将不会被认为是假劣药品的潜在合理解释的一个例子，但不仅限于：●企业没有正在生产，例如每个月只生产一次，企业要求检查日期另定，以便FDA检查时生产正在进行中。
B、检查期间的延迟以下检查期间的延迟情况将会被认为产品是假劣药品，包括但不仅限于：●企业不允许FDA检查官进入某个区域直至一段时间过去之后，即使这个区域是正在进行操作的并且是FDA有权检查的区域，对于这种行为没有合理的解释。
●企业长时间把FDA检查官单独撂在会议室，没有相应的文件或责任人供审查和询问，从而干扰检查官完成其相应的检查。
下面给出了将不会被认为是假劣药品的潜在合理解释的一个例子，但不仅限于：●企业不允许FDA检查官进入无菌工艺区域，直至检查官能满足企业的无菌更衣程序要求。
C、记录提供延迟以下记录提供延迟的情况将会被认为产品是假劣药品，包括但不仅限于：●在检查期间，FDA检查官要求在合理的时间内提供其有权查看的文件和记录，但是企业不能按时提供，且没有合理的解释。
新版GMP对工艺验证要求及思路
一、新版GMP对工艺验证的要求 5、工艺验证的批准： －验证方案和报告必须经质量管理部门审 核和批准确认； －药品监督管理部门批准原辅料、工艺变 更等。 6、对工艺验证结果的要求： －根据工艺验证结果最终确定工艺规程。 －保持持续的验证状态。
一、新版GMP对工艺验证的要求
7、工艺验证处于验证管理的中心地位，厂房设施、设 备、清洁等验证为工艺验证打下基础，工艺确认又是产品 工艺验证的前奏。
厂房与设施验证 计量验证 空气净化系统验证 制药用水验证 设备验证 检验方法验证 工艺确认 产品工艺验证 清洁验证
计算机系统验证
一、新版GMP对工艺验证的要求
8、工艺确认与产品工艺验证的关系： 工艺确认：主要指具体的工艺，工艺参数的确 认，可分段进行，可多次进行，直至参数确认。 通常在商业批工艺验证之前就完成工艺确认 。 产品工艺验证：在空气净化系统、制药用水系 统、设备验证、清洁验证、检验方法等验证完成 和工艺确认都完成的基础上，对工艺整体、参数 确认的过程，至少连续三批。
确认与验证
确认的定义： 证明厂房、设施、设备能正确运行并可达 到预期结果的一系列活动。 验证的定义： 证明任何操作规程（或方法）、生产工艺 或系统能够达到预期结果的一系列活动。
一、新版GMP对工艺验证的要求 第一百三十八条 企业应当确定需要进行 的确认或验证工作，以证明有关操作的关 键要素能够得到有效控制。确认或验证的 范围和程度应当经过风险评估来确定。
一、新版GMP对工艺验证的要求
无菌生产工艺的验证应当包括培养基模拟灌装试验。 应当根据产品的剂型、培养基的选择性、澄清度、浓度和灭菌的适用性选择 培养基。应当尽可能模拟常规的无菌生产工艺，包括所有对无菌结果有影响 的关键操作，及生产中可能出现的各种干预和最差条件。 培养基模拟灌装试验的首次验证，每班次应当连续进行3次合格试验。空气净 化系统、设备、生产工艺及人员重大变更后，应当重复进行培养基模拟灌装 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。 培养基灌装容器的数量应当足以保证评价的有效性。批量较小的产品，培养 基灌装的数量应当至少等于产品的批量。培养基模拟灌装试验的目标是零污 染，应当遵循以下要求： （一）灌装数量少于5000支时，不得检出污染品。 （二）灌装数量在5000至10000支时： 1.有1支污染，需调查，可考虑重复试验； 2.有2支污染，需调查后，进行再验证。 （三）灌装数量超过10000支时： 1.有1支污染，需调查； 2.有2支污染，需调查后，进行再验证。 （四）发生任何微生物污染时，均应当进行调查。
工艺验证(杭州)
工艺验证Process validation程秀温chengxiuwen@2012年3月6日内容2010版GMP对工艺验证的要求1FDA2011版工艺验证指南的基本内容2工艺验证的新思路3工艺验证的定义工艺验证应当证明一个生产工艺按照规定的工艺参数能够持续生产出符合预定用途和注册要求的产品。
（中国2010版GMP）收集并评估从工艺设计阶段一直到商业化生产的数据，用这些数据确立科学证据，证明该工艺能够始终如一地生产出优质产品。
(FDA2011工艺验证指南）书面化的证据，证明工艺在所建立的参数范围内能有效和重复生产出符合预期标准和质量属性的医药产品。
(EU 2001GMP)规定的工艺能始终如一地生产出符合预期标准和质量属性的产品。
（PIC/S 2001）一、新版GMP对工艺验证的要求第一百三十八条企业应当确定需要进行的确认或验证工作，以证明有关操作的关键要素能够得到有效控制。
确认或验证的范围和程度应当经过风险评估来确定。
理解：对验证的范围和程度进行风险评估，范围主要指影响产品质量的关键质量属性和工艺参数，程度主要指风险的大小。
确认与验证确认（Qualification)的定义：证明厂房、设施、设备能正确运行并可达到预期结果的一系列活动。
（2010版GMP附则）验证（Validation）的定义：证明任何操作规程（或方法）、生产工艺或系统能够达到预期结果的一系列活动。
（2010版GMP附则）验证与确认之间的关系：验证和确认本质上是相同的概念，术语“确认”通常用于设备、公用设施和系统，而“验证”则用于工艺，在此意义上确认是验证的一部分。
（WHO）一、新版GMP对工艺验证的要求应用领域风险管理目标推荐工具验证管理通过过程工艺分析，确定哪些步骤和具体操作是决定产品的关键质量属性。
验证过程中应注意这些“关键的”步骤或操作。
且通过进一步分析识别关键参数。
此外，新的或变更的产品/工艺的验证评估可以启动变更控制需求，以确保考虑、评估，降低和记录风险失效模式和影响分析、工艺流程图、关键性分析、知识成熟设施、设备和公用系统的确认有助于基于使用的关键性确定试机及确认的范围与程度。
工艺验证的一般原则和方法20110124稿比较解读
FDA工艺验证指南新旧版透彻比较解读【整理者提醒】1-左侧文本为2011年1月最新修订版本，右侧文本为2008年11月草案版本。
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5-注释前面加【注释】2字注明。
6-Zhulikou431关于FDA2008年11月草案彻底解读版本可以在丁香园论坛搜索到，欢迎下载阅读、讨论。
7-不得用于商业用途，转载请注明丁香园信息。
8-增加了新旧版本的中文译文。
9-欢迎各位朋友提出宝贵建议，联系邮箱zhulikou431@.丁香园zhulikou431 2011年2月3日Guidance for IndustryProcess Validation: General Principles and PracticesFinal Version January 2011 Draft 2008I. INTRODUCTIONI. INTRODUCTION简介This guidance outlines the general principles and approaches that FDA considers appropriate elements of process validation for the manufacture of human and animal drug and biological products, including active pharmaceutical ingredients (APIs or drug substances), collectively referred to in this guidance as drugs or products. This guidance incorporates principles and approaches that all manufacturers can use to validate manufacturing processes. 本指南概括了一般的原则与方法，这些原则与方法是FDA 认为进行工艺验证的恰当要素，这些工艺被用于生产人用药、动物用药以及生物制品，包括活性药物成分(API 或药用物质)，在本指南中以上统称为药品或产品。
美国FDA分析方法验证指南中英文对照--6
美国FDA分析⽅法验证指南中英⽂对照--6XI. METHODOLOGYSections II through IX provide general information on the submission of analytical procedures and methods validation information, including validation characteristics. Additional information on certain methodologies is provided below.XI．⽅法学II章到第IX章提供了分析⽅法和分析⽅法验证资料⽅⾯的基本信息，包括验证项⽬。
下⽂就⼀些具体的⽅法给出了说明：A. High-Pressure Liquid Chromatography (HPLC)The widespread use of HPLC analytical procedures and the multitude of commercial sources of columns and packings frequently have created problems in assessing comparability. Many of the following points may also apply to other chromatographic analytical procedures.⾊谱(HPLC)⾼效液相⾊谱A．⾼效液相HPLC分析⽅法的⼴泛应⽤及⾊谱柱和柱填充的众多来源都经常会给可⽐性评估带来很多问题。
如下这些要点中，很多都适⽤于其它⾊谱分析⽅法。
1. ColumnThe following characteristics are useful for defining a particular column and, if known, should be included in the analytical procedure description. If method development has indicated that columns from only one commercial source are suitable, this information should be included as part of the analytical procedure. If more than one column is suitable, a listing of columns found to be equivalent should be included.1.⾊谱柱在定义某⼀⾊谱柱时，如下这些性质是很有⽤的，也应当要包括在分析⽅法描述中。
FDA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。
美国FDA药物分析程序及方法验证指导原则(中文版)
药品及生物制品的分析方法和方法验证指导原则目录1.介绍...................... (1)2.背景..................... .. (2)3.分析方法开发. ..................... . (3)4.分析程序内容.............................................. ......... ..................................... .. 3A.原则/范围 (4)B.仪器/设备............................................. . (4)C.操作参数.............................................. .. (4)D.试剂/标准............................................. . (4)E.样品制备.............................................. .. (4)F.标准对照品溶液的制备............................................ .. (5)G.步骤......... ....................................... (5)H.系统适应性..... (5)I.计算 (5)J.数据报告 (5)5.参考标准和教材............................................ (6)6分析方法验证用于新药，仿制药，生物制品和DMF (6)A.非药典分析方法............................................. (6)B.验证特征 (7)C.药典分析方法............................................. .. (8)7.统计分析和模型 (8)A.统计 (8)B.模型 (8)8.生命周期管理分析程序 (9)A.重新验证 (9)B.分析方法的可比性研究............................................ . (10)1.另一种分析方法............................................... .. (10)2.分析方法转移的研究 (11)C.报告上市后变更已批准的新药，仿制药，或生物制品 (11)9.美国FDA方法验证............................................... . (12)10.参考文献前言本指导原则草案，定稿后，将代表美国食品和药物管理局（FDA）目前关于这个话题目前的想法。
7工艺验证
工艺验证工艺验证——概念FDA 2011：收集并评估从工艺设计阶段到商业化生产的整个过程中的数据，基于数据建立科学证据，证明生产工艺能够始终如一地生产出优质产品。
EU 2001：书面化的证据，证明工艺在所建立的参数范围内能有效和重复生产出符合预期标准和质量属性的医药产品。
PIC/S 2001：规定的工艺能始终如一地生产出符合预期标准和质量属性的产品。
中国新版GMP：工艺验证应当证明一个生产工艺按照规定的工艺参数能够持续生产出符合预定用途和注册要求的产品。
中国新版GMP对验证的定义：证明任何操作规程（或方法）、生产工艺或系统能够达到预期结果的一系列活动。
工艺验证目的提供文件化证据；评价生产方法；保证工艺的可靠性；减少失败、降低成本、提高效益。
法规的要求中国GMP(2010版)：---138条企业应当确定需要进行的确认或验证工作，以证明有关操作的关键要素能够得到有效控制。
确认或验证的范围和程度应当经过风险评估来确定。
* 完善条款—提出确认与验证的概念。
—增加验证的目的阐述，确定验证范围和程度的确定方法。
法规的要求中国GMP(2010版)：---139条企业的厂房、设施、设备和检验仪器应当经过确认，应当采用经过验证的生产工艺、操作规程和检验方法进行生产、操作和检验，并保持持续的验证状态。
* 完善条款—根据98版规范第五十八条有关验证实施的要求，进一步提出验证状态保持的理念。
—验证状态保持的主要手段有：法规的要求中国GMP(2010版)：---139条—验证状态保持的主要手段有：✓预防性维护保养（设备）✓校验（设备)✓变更控制(质量保证）✓生产过程控制（物料采购、生产管理、质量检验）✓产品年度回顾（质量保证）✓再验证管理（质量保证、验证管理）法规的要求中国GMP(2010版)：---140条应当建立确认与验证的文件和记录，并能以文件和记录证明达到以下预定的目标：（一）设计确认应当证明厂房、设施、设备的设计符合预定用途和本规范要求（二）安装确认应当证明厂房、设施、设备的建造和安装符合设计标准；（三）运行确认应当证明厂房、设施、设备的运行符合设计标准；（四）性能确认应当证明厂房、设施、设备在正常操作方法和工艺条件下能够持地符合标准；（五）工艺验证应当证明一个生产工艺按规定的工艺参数能够持续有效地生产出合预定用途和注册要求的产品。
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Guidance for Industry 行业指南Process Validation: General Principles and Practices工艺验证：一般原则与规范U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Research (CBER)Center for Veterinary Medicine (CVM)January 2011Current Good Manufacturing Practices (CGMP)Revision 1美国卫生与人类服务部食品药品管理局药物评价和研究中心（CDER）生物制品评价和研究中心（CBER）兽药中心（CVM）2011年1月现行药品质量生产管理规范（CGMP）修订版1包含不具约束力的建议中文译稿：北京大学药物信息与工程研究中心************** Guidance for Industry 行业指南Process Validation: General Principles and Practices工艺验证：一般原则与规范Additional copies are available from:Office of CommunicationsDivision of Drug Information, WO51, Room 220110903 New Hampshire Ave.Silver Spring, MD 20993Phone: 301-796-3400; Fax: 301-847-8714****************.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htmand/orOffice of Communication, Outreach and Development, HFM-40Center for Biologics Evaluation and ResearchFood and Drug Administration1401 Rockville Pike, Rockville, MD 20852-1448(Tel) 800-835-4709 or 301-827-1800/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm and/orCommunications Staff, HFV-12Center for Veterinary MedicineFood and Drug Administration7519 Standish Place,Rockville, MD 20855(Tel) 240-276-9300/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/default.htm包含不具约束力的建议中文译稿：北京大学药物信息与工程研究中心**************另外的副本可从以下部门得到：马里兰州银泉市新罕布什尔大道10193号2201室药品信息处，对外信息办公室，邮政编码：20993电话：301-796-3400; 传真：301-847-8714****************.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm和/或马里兰州洛克维尔市洛克维尔大道1401号HFM-40 FDA生物制品评价和研究中心对外信息、外联与发展办公室邮政编码：20852-1448电话：800-835-4709 或301-827-1800/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm和/或马里兰州洛克维尔市Standish Place 7519号食品药品管理局兽药中心HFV-12通讯处，邮政编码：20885电话：240-276-9300/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/default.htmU.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Research (CBER)Center for Veterinary Medicine (CVM)January 2011Current Good Manufacturing Practices (CGMP)Revision 1美国卫生与人类服务部食品药品管理局药物评估和研究中心（CDER）生物制品评估和研究中心（CBER）兽药中心（CVM）2011年1月现行药品质量生产管理规范（CGMP）修订版 1包含不具约束力的建议中文译稿：北京大学药物信息与工程研究中心**************Table of Contents目录I. INTRODUCTION (1)一. 简介 (1)II. BACKGROUND (3)二. 背景 (3)A. Process Validation and Drug Quality (4)A. 工艺验证与药品质量 (4)B. Approach to Process Validation (5)B. 工艺验证方法 (5)III. STATUTORY AND REGULATORY REQUIREMENTS FOR PROCESS VALIDATION (7)三. 对工艺验证的法规和监管要求 (7)IV. RECOMMENDATIONS (9)四. 建议 (9)A. General Considerations for Process Validation (9)A. 对工艺验证的总体考虑 (9)B. Stage 1 - Process Design (10)B. 第一阶段- 工艺设计 (10)1. Building and Capturing Process Knowledge and Understanding (11)1. 建立和捕获工艺知识与理解 (11)2. Establishing a Strategy for Process Control (12)2. 建立工艺控制策略 (12)C. Stage 2 - Process Qualification (14)C. 第二阶段- 工艺确认 (14)1. Design of a Facility and Qualification of Utilities and Equipment (14)1. 厂房设施设计以及公用设施与设备确认 (14)2. Process Performance Qualification (16)2. 工艺性能确认 (16)3. PPQ Protocol (17)3. 工艺性能确认方案 (17)4. PPQ Protocol Execution and Report (19)4. 工艺性能确认执行与报告 (19)D. Stage 3 - Continued Process Verification (20)D. 第三阶段- 持续工艺验证 (20)V. CONCURRENT RELEASE OF PPQ BATCHES (22)五. 工艺性能确认批次的同时放行 (22)VI. DOCUMENTATION (24)六. 文件记录 (24)VII. ANALYTICAL METHODOLOGY (24)七. 分析方法 (24)GLOSSARY (26)术语表 (26)REFERENCES (28)参考资料 (28)包含不具约束力的建议中文译稿：北京大学药物信息与工程研究中心**************1Guidance for Industry1行业指南1Process Validation: General Principles and Practices工艺验证：一般原则与实施This guidance represents the Food and Drug Administration’s (FDA’s) current thin king on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance.本指南体现了食品药品管理局（FDA）关于这一主题的最新见解。
本指南不为任何人或对任何人才创造或赋予任何权利，不起束缚FDA 或公众的作用。
如果替代方法能够满足适用法律、法规的要求，您可以使用替代方法。
如果您希望讨论一种替代性方法，请与负责执行本指南的FDA 工作人员联系。
如果您不能确定相应的FDA 工作人员，请拨打本指南标题页所列的相应电话号码。
I. INTRODUCTION一. 简介This guidance outlines the general principles and approaches that FDA considers appropriate elements ofprocess validation for the manufacture of human and animal drug and biological products, including active pharmaceutical ingredients (APIs or drug substances), collectively referred to in this guidance as drugs or products. This guidance incorporates principles and approaches that all manufacturers can use to validate manufacturing processes.本指南概述了FDA 认为是包括原料药在内的人与动物用药和生物制品（在本指南中合称为药品或制品）生产工艺验证相应要素的一般原则和方法。