The RDF Schema Specification Revisited

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。

欧洲药物管理EDMF&CTD基本介绍EDMF文件简介：欧洲药物管理档案（EDMF，即 European Drug Master File）是药品制剂的制造商为取得上市许可而必须向注册当局提交的关于在制剂产品中所使用的原料药的基本情况的支持性技术文件。

它的申请必须与使用该原料药的制剂的上市许可申请同时进行。

当原料药物的生产厂家（ASM，即 The Active Substance Manufacturer）不是药品制剂上市许可证的申请人时，也就是说当制剂生产厂家使用其它厂家生产的原料药物生产制剂时，为了保护原料药物的生产及质量管理等方面有价值的技术机密而由原料药物的生产厂家提交给欧洲官方机构的文件。

分为公开部分和保密部分。

与美国FDA的DMF涵概药品生产的全过程CMC（Chemistry, Manufacturing and Control）不同，欧洲DMF则主要强调第一个C，即Chemistry。

具体的说，EDMF 的主要内容是药物及其相关杂质的化学，包括化学结构及结构解析、化学性质、杂质及其限度、杂质检查等等。

EDMF的适用范围：EDMF适用于以下三类原料药的申请：--仍由专利保护的新的原料药，并且这种原料药没有包括在欧洲药典或任何一个成员国的药典之中；--已过专利保护期的原料药，并且这种原料药没有包括在欧洲药典或任何一个成员国的药典之中；--包括在欧洲药典或任何一个成员国的药典之中的原料药，当这种原料药使用一个可能留下药典专论没有提到的杂质并且药典专论不能足够控制其质量的方法生产时。

EDMF的变动和更新如果EDMF持有人需要对EDMF的公开部分和保密部分做出变动，则任何变动均要向主管当局或EMEA上报，并通知所有申请人。

若仅是修改EDMF 的保密部分，并且生产采用的质量标准和杂质范围均没有发生改变，修改信息只需提供给主管当局；如果需要修改EDMF的公开部分，此信息必须提供给其他申请人和使用此EDMF的药品上市许可证的持有人，所有涉及到的申请人将通过适当的变更程序修改他们的上市许可证申请文档。

Analytical Procedures and Methods Validation for Drugsand BiologicsDRAFT GUIDANCEThis guidance document is being distributed for comment purposes only. Comments and suggestions regarding this draft document should be submitted within 90 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit electronic comments to . Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Registe r.For questions regarding this draft document contact (CDER) Lucinda Buhse 314-539-2134, or (CBER) Office of Communication, Outreach and Development at 800-835-4709 or 301-827-1800.U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Research (CBER)February 2014CMCAnalytical Procedures and Methods Validation for Drugsand BiologicsAdditional copies are available from:Office of CommunicationsDivision of Drug Information, WO51, Room 2201Center for Drug Evaluation and ResearchFood and Drug Administration10903 New Hampshire Ave., Silver Spring, MD 20993Phone: 301-796-3400; Fax: 301-847-8714druginfo@/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htmand/orOffice of Communication, Outreach andDevelopment, HFM-40Center for Biologics Evaluation and ResearchFood and Drug Administration1401 Rockville Pike, Rockville, MD 20852-1448ocod@/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm(Tel) 800-835-4709 or 301-827-1800U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Research (CBER)Febr uary 2014CMCTABLE OF CONTENTSI.INTRODUCTION (1)II.BACKGROUND (2)III.ANALYTICAL METHODS DEVELOPMENT (3)IV.CONTENT OF ANALYTICAL PROCEDURES (3)A.Principle/Scope (4)B.Apparatus/Equipment (4)C.Operating Parameters (4)D.Reagents/Standards (4)E.Sample Preparation (4)F.Standards Control Solution Preparation (5)G.Procedure (5)H.System Suitability (5)I.Calculations (5)J.Data Reporting (5)V.REFERENCE STANDARDS AND MATERIALS (6)VI.ANALYTICAL METHOD VALIDATION FOR NDA, ANDAs, BLAs, AND DMFs (6)A.Noncompendial Analytical Procedures (6)B.Validation Characteristics (7)pendial Analytical Procedures (8)VII.STATISTICAL ANALYSIS AND MODELS (8)A.Statistics (8)B.Models (8)VIII.LIFE CYCLE MANAGEMENT OF ANALYTICAL PROCEDURES (9)A.Revalidation (9)B.Analytical Method Comparability Studies (10)1.Alternative Analytical Procedures (10)2.Analytical Methods Transfer Studies (11)C.Reporting Postmarketing Changes to an Approved NDA, ANDA, or BLA (11)IX.FDA METHODS VERIFICATION (12)X.REFERENCES (12)Guidance for Industry11Analytical Procedures and Methods Validation for Drugs and2Biologics345This draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA’s) current 6thinking on this topic. It does not create or confer any rights for or on any person and does not operate to 7bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of 8the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA9staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call 10the appropriate number listed on the title page of this guidance.11121314I. INTRODUCTION1516This revised draft guidance supersedes the 2000 draft guidance for industry on Analytical17Procedures and Methods Validation2,3 and, when finalized, will also replace the 1987 FDA18guidance for industry on Submitting Samples and Analytical Data for Methods Validation. It19provides recommendations on how you, the applicant, can submit analytical procedures4 and20methods validation data to support the documentation of the identity, strength, quality, purity,21and potency of drug substances and drug products.5It will help you assemble information and 22present data to support your analytical methodologies. The recommendations apply to drug23substances and drug products covered in new drug applications (NDAs), abbreviated new drug 24applications (ANDAs), biologics license applications (BLAs), and supplements to these25applications. The principles in this revised draft guidance also apply to drug substances and drug 26products covered in Type II drug master files (DMFs).2728This revised draft guidance complements the International Conference on Harmonisation (ICH) 29guidance Q2(R1)Validation of Analytical Procedures: Text and Methodology(Q2(R1)) for30developing and validating analytical methods.3132This revised draft guidance does not address investigational new drug application (IND) methods 33validation, but sponsors preparing INDs should consider the recommendations in this guidance.34For INDs, sufficient information is required at each phase of an investigation to ensure proper35identity, quality, purity, strength, and/or potency. The amount of information on analytical36procedures and methods validation will vary with the phase of the investigation.6 For general371 This guidance has been prepared by the Office of Pharmaceutical Science, in the Center for Drug Evaluation andResearch (CDER) and the Center for Biologics Evaluation and Research (CBER) at the Food and DrugAdministration.2 Sample submission is described in section IX, FDA Methods Verification.3 We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDADrugs guidance Web page at/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.4Analytical procedure is interchangeable with a method or test procedure.5The terms drug substance and drug product, as used in this guidance, refer to human drugs and biologics.6 See 21 CFR 312.23(a)(7).guidance on analytical procedures and methods validation information to be submitted for phase 38one studies, sponsors should refer to the FDA guidance for industry on Content and Format of39Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including40Well-Characterized, Therapeutic, Biotechnology-Derived Products. General considerations for 41analytical procedures and method validation (e.g., bioassay) before conduct of phase three42studies are discussed in the FDA guidance for industry on IND Meetings for Human Drugs and 43Biologics, Chemistry, Manufacturing, and Controls Information.4445This revised draft guidance does not address specific method validation recommendations for46biological and immunochemical assays for characterization and quality control of many drug47substances and drug products. For example, some bioassays are based on animal challenge48models, and immunogenicity assessments or other immunoassays have unique features that49should be considered during development and validation.5051In addition, the need for revalidation of existing analytical methods may need to be considered 52when the manufacturing process changes during the product’s life cycle. For questions on53appropriate validation approaches for analytical procedures or submission of information not54addressed in this guidance, you should consult with the appropriate FDA product quality review 55staff.5657If you choose a different approach than those recommended in this revised draft guidance, we58encourage you to discuss the matter with the appropriate FDA product quality review staff before 59you submit your application.6061FDA’s guidance documents, including this guidance, do not establish legally enforceable62responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should 63be viewed only as recommendations, unless specific regulatory or statutory requirements are64cited. The use of the word should in Agency guidances means that something is suggested or65recommended, but not required.666768II.BACKGROUND6970Each NDA and ANDA must include the analytical procedures necessary to ensure the identity, 71strength, quality, purity, and potency of the drug substance and drug product.7 Each BLA must 72include a full description of the manufacturing methods, including analytical procedures that73demonstrate the manufactured product meets prescribed standards of identity, quality, safety,74purity, and potency.8 Data must be available to establish that the analytical procedures used in 75testing meet proper standards of accuracy and reliability and are suitable for their intended76purpose.9 For BLAs and their supplements, the analytical procedures and their validation are77submitted as part of license applications or supplements and are evaluated by FDA quality78review groups.79807 See 21 CFR 314.50(d)(1) and 314.94(a)(9)(i).8 See 21 CFR 601.2(a) and 601.2(c).9 See 21 CFR 211.165(e) and 211.194(a)(2).Analytical procedures and validation data should be submitted in the corresponding sections of 81the application in the ICH M2 eCTD: Electronic Common Technical Document Specification.108283When an analytical procedure is approved/licensed as part of the NDA, ANDA, or BLA, it84becomes the FDA approved analytical procedure for the approved product. This analytical85procedure may originate from FDA recognized sources (e.g., a compendial procedure from the 86United States Pharmacopeia/National Formulary (USP/NF)) or a validated procedure you87submitted that was determined to be acceptable by FDA. To apply an analytical method to a88different product, appropriate validation studies with the matrix of the new product should be89considered.909192III.ANALYTICAL METHODS DEVELOPMENT9394An analytical procedure is developed to test a defined characteristic of the drug substance or95drug product against established acceptance criteria for that characteristic. Early in the96development of a new analytical procedure, the choice of analytical instrumentation and97methodology should be selected based on the intended purpose and scope of the analytical98method. Parameters that may be evaluated during method development are specificity, linearity, 99limits of detection (LOD) and quantitation limits (LOQ), range, accuracy, and precision.100101During early stages of method development, the robustness of methods should be evaluated102because this characteristic can help you decide which method you will submit for approval.103Analytical procedures in the early stages of development are initially developed based on a104combination of mechanistic understanding of the basic methodology and prior experience.105Experimental data from early procedures can be used to guide further development. You should 106submit development data within the method validation section if they support the validation of 107the method.108109To fully understand the effect of changes in method parameters on an analytical procedure, you 110should adopt a systematic approach for method robustness study (e.g., a design of experiments 111with method parameters). You should begin with an initial risk assessment and follow with112multivariate experiments. Such approaches allow you to understand factorial parameter effects 113on method performance. Evaluation of a method’s performance may include analyses of114samples obtained from in-process manufacturing stages to the finished product. Knowledge115gained during these studies on the sources of method variation can help you assess the method 116performance.117118119IV.CONTENT OF ANALYTICAL PROCEDURES120121You should describe analytical procedures in sufficient detail to allow a competent analyst to 122reproduce the necessary conditions and obtain results within the proposed acceptance criteria. 123You should also describe aspects of the analytical procedures that require special attention. An 124analytical procedure may be referenced from FDA recognized sources (e.g., USP/NF,12510 See sections 3.2.S.4 Control of Drug Substance, 3.2.P.4 Control of Excipients, and 3.2.P.5 Control of DrugProduct.Association of Analytical Communities (AOAC) International)11 if the referenced analytical126procedure is not modified beyond what is allowed in the published method. You should provide 127in detail the procedures from other published sources. The following is a list of essential128information you should include for an analytical procedure:129130A.Principle/Scope131132A description of the basic principles of the analytical test/technology (separation, detection, etc.); 133target analyte(s) and sample(s) type (e.g., drug substance, drug product, impurities or compounds 134in biological fluids, etc.).135136B.Apparatus/Equipment137138All required qualified equipment and components (e.g., instrument type, detector, column type, 139dimensions, and alternative column, filter type, etc.).140141C.Operating Parameters142143Qualified optimal settings and ranges (allowed adjustments) critical to the analysis (e.g., flow144rate, components temperatures, run time, detector settings, gradient, head space sampler). A145drawing with experimental configuration and integration parameters may be used, as applicable. 146147D.Reagents/Standards148149The following should be listed:150151•Grade of chemical (e.g., USP/NF, American Chemical Society, High152Performance or Pressure Liquid Chromatography, or Gas153Chromatography and preservative free).154•Source (e.g., USP reference standard or qualified in-house reference material). 155•State (e.g., dried, undried, etc.) and concentration.156•Standard potencies (purity correction factors).157•Storage controls.158•Directions for safe use (as per current Safety Data Sheet).159•Validated or useable shelf life.160161New batches of biological reagents, such as monoclonal antibodies, polyclonal antisera, or cells, 162may need extensive qualification procedures included as part of the analytical procedure.163164E.Sample Preparation165166Procedures (e.g., extraction method, dilution or concentration, desalting procedures and mixing 167by sonication, shaking or sonication time, etc.) for the preparations for individual sample tests. 168A single preparation for qualitative and replicate preparations for quantitative tests with16911 See 21 CFR 211.194(a)(2).appropriate units of concentrations for working solutions (e.g., µg/ml or mg/ml) and information 170on stability of solutions and storage conditions.171172F.Standards Control Solution Preparation173174Procedures for the preparation and use of all standard and control solutions with appropriate175units of concentration and information on stability of standards and storage conditions,176including calibration standards, internal standards, system suitability standards, etc.177178G.Procedure179180A step-by-step description of the method (e.g., equilibration times, and scan/injection sequence 181with blanks, placeboes, samples, controls, sensitivity solution (for impurity method) and182standards to maintain validity of the system suitability during the span of analysis) and allowable 183operating ranges and adjustments if applicable.184185H.System Suitability186187Confirmatory test(s) procedures and parameters to ensure that the system (equipment,188electronics, and analytical operations and controls to be analyzed) will function correctly as an 189integrated system at the time of use. The system suitability acceptance criteria applied to190standards and controls, such as peak tailing, precision and resolution acceptance criteria, may be 191required as applicable. For system suitability of chromatographic systems, refer to CDER192reviewer guidance on Validation of Chromatographic Methods and USP General Chapter <621> 193Chromatography.194195I.Calculations196197The integration method and representative calculation formulas for data analysis (standards,198controls, samples) for tests based on label claim and specification (e.g., assay, specified and199unspecified impurities and relative response factors). This includes a description of any200mathematical transformations or formulas used in data analysis, along with a scientific201justification for any correction factors used.202203J.Data Reporting204205A presentation of numeric data that is consistent with instrumental capabilities and acceptance 206criteria. The method should indicate what format to use to report results (e.g., percentage label 207claim, weight/weight, and weight/volume etc.) with the specific number of significant figures 208needed. The American Society for Testing and Materials (ASTM) E29 describes a standard209practice for using significant digits in test data to determine conformance with specifications. For 210chromatographic methods, you should include retention times (RTs) for identification with211reference standard comparison basis, relative retention times (RRTs) (known and unknown212impurities) acceptable ranges and sample results reporting criteria.213214215V.REFERENCE STANDARDS AND MATERIALS216217Primary and secondary reference standards and materials are defined and discussed in the218following ICH guidances: Q6A Specifications: Test Procedures and Acceptance Criteria for 219New Drug Substances and New Drug Products: Chemical Substances (ICH Q6A), Q6B220Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological221Products, and Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical222Ingredients. For all standards, you should ensure the suitability for use. Reference standards for 223drug substances are particularly critical in validating specificity for an identity test. You should 224strictly follow storage, usage conditions, and handling instructions for reference standards to225avoid added impurities and inaccurate analysis. For biological products, you should include226information supporting any reference standards and materials that you intend to use in the BLA 227and in subsequent annual reports for subsequent reference standard qualifications. Information 228supporting reference standards and materials include qualification test protocols, reports, and 229certificates of analysis (including stability protocols and relevant known impurity profile230information, as applicable).231232Reference standards can often be obtained from USP and may also be available through the233European Pharmacopoeia, Japanese Pharmacopoeia, World Health Organization, or National 234Institute of Standards and Technology. Reference standards for a number of biological products 235are also available from CBER. For certain biological products marketed in the U.S., reference 236standards authorized by CBER must be used before the product can be released to the market.12 237Reference materials from other sources should be characterized by procedures including routine 238and beyond routine release testing as described in ICH Q6A. You should consider orthogonal 239methods. Additional testing could include attributes to determine the suitability of the reference 240material not necessarily captured by the drug substance or product release tests (e.g., more241extensive structural identity and orthogonal techniques for purity and impurities, biological242activity).243244For biological reference standards and materials, we recommend that you follow a two-tiered 245approach when qualifying new reference standards to help prevent drift in the quality attributes 246and provide a long-term link to clinical trial material. A two-tiered approach involves a247comparison of each new working reference standard with a primary reference standard so that it 248is linked to clinical trial material and the current manufacturing process.249250251VI.ANALYTICAL METHOD VALIDATION FOR NDA, ANDAs, BLAs, AND 252DMFs253254A.Noncompendial Analytical Procedures255256Analytical method validation is the process of demonstrating that an analytical procedure is257suitable for its intended purpose. The methodology and objective of the analytical procedures 258should be clearly defined and understood before initiating validation studies. This understanding 25912 See 21 CFR 610.20.is obtained from scientifically-based method development and optimization studies. Validation 260data must be generated under an protocol approved by the sponsor following current good261manufacturing practices with the description of methodology of each characteristic test and262predetermined and justified acceptance criteria, using qualified instrumentation operated under 263current good manufacturing practices conditions.13 Protocols for both drug substance and264product analytes or mixture of analytes in respective matrices should be developed and executed. 265266ICH Q2(R1) is considered the primary reference for recommendations and definitions on267validation characteristics for analytical procedures. The FDA Reviewer Guidance: Validation of 268Chromatographic Methods is available as well.269270B.Validation Characteristics271272Although not all of the validation characteristics are applicable for all types of tests, typical273validation characteristics are:274275•Specificity276•Linearity277•Accuracy278•Precision (repeatability, intermediate precision, and reproducibility)279•Range280•Quantitation limit281•Detection limit282283If a procedure is a validated quantitative analytical procedure that can detect changes in a quality 284attribute(s) of the drug substance and drug product during storage, it is considered a stability285indicating assay. To demonstrate specificity of a stability-indicating assay, a combination of286challenges should be performed. Some challenges include the use of samples spiked with target 287analytes and all known interferences; samples that have undergone various laboratory stress288conditions; and actual product samples (produced by the final manufacturing process) that are289either aged or have been stored under accelerated temperature and humidity conditions.290291As the holder of the NDA, ANDA, or BLA, you must:14 (1) submit the data used to establish292that the analytical procedures used in testing meet proper standards of accuracy and reliability, 293and (2) notify the FDA about each change in each condition established in an approved294application beyond the variations already provided for in the application, including changes to 295analytical procedures and other established controls.296297The submitted data should include the results from the robustness evaluation of the method,298which is typically conducted during method development or as part of a planned validation299study.1530013 See 21 CFR 211.165(e); 21 CFR 314.50 (d), and for biologics see 21 CFR 601.2(a), 601.2(c), and 601.12(a).14 For drugs see 21 CFR 314.50 (d), 314.70(d), and for biologics see 21 CFR 601.2(a), 601.2(c), and 601.12(a). For aBLA, as discussed below, you must obtain prior approval from FDA before implementing a change in analyticalmethods if those methods are specified in FDA regulations15 See section III and ICH Q2(R1).pendial Analytical Procedures302303The suitability of an analytical procedure (e.g., USP/NF, the AOAC International Book of304Methods, or other recognized standard references) should be verified under actual conditions of 305use.16 Compendial general chapters, which are complex and mention multiple steps and/or306address multiple techniques, should be rationalized for the intended use and verified. Information 307to demonstrate that USP/NF analytical procedures are suitable for the drug product or drug308substance should be included in the submission and generated under a verification protocol.309310The verification protocol should include, but is not limited to: (1) compendial methodology to 311be verified with predetermined acceptance criteria, and (2) details of the methodology (e.g.,312suitability of reagent(s), equipment, component(s), chromatographic conditions, column, detector 313type(s), sensitivity of detector signal response, system suitability, sample preparation and314stability). The procedure and extent of verification should dictate which validation characteristic 315tests should be included in the protocol (e.g., specificity, LOD, LOQ, precision, accuracy, etc.). 316Considerations that may influence what characteristic tests should be in the protocol may depend 317on situations such as whether specification limits are set tighter than compendial acceptance318criteria, or RT or RRT profiles are changing in chromatographic methods because of the319synthetic route of drug substance or differences in manufacturing process or matrix of drug320product. Robustness studies of compendial assays do not need to be included, if methods are 321followed without deviations.322323324VII.STATISTICAL ANALYSIS AND MODELS325326A.Statistics327328Statistical analysis of validation data can be used to evaluate validation characteristics against 329predetermined acceptance criteria. All statistical procedures and parameters used in the analysis 330of the data should be based on sound principles and appropriate for the intended evaluation.331Reportable statistics of linear regression analysis R (correlation coefficient), R square332(coefficient of determination), slope, least square, analysis of variance (ANOVA), confidence 333intervals, etc., should be provided with justification.For information on statistical techniques 334used in making comparisons, as well as other general information on the interpretation and335treatment of analytical data, appropriate literature or texts should be consulted.17336337B.Models338339Some analytical methods might use chemometric and/or multivariate models. When developing 340these models, you should include a statistically adequate number and range of samples for model 341development and comparable samples for model validation. Suitable software should be used for 342data analysis. Model parameters should be deliberately varied to test model robustness.34334416 See 21 CFR 211.194(a)(2) and USP General Chapter <1226> Verification of Compendial Procedures.17 See References section for examples including USP <1010> Analytical Data – Interpretation and Treatment.。

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No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of SAE.TO PLACE A DOCUMENT ORDER: Tel: 877-606-7323 (inside USA and Canada)Tel: +1 724-776-4970 (outside USA)Fax: 724-776-0790Email: CustomerService@SAE WEB ADDRESS: SAE values your input. To provide feedback on this Technical Report, please visit/technical/standards/AMS2241SAEROSPACEMATERIAL SPECIFICATION AMS2241™REV. SIssued 1945-05Reaffirmed 2012-10Revised 2016-01Superseding AMS2241RTolerances, Corrosion and Heat-Resistant Steel, Iron Alloy,Titanium, and Titanium Alloy Bars and WireRATIONALEAMS2241S revises tolerances for machined bars (2.1.4, Table 3), clarifies the intent of precision ground or precision polished rounds (2.1.6, Table 5), and is a Five Year Review and update of this specification.1. SCOPEThis specification covers established manufacturing tolerances applicable to corrosion and heat-resistant steel, iron alloy, titanium, and titanium alloy bars and wire. These tolerances apply to all conditions, unless otherwise noted. The term “excl” is used to apply only to the higher figure of the specified range.2. DIAMETER, THICKNESS, AND WIDTHSpecified dimensions apply to diameter of rounds, to distance between parallel sides of hexagons and squares, and separately to width and thickness of rectangles.2.1 Cold Finished2.1.1 Cold Drawn Rounds, Squares, Hexagons, and Octagons (see 2.1.3)Shall be as shown in Table 1.Table 1A - Tolerances, diameter or thickness, inch/pound unitsSpecified Diameter or ThicknessInches Tolerance, InchPlus and Minus(see 2.1.1.1)RoundsTolerance, InchMinus OnlySquares, Hexagons,and Octagons(see 2.1.1.2)Over 0.500 to 1.000, excl 0.002 0.0041.000 0.0025 0.004 Over 1.000 to 1.500, excl 0.0025 0.0061.500 to2.000, incl 0.003 0.006 Over 2.000 to3.000, incl 0.003 0.008 Over 3.000 to4.000, incl 0.003 0.010 Table 1B - Tolerances, diameter or thickness, SI unitsSpecified Diameter or ThicknessMillimeters Tolerance, MillimeterPlus and Minus(see 2.1.1.1)RoundsTolerance, MillimeterMinus OnlySquares, Hexagons,and Octagons(see 2.1.1.2)Over 12.50 to 25.00, excl 0.05 0.1025.00 0.062 0.10Over 25.00 to 37.50, excl 0.062 0.1537.50 to 50.00, incl 0.08 0.15Over 50.00 to 75.00, incl 0.08 0.20Over 75.00 to 100.00, incl 0.08 0.252.1.1.1 Size tolerances for round bars are plus and minus as shown in Table 1. When required, however, they may bespecified all plus and nothing minus, or all minus and nothing plus, or any combination of plus and minus, if the total spread in size tolerance for a specified size is not less than the total spread shown in Table 1.2.1.1.2 For titanium and titanium alloys, the difference among the three measurements of the distance between oppositefaces of hexagons shall be not greater than one-half the size tolerance and the difference between the measurements of the distance between opposite faces of octagons shall be not greater than the size tolerance.2.1.2 Cold Drawn Flats (see 2.1.3)Shall be as shown in Table 2.Table 2A - Tolerances, thickness and width, inch/pound unitsSpecified WidthInchesThicknessTolerance, InchPlus and MinusWidthTolerance, InchPlus and Minus0.125 to 0.250, incl 0.002 0.004 Over 0.250 to 1.000, incl 0.002 0.002 Over 1.000 to 2.000, incl 0.003 0.003 Over 2.000 to 3.000, incl 0.004 0.004 Over 3.000 to 4.500, incl 0.005 0.005Table 2B - Tolerances, thickness and width, SI unitsSpecified Width MillimetersThicknessTolerance, MillimeterPlus and MinusWidthTolerance, MillimeterPlus and Minus3.00 to 6.00, incl 0.05 0.10Over 6.00 to 25.00, incl 0.05 0.05Over 25.00 to 50.00, incl 0.08 0.08Over 50.00 to 75.00, incl 0.10 0.10Over 75.00 to 115.00, incl 0.12 0.12If cold drawn bars are ordered heat treated or heat treated and pickled after cold finishing, tolerances shall be double those of Table 1 and Table 2.2.1.3 Machined or Turned Bars2.1.3.1 RoundsTolerances for machined or turned round bars 0.375 inch (9.53 mm) and over in specified diameter or thickness are shown in Table 3. Bars up to 0.375 inch (9.53 mm), exclusive, in specified diameter or thickness are commonly supplied centerless ground.Table 3A - Tolerances, machined or turned bars, inch/pound unitsSpecified Diameter or ThicknessInches Toleranceplus onlyInchOut of RoundInch0.375 to 2.000, incl 0.016 0.008 Over 2.000 to 4.000, incl 0.031 0.016Over 4.000 to 4.500, incl Over 4.500 to 5.500, incl Over 5.500 to 6.500, incl Over 6.500 to 8.000, incl Over 8.000 to 12.000, incl Over 12.000 to 15.000, incl Over 15.000 to 25.000, incl 0.0620.0780.1250.1560.1870.2190.2500.0460.0580.0700.0850.0940.1090.125Table 3B - Tolerances, machined or turned bars, SI unitsSpecified Diameter or ThicknessMillimeters Toleranceplus onlyMillimeterOut of RoundMillimeter9.525 to 50.80, incl 0.406 0.203 Over 50.80 to 101.6, incl 0.787 0.406Over 101.6 to 115.0, incl Over 115.0 to 140.0, incl Over 140.0 to 165.0, incl Over 165.0 to 200.0, incl Over 200.0 to 300.0, incl Over 300.0 to 400.0, incl Over 400.0 to 625.0, incl 1.6002.0003.0004.0004.8005.5006.5001.2001.5001.8002.2002.4002.8003.2002.1.3.2FlatsTolerances for machined flat bars shall be as agreed upon by purchaser and producer. 2.1.4Centerless Ground or Polished Round BarsTolerances for centerless ground or polished bars 0.125 to 4.062 inches (3.18 to 103.17 mm), inclusive, in specified diameter are shown in Table 4. Bars over 4.062 inches (103.17 mm) specified diameter are commonly supplied machined.Table 4A - Tolerances, centerless-ground or polished bars, inch/pound unitsSpecified Diameter InchesTolerance plus or minusInch Out of RoundInch 0.125 to 0.3125, excl 0.001 0.001 0.3125 to 0.500, excl 0.0015 0.0015 0.500 to 1.000, excl 0.002 0.002 1.000 to 1.500, incl 0.0025 0.0025 Over 1.500 to 3.250, incl 0.003 0.003 Over 3.250 to 4.0620.0050.005Table 4B - Tolerances, centerless-ground or polished bars, SI units Specified Diameter Millimeters Tolerance plus or minus Millimeter Out of Round Millimeter 3.175 t o 7.938 , excl 0.025 0.025 7.938 t o 12.70, excl 0.038 0.038 12.70 to 25.40, excl 0.051 0.051 25.40 to 38.10, incl 0.064 0.064 Over 38.10 to 82.55, incl 0.076 0.076 Over 82.55 to 103.20.1270.1272.1.5Precision Ground or Precision Polished Round BarsShall be as shown in Table 5.Table 5A - Tolerances, precision ground or precision polished rounds, inch/pound unitsSpecified DiameterInchesTolerance Inch Minus only Up to 1.500, incl0.001 Over 1.500 to 2.500, excl 0.0015 Over 2.500 to 3.000, incl 0.002 Over 3.000 to 4.000, incl0.003Table 5B - Tolerances, precision ground or precision polished rounds, SI unitsSpecified DiameterMillimetersTolerance Millimeter Minus only Up to 38.1, incl0.03 Over 38.1 to 63.5, excl0.04 63.5 to 76.2, incl 0.05 Over 76.2 to 101.6, incl0.082.2 Cold Drawn Wire2.2.1 Rounds, Squares, Hexagons, and Octagons (see 2.2.1.1)Shall be as shown in Table 6.Table 6A - Tolerances, diameter or thickness, inch/pound unitsSpecified Diameter or ThicknessInchTolerance, InchPlus and MinusRounds and SquaresTolerance, InchMinus OnlyHexagons and Octagons(see 2.2.1.3)0.003 to 0.0048, excl 0.0001 -- 0.0048 to 0.008, excl 0.0002 -- 0.008 to 0.012, excl 0.0003 -- 0.012 to 0.024, excl 0.0004 (see 2.2.1.2) -- 0.024 to 0.033, excl 0.0005 (see 2.2.1.2) -- 0.033 to 0.044, excl 0.0008 -- 0.044 to 0.125, excl 0.001 -- 0.125 to 0.3125, excl 0.001 0.002 0.3125 to 0.500, excl 0.0015 0.003 0.500 0.002 0.004Table 6B - Tolerances, diameter or thickness, SI unitsSpecified Diameter or ThicknessMillimeters Tolerance, MillimeterPlus and MinusRounds and SquaresTolerance, MillimeterMinus OnlyHexagons and Octagons(see 2.2.1.3)0.08 to 0.12, excl 0.002 --0.12 to 0.20, excl 0.005 --0.20 to 0.30, excl 0.008 --0.30 to 0.60, excl 0.010 (see 2.2.1.2) --0.60 to 0.85, excl 0.012 (see 2.2.1.2) --0.85 to 1.10, excl 0.020 --1.10 to 3.15, excl 0.02 --3.15 to 7.80, excl 0.02 0.057.80 to 12.50, excl 0.038 0.0812.50 0.05 0.102.2.1.1 If cold drawn wire is ordered heat treated or heat treated and pickled after cold finishing, tolerances shall bedouble those of Table 6 for nominal sizes 0.024 inch (0.60 mm) and over.2.2.1.2 For titanium and titanium alloys, tolerances for these sizes are ±0.00075 inch (0.019 mm).2.2.1.3 For titanium and titanium alloys, the difference among the three measurements of the distance between oppositefaces of hexagons shall be not greater than one-half the size tolerance, and the difference among the four measurements of the distance between opposite faces of octagons shall be not greater than one-half the size tolerance.2.2.1.4 Out-of-RoundRound wire shall not be out-of-round by more than one-half of the total tolerance shown in Table 6.2.2.2 FlatsShall be as shown in Table 7.Table 7A - Tolerances, thickness, inch/pound unitsSpecified ThicknessInch Tolerance, Inch Plus and MinusUp to 0.029, excl 0.001 0.029 to 0.035, excl 0.0015 0.035 to 0.1875, excl 0.002 Table 7B - Tolerances, thickness, SI unitsSpecified Thickness Millimeters Tolerance, Millimeter Plus and MinusUp to 0.70, excl 0.020.70 to 0.90, excl 0.0380.90 to 4.75, excl 0.042.2.2.1 Width tolerances shall be ± 0.005 inch (0.12 mm) for nominal widths 0.0625 to 0.375 inch (1.59 to 9.53 mm),exclusive.2.3 Hot Finished Bars2.3.1 Hot Rolled2.3.1.1 Rounds and SquaresShall be as shown in Table 8. Out-of-round is the difference between the maximum and minimum diameters of the bar, measured at the same cross section. Out-of-square is the difference in the two dimensions at the same cross section of a square bar, each dimension being the distance between opposite faces.Table 8A - Tolerances, diameter or thickness, inch/pound unitsSpecifiedDiameter or ThicknessInches Tolerance, InchPlusTolerance, InchMinusOut-of-Roundor Out-or-SquareInch0.250 to 0.3125, incl 0.005 0.005 0.008 Over 0.3125 to 0.4375, incl 0.006 0.006 0.009 Over 0.4375 to 0.625, incl 0.007 0.007 0.010 Over 0.625 to 0.875, incl 0.008 0.008 0.012 Over 0.875 to 1.000, incl 0.009 0.009 0.013 Over 1.000 to 1.125, incl 0.010 0.010 0.015 Over 1.125 to 1.250, incl 0.011 0.011 0.016 Over 1.250 to 1.375, incl 0.012 0.012 0.018 Over 1.375 to 1.500, incl 0.014 0.014 0.021 Over 1.500 to 2.000, incl 1/64 1/64 0.023 Over 2.000 to 2.500, incl 1/32 0 0.023 Over 2.500 to 3.500, incl 3/64 0 0.035 Over 3.500 to 4.500, incl 1/16 0 0.046 Over 4.500 to 5.500, incl 5/64 0 0.058 Over 5.500 to 6.500, incl 1/8 0 0.070 Over 6.500 to 8.000, incl 5/32 0 0.085Table 8B - Tolerances, diameter or thickness, SI unitsSpecified Diameter or ThicknessMillimeters Tolerance,MillimetersPlusTolerance, MillimeterMinusOut-of-Roundor Out-or-SquareMillimeters6.25 to7.80, incl 0.12 0.12 0.20Over 7.80 to 11.00, incl 0.15 0.15 0.22 Over 11.00 to 15.75, incl 0.18 0.18 0.25 Over 15.75 to 22.00, incl 0.20 0.20 0.30 Over 22.00 to 25.00, incl 0.22 0.22 0.32 Over 25.00 to 28.00, incl 0.25 0.25 0.38 Over 28.00 to 31.00, incl 0.28 0.28 0.40 Over 31.00 to 34.00, incl 0.30 0.30 0.45 Over 34.00 to 37.50, incl 0.35 0.35 0.52 Over 37.50 to 50.00, incl 0.40 0.40 0.58 Over 50.00 to 62.50, incl 0.80 0 0.58 Over 62.50 to 87.50, incl 1.20 0 0.88 Over 87.50 to 115.00 incl 1.60 0 1.15 Over 115.00 to 138.00 incl 2.00 0 1.45 Over 138.00 to 165.00 incl 3.15 0 1.75 Over 165.00 to 200.00, incl 3.90 0 2.12 2.3.1.2 Hexagons and OctagonsShall be as shown in Table 9.Table 9A - Tolerances, thickness, inch/pound unitsSpecified ThicknessInches Tolerance, InchPlus and MinusMaximum Difference3 MeasurementsHexagons OnlyInch0.250 to 0.500, incl 0.007 0.011 Over 0.500 to 1.000, incl 0.010 0.015 Over 1.000 to 1.500, incl 0.021 0.025 Over 1.500 to 2.000, incl 1/32 1/32 Over 2.000 to 2.500, incl 3/64 3/64 Over 2.500 to 3.500, incl 1/16 1/16Table 9B - Tolerances, thickness, SI unitsSpecified Thickness Millimeters Tolerance, MillimetersPlus and MinusMaximum Difference3 MeasurementsHexagons OnlyMillimeters6.25 to 12.50, incl 0.18 0.28 Over 12.50 to 25.00, incl 0.25 0.38 Over 25.00 to 37.50, incl 0.52 0.62 Over 37.50 to 50.00, incl 0.78 0.78 Over 50.00 to 62.50, incl 1.18 1.18 Over 62.50 to 87.50, incl 1.56 1.56Shall be as shown in Tables 10 and 11.Table 10A - Tolerances, thickness, inch; for thickness ranges, inches, inch/pound unitsSpecified Width,Inches 0.125 to0.500,inclPlus &MinusOver0.500 to1.000,inclPlus &MinusOver1.000 to2.000,inclPlus &MinusOver2.000 to4.000,inclPlusOver2.000 to4.000,inclMinusOver4.000 to6.000,inclPlusOver4.000 to6.000,inclMinusOver6.000 to8.000,inclPlusOver6.000 to8.000,inclMinusUp to 1.000, incl 0.008 0.010 - - - - - - - Over 1.000 to 2.000, incl 0.012 0.015 0.031 - - - - - - Over 2.000 to 4.000, incl 0.015 0.020 0.031 0.062 0.031 - - - - Over 4.000 to 6.000, incl 0.015 0.020 0.031 0.062 0.031 0.093 0.062 - - Over 6.000 to 8.000, incl 0.016 0.025 0.031 0.062 0.031 0.093 0.062 0.125 0.156 Over 8.000 to 10.000, incl 0.021 0.031 0.031 0.062 0.031 0.093 0.062 0.125 0.156 Table 10B - Tolerances, thickness, millimeters; for thickness ranges, millimeters, SI unitsSpecified Width, Millimeters 3.10 to12.50,inclPlus &MinusOver12.50 to25.00,inclPlus &MinusOver25.00 to50.00,inclPlus &MinusOver50.00 to100.00,inclPlusOver50.00 to100.00,inclMinusOver100.00 to150.00,inclPlusOver100.00 to150.00,inclMinusOver150.00 to200.00,inclPlusOver150.00 to200.00,inclMinusUp to 25.00, incl 0.20 0.25 - - - - - - - Over 25.00 to 50.00, incl 0.30 0.38 0.78 - - - - - - Over 50.00 to 100.00, incl 0.38 0.50 0.78 1.55 0.78 - - - - Over 100.00 to 150.00, incl 0.38 0.50 0.78 1.55 0.78 2.32 1.55 - - Over 150.00 to 200.00, incl 0.40 0.62 0.78 1.55 0.78 2.32 1.55 3.12 3.90 Over 200.00 to 250.00, incl 0.52 0.78 0.78 1.55 0.78 2.32 1.55 3.12 3.90Table 11A - Tolerances, width, inch/pound unitsSpecified Width,Inches Tolerance, InchPlusTolerance, InchMinusUp to 1.000, incl 0.015 0.015 Over 1.000 to 2.000, incl 0.031 0.031 Over 2.000 to 4.000, incl 0.062 0.031 Over 4.000 to 6.000, incl 0.093 0.062 Over 6.000 to 8.000, incl 0.125 0.156 Over 8.000 to 10.000, incl 0.156 0.187 Table 11B - Tolerances, width, SI unitsSpecified Width, Millimeters Tolerance,MillimetersPlusTolerance,MillimetersMinusUp to 25.00, incl 0.38 0.38 Over 25.00 to 50.00, incl 0.78 0.78 Over 50.00 to 100.00, incl 1.55 0.78 Over 100.00 to 150.00, incl 2.32 1.55 Over 150.00 to 200.00, incl 3.12 3.90 Over 200.00 to 250.00, incl 3.90 4.68Tolerances shall be as agreed upon by purchaser and producer.3. LENGTHTolerances in Table 12 and Table 13 shall apply only when exact lengths are ordered.3.1 Hot or Cold Finished BarsShall be as shown in Table 12.Table 12A - Tolerances, length, inches, plus only;for length ranges, feet, inch/pound unitsSpecifiedDiameter of Rounds,Thickness of Squares,Hexagons, and Octagons, Width of FlatsInchesLengthUp to 12 feet,Incl (inches)LengthOver 12 to 25 feet,Incl (inches)Up to 2.000, incl 1/2 3/4 Over 2.000 to 4.000, incl 3/4 1 Over 4.000 to 6.000, incl 1 1-1/4 Over 6.000 to 9.000, incl 1-1/4 1-1/2 Over 9.000 to 12.000, incl 1-1/2 2 Table 12B - Tolerances, length, millimeters, plus only;for length ranges, millimeters, SI unitsSpecifiedDiameter of Rounds,Thickness of Squares,Hexagons, and Octagons, Width of FlatsMillimetersLengthUp to 3600,InclLengthOver 3600 to 7500,InclUp to 50.00, incl 12.5 19.0Over 50.00 to 100.00, incl 19.0 25.0Over 100.00 to 150.00, incl 25.0 31.0Over 150.00 to 225.00, incl 31.0 37.5Over 225.00 to 300.00, incl 37.5 50.0 3.2 Wire3.2.1 Round and Shape, Straightened and Cut, Exact Length ReshearedShall be as shown in Table 13.Table 13A - Tolerances, length, inch, plus only;for length ranges, feet, inch/pound unitsSpecifiedDiameter of Rounds,Thickness of Squares, Hexagons, and Octagons,InchesLengthUp to 3 feet,Excl (inches)Length3 to 12 feet,Incl (inches)LengthOver 12 to 25 feet,Incl (inches)Up to 0.125, incl 1/16 1/16 1/8 Over 0.125 to 0.500, incl 1/32 (see 3.2.1.1) 1/16 1/8Table 13B - Tolerances, length, millimeters, plus only;for length ranges, millimeters, SI units SpecifiedDiameter of Rounds,Thickness of Squares, Hexagons, and Octagons,MillimetersLengthUp to 900,ExclLength900 to 3600,InclLengthOver 3600 to 7500,InclUp to 3.12, incl 1.6 1.6 3.1Over 3.12 to 12.50, incl 0.8 (see 3.2.1.1) 1.6 3.13.2.1.1 For titanium and titanium alloys, tolerance for these sizes is +1/16 inch, -0 inch (+1.6 mm, -0 mm).4. STRAIGHTNESS4.1 Cold FinishedBars shall be of such straightness that the maximum curvature (depth of arc) shall not exceed 0.0625 inch (1.59 mm) in any 5 feet (1500 mm) of length, but shall not exceed 0.0125 inch (1.04 mm) x length in feet (meters).4.2 Hot Finished or Heat TreatedUnless otherwise ordered, bars shall be of such straightness that the maximum curvature (depth of arc) shall not exceed 0.125 inch (3.13 mm) in any 5 feet (1500 mm) of length, but shall not exceed 0.025 inch (2.08 mm) x length in feet (meters).5. SPECIAL TOLERANCES5.1 Across Corners, HexagonsThe requirements shown in Table 14 apply to cold finished hexagons, when specified.Table 14A - Minimum distance across corners, inch/pound unitsSpecified ThicknessInches Distance Across CornersInches0.1875 0.2188 0.250 0.3125 0.375 0.210 0.245 0.280 0.351 0.4230.4375 0.500 0.5625 0.5938 0.625 0.492 0.564 0.635 0.670 0.7060.6875 0.750 0.8125 0.875 0.9375 0.775 0.848 0.9190.9901.0621.000 1.0625 1.133 1.203SAE INTERNATIONAL AMS2241™S Page 11 of 11Table 14B - Minimum distance across corners, SI unitsSpecified Thickness Millimeters Distance Across CornersMillimeters4.505.506.508.009.5011.0012.5014.0015.0016.0017.5019.0020.50 22.0024.0025.00 27.005.046.177.318.97 10.67 12.3714.0515.7516.8818.0119.71 21.4123.1124.8127.0828.21 30.426. NOTES6.1 Revision IndicatorA change bar (l) located in the left margin is for the convenience of the user in locating areas where technical revisions, not editorial changes, have been made to the previous issue of this document. An (R) symbol to the left of the document title indicates a complete revision of the document, including technical revisions. Change bars and (R) are not used in original publications, nor in documents that contain editorial changes only.6.2 Terms used in AMS are clarified in ARP1917.6.3 Dimensions and properties in inch/pound units and the Fahrenheit temperatures are primary; dimensions andproperties in SI units and the Celsius temperatures are shown as the approximate equivalents of the primary units and are presented only for information.PREPARED BY AMS COMMITTEE “F”。

【转载】自Tim Berners-Lee于1998年提出了语义网(the Semantic Web)的概念之后，就一直成为人们讨论与研究的热点。

当前国际上关于语义网的研究刚刚处于起步阶段，而我国对语义网的研究不论是从标准规范、系统试验、研究深度，还是从规模层次、具体应用方面都相对落后。

另人欣慰的是，我国学者已经认识到了语义网及其相关技术对未来互联网发展的影响，并开始着手研究语义网及其相关的关键技术与应用。

本文将从以下四个方面对我国语义网研究作综合述评： (1)基本情况，对当前国内语义网的研究情况做一总体介绍；(2)体系结构，即对语义网体系结构研究的情况；(3)关键技术，讨论对 RDF(Resource Description Framework，即资源描述框架)和Ontology(本体或本体论)的研究情况；(4)试验与应用，即当前针对语义网或利用其中的关键技术所做的具体试验与应用。

最后，在对以上四个方面的情况进行综合述评的基础上总结当前国内语义网研究的特点和存在的主要问题并指出今后主要的研究方向与重点。

1 基本概况当前对语义网的概念还没有形成统一的定义，对语义网的理解表述不一。

如语义网是“第三代Web，其目标是实现机器自动处理信息，它提供诸如信息代理、搜索代理、信息过滤等智能服务”[1]；语义网“不同于现存的万维网，其数据主要供人类使用，新一代WWW中将提供也能为计算机所处理的数据，这将使得大量的智能服务成为可能”[2]；语义网研究活动的目标是“开发一系列计算机可理解和处理的表达语义信息的语言和技术，以支持网络环境下广泛有效的自动推理”[3]。

语义网的创始人Tim Berners-Lee对语义网的定义如下：“语义网是一个网，它包含了文档或文档的一部分，描述了事物间的明显关系，且包含语义信息，以利于机器的自动处理”［4］。

尽管对语义网的理解与描述不同，但仍能从这些描述与理解中看出语义网的一些基本特征：(1)语义网不同于现在WWW，它是现有WWW的扩展与延伸；(2) 现有的WWW是面向文档而语义网则面向文档所表示的数据；(3) 语义网将更利于计算机“理解与处理”，并将具有一定的判断、推理能力。

IEEE Std1241-2000 IEEE Standard for Terminology and Test Methods for Analog-to-Digital ConvertersSponsorWaveform Measurement and Analysis Technical Committeeof theof theIEEE Instrumentation and Measurement SocietyApproved7December2000IEEE-SA Standards BoardAbstract:IEEE Std1241-2000identifies analog-to-digital converter(ADC)error sources and provides test methods with which to perform the required error measurements.The information in this standard is useful both to manufacturers and to users of ADCs in that it provides a basis for evaluating and comparing existing devices,as well as providing a template for writing specifications for the procurement of new ones.In some applications,the information provided by the tests described in this standard can be used to correct ADC errors, e.g.,correction for gain and offset errors.This standard also presents terminology and definitions to aid the user in defining and testing ADCs.Keywords:ADC,A/D converter,analog-to-digital converter,digitizer,terminology,test methodsThe Institute of Electrical and Electronics Engineers,Inc.3Park Avenue,New York,NY10016-5997,USACopyrightß2001by the Institute of Electrical and Electronics Engineers,Inc.All rights reserved. Published 13 June 2001. 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To arrange for payment of licensing fee,please contact Copyright Clearance Center,Customer Service,222Rosewood Drive,Danvers,MA01923USA;(978)750-8400.Permission to photocopy portions of any individual standard for educational classroom use can also be obtained through the Copyright Clearance Center.Introduction(This introduction is not a part of IEEE Std1241-2000,IEEE Standard for Terminology and Test Methods for Analog-to-Digital Converters.)This standard defines the terms,definitions,and test methods used to specify,characterize,and test analog-to-digital converters(ADCs).It is intended for the following:—Individuals and organizations who specify ADCs to be purchased—Individuals and organizations who purchase ADCs to be applied in their products —Individuals and organizations whose responsibility is to characterize and write reports on ADCs available for use in specific applications—Suppliers interested in providing high-quality and high-performance ADCs to acquirersThis standard is designed to help organizations and individuals—Incorporate quality considerations during the definition,evaluation,selection,and acceptance of supplier ADCs for operational use in their equipment—Determine how supplier ADCs should be evaluated,tested,and accepted for delivery to end users This standard is intended to satisfy the following objectives:—Promote consistency within organizations in acquiring third-party ADCs from component suppliers—Provide useful practices on including quality considerations during acquisition planning —Provide useful practices on evaluating and qualifying supplier capabilities to meet user requirements—Provide useful practices on evaluating and qualifying supplier ADCs—Assist individuals and organizations judging the quality and suitability of supplier ADCs for referral to end usersSeveral standards have previously been written that address the testing of analog-to-digital converters either directly or indirectly.These include—IEEE Std1057-1994a,which describes the testing of waveform recorders.This standard has been used as a guide for many of the techniques described in this standard.—IEEE Std746-1984[B16]b,which addresses the testing of analog-to-digital and digital-to-analog converters used for PCM television video signal processing.—JESD99-1[B21],which deals with the terms and definitions used to describe analog-to-digital and digital-to-analog converters.This standard does not include test methods.IEEE Std1241-2000for analog-to-digital converters is intended to focus specifically on terms and definitions as well as test methods for ADCs for a wide range of applications.a Information on references can be found in Clause2.b The numbers in brackets correspond to those in the bibliography in Annex C.As of October2000,the working group had the following membership:Steve Tilden,ChairPhilip Green,Secretary&Text EditorW.Thomas Meyer,Figures EditorPasquale Arpaia Giovanni Chiorboli Tom Linnenbrink*B.N.Suresh Babu Pasquale Daponte Solomon MaxAllan Belcher David Hansen Carlo MorandiDavid Bergman Fred Irons Bill PetersonEric Blom Dan Kien Pierre-Yves RoyDan Knierim*Chairman,TC-10CommitteeContributions were also made in prior years by:Jerry Blair John Deyst Norris NahmanWilliam Boyer Richard Kromer Otis M.SolomonSteve Broadstone Yves Langard T.Michael SoudersThe following members of the balloting committee voted on this standard:Pasquale Arpaia Pasquale Daponte W.Thomas MeyerSuresh Babu Philip Green Carlo MorandiEric Blom Fred Irons William E.PetersonSteven Broadstone Dan Knierim Pierre-Yves RoyGiovanni Chiorboli T.E.Linnenbrink Steven J.TildenSolomon MaxWhen the IEEE-SA Standards Board approved this standard on21September2000,it had the following membership:Donald N.Heirman,ChairJames T.Carlo,Vice-ChairJudith Gorman,SecretarySatish K.Aggarwal James H.Gurney James W.MooreMark D.Bowman Richard J.Holleman Robert F.MunznerGary R.Engmann Lowell G.Johnson Ronald C.PetersenHarold E.Epstein Robert J.Kennelly Gerald H.Petersonndis Floyd Joseph L.Koepfinger*John B.PoseyJay Forster*Peter H.Lips Gary S.RobinsonHoward M.Frazier L.Bruce McClung Akio TojoRuben D.Garzon Daleep C.Mohla Donald W.Zipse*Member EmeritusAlso included are the following nonvoting IEEE-SA Standards Board liaisons:Alan Cookson,NIST RepresentativeDonald R.Volzka,TAB RepresentativeDon MessinaIEEE Standards Project EditorContents1.Overview (1)1.1Scope (1)1.2Analog-to-digital converter background (2)1.3Guidance to the user (3)1.4Manufacturer-supplied information (5)2.References (7)3.Definitions and symbols (7)3.1Definitions (7)3.2Symbols and acronyms (14)4.Test methods (18)4.1General (18)4.2Analog input (41)4.3Static gain and offset (43)4.4Linearity (44)4.5Noise(total) (51)4.6Step response parameters (63)4.7Frequency response parameters (66)4.8Differential gain and phase (71)4.9Aperture effects (76)4.10Digital logic signals (78)4.11Pipeline delay (78)4.12Out-of-range recovery (78)4.13Word error rate (79)4.14Differential input specifications (81)4.15Comments on reference signals (82)4.16Power supply parameters (83)Annex A(informative)Comment on errors associated with word-error-rate measurement (84)Annex B(informative)Testing an ADC linearized with pseudorandom dither (86)Annex C(informative)Bibliography (90)IEEE Standard for Terminology and Test Methods for Analog-to-Digital Converters1.OverviewThis standard is divided into four clauses plus annexes.Clause1is a basic orientation.For further investigation,users of this standard can consult Clause2,which contains references to other IEEE standards on waveform measurement and relevant International Standardization Organization(ISO) documents.The definitions of technical terms and symbols used in this standard are presented in Clause3.Clause4presents a wide range of tests that measure the performance of an analog-to-digital converter.Annexes,containing the bibliography and informative comments on the tests presented in Clause4,augment the standard.1.1ScopeThe material presented in this standard is intended to provide common terminology and test methods for the testing and evaluation of analog-to-digital converters(ADCs).This standard considers only those ADCs whose output values have discrete values at discrete times,i.e., they are quantized and sampled.In general,this quantization is assumed to be nominally uniform(the input–output transfer curve is approximately a straight line)as discussed further in 1.3,and the sampling is assumed to be at a nominally uniform rate.Some but not all of the test methods in this standard can be used for ADCs that are designed for non-uniform quantization.This standard identifies ADC error sources and provides test methods with which to perform the required error measurements.The information in this standard is useful both to manufacturers and to users of ADCs in that it provides a basis for evaluating and comparing existing devices,as well as providing a template for writing specifications for the procurement of new ones.In some applications, the information provided by the tests described in this standard can be used to correct ADC errors, e.g.,correction for gain and offset errors.The reader should note that this standard has many similarities to IEEE Std1057-1994.Many of the tests and terms are nearly the same,since ADCs are a necessary part of digitizing waveform recorders.IEEEStd1241-2000IEEE STANDARD FOR TERMINOLOGY AND TEST METHODS 1.2Analog-to-digital converter backgroundThis standard considers only those ADCs whose output values have discrete values at discrete times, i.e.,they are quantized and sampled.Although different methods exist for representing a continuous analog signal as a discrete sequence of binary words,an underlying model implicit in many of the tests in this standard assumes that the relationship between the input signal and the output values approximates the staircase transfer curve depicted in Figure1a.Applying this model to a voltage-input ADC,the full-scale input range(FS)at the ADC is divided into uniform intervals,known as code bins, with nominal width Q.The number of code transition levels in the discrete transfer function is equal to 2NÀ1,where N is the number of digitized bits of the ADC.Note that there are ADCs that are designed such that N is not an integer,i.e.,the number of code transition levels is not an integral power of two. Inputs below thefirst transition or above the last transition are represented by the most negative and positive output codes,respectively.Note,however,that two conventions exist for relating V min and V max to the nominal transition points between code levels,mid-tread and mid-riser.The dotted lines at V min,V max,and(V minþV max)/2indicate what is often called the mid-tread convention,where thefirst transition is Q/2above V min and the last transition is3Q/2,below V max. This convention gets its name from the fact that the midpoint of the range,(V minþV max)/2,occurs in the middle of a code,i.e.,on the tread of the staircase transfer function.The second convention,called the mid-riser convention,is indicated in thefigure by dashed lines at V min,V max,and(V minþV max)/2. In this convention,V min isÀQ from thefirst transition,V max isþQ from the last transition,and the midpoint,(V minþV max)/2,occurs on a staircase riser.The difference between the two conventions is a displacement along the voltage axis by an amount Q/2.For all tests in this standard,this displacement has no effect on the results and either convention may be used.The one place where it does matter is when a device provides or expects user-provided reference signals.In this case the manufacturer must provide the necessary information relating the reference levels to the code transitions.In both conventions the number of code transitions is 2NÀ1and the full-scale range,FSR,is from V min to V max.Even in an ideal ADC,the quantization process produces errors.These errors contribute to the difference between the actual transfer curve and the ideal straight-line transfer curve,which is plotted as a function of the input signal in Figure1b.To use this standard,the user must understand how the transfer function maps its input values to output codewords,and how these output codewords are converted to the code bin numbering convention used in this standard.As shown in Figure1a,the lowest code bin is numbered0, the next is1,and so on up to the highest code bin,numbered(2NÀ1).In addition to unsigned binary(Figure1a),ADCs may use2’s complement,sign-magnitude,Gray,Binary-Coded-Decimal (BCD),or other output coding schemes.In these cases,a simple mapping of the ADC’s consecutive output codes to the unsigned binary codes can be used in applying various tests in this standard.Note that in the case of an ADC whose number of distinct output codes is not an integral power of2(e.g.,a BCD-coded ADC),the number of digitized bits N is still defined,but will not be an integer.Real ADCs have other errors in addition to the nominal quantization error shown in Figure1b.All errors can be divided into the categories of static and dynamic,depending on the rate of change of the input signal at the time of digitization.A slowly varying input can be considered a static signal if its effects are equivalent to those of a constant signal.Static errors,which include the quantization error, usually result from non-ideal spacing of the code transition levels.Dynamic errors occur because of additional sources of error induced by the time variation of the analog signal being sampled.Sources include harmonic distortion from the analog input stages,signal-dependent variations in the time of samples,dynamic effects in internal amplifier and comparator stages,and frequency-dependent variation in the spacing of the quantization levels.1.3Guidance to the user1.3.1InterfacingADCs present unique interfacing challenges,and without careful attention users can experience substandard results.As with all mixed-signal devices,ADCs perform as expected only when the analog and digital domains are brought together in a well-controlled fashion.The user should fully understand the manufacturer’s recommendations with regard to proper signal buffering and loading,input signal connections,transmission line matching,circuit layout patterns,power supply decoupling,and operating conditions.Edge characteristics for start-convert pulse(s)and clock(s)must be carefully chosen to ensure that input signal purity is maintained with sufficient margin up to the analog input pin(s).Most manufacturers now provide excellent ADC evaluation boards,which demonstrate IN P U T IN P U T(a)Figure 1—Staircase ADC transfer function,having full-scale range FSR and 2N À1levels,corresponding to N -bit quantizationIEEE FOR ANALOG-TO-DIGITAL CONVERTERS Std 1241-2000IEEEStd1241-2000IEEE STANDARD FOR TERMINOLOGY AND TEST METHODS recommended layout techniques,signal conditioning,and interfacing for their ADCs.If the characteristics of a new ADC are not well understood,then these boards should be analyzed or used before starting a new layout.1.3.2Test conditionsADC test specifications can be split into two groups:test conditions and test results.Typical examples of the former are:temperature,power supply voltages,clock frequency,and reference voltages. Examples of the latter are:power dissipation,effective number of bits,spurious free dynamic range (SFDR),and integral non-linearity(INL).The test methods defined in this standard describe the measurement of test results for given test conditions.ADC specification sheets will often give allowed ranges for some test condition(e.g.,power supply ranges).This implies that the ADC will function properly and that the test results will fall within their specified ranges for all test conditions within their specified ranges.Since the test condition ranges are generally specified in continuous intervals,they describe an infinite number of possible test conditions,which obviously cannot be exhaustively tested.It is up to the manufacturer or tester of an ADC to determine from design knowledge and/or testing the effect of the test conditions on the test result,and from there to determine the appropriate set of test conditions needed to accurately characterize the range of test results.For example,knowledge of the design may be sufficient to know that the highest power dissipation(test result)will occur at the highest power supply voltage(test condition),so the power dissipation test need be run only at the high end of the supply voltage range to check that the dissipation is within the maximum of its specified range.It is very important that relevant test conditions be stated when presenting test results.1.3.3Test equipmentOne must ensure that the performance of the test equipment used for these tests significantly exceeds the desired performance of the ADC under ers will likely need to include additional signal conditioning in the form offilters and pulse shapers.Accessories such as terminators, attenuators,delay lines,and other such devices are usually needed to match signal levels and to provide signal isolation to avoid corrupting the input stimuli.Quality testing requires following established procedures,most notably those specified in ISO9001: 2000[B18].In particular,traceability of instrumental calibration to a known standard is important. Commonly used test setups are described in4.1.1.1.3.4Test selectionWhen choosing which parameters to measure,one should follow the outline and hints in this clause to develop a procedure that logically and efficiently performs all needed tests on each unique setup. The standard has been designed to facilitate the development of these test procedures.In this standard the discrete Fourier transform(DFT)is used extensively for the extraction of frequency domain parameters because it provides numerous evaluation parameters from a single data record.DFT testing is the most prevalent technique used in the ADC manufacturing community,although the sine-fit test, also described in the standard,provides meaningful data.Nearly every user requires that the ADC should meet or exceed a minimum signal-to-noise-and-distortion ratio(SINAD)limit for the application and that the nonlinearity of the ADC be well understood.Certainly,the extent to whichthis standard is applied will depend upon the application;hence,the procedure should be tailored for each unique characterization plan.1.4Manufacturer-supplied information1.4.1General informationManufacturers shall supply the following general information:a)Model numberb)Physical characteristics:dimensions,packaging,pinoutsc)Power requirementsd)Environmental conditions:Safe operating,non-operating,and specified performance tempera-ture range;altitude limitations;humidity limits,operating and storage;vibration tolerance;and compliance with applicable electromagnetic interference specificationse)Any special or peculiar characteristicsf)Compliance with other specificationsg)Calibration interval,if required by ISO10012-2:1997[B19]h)Control signal characteristicsi)Output signal characteristicsj)Pipeline delay(if any)k)Exceptions to the above parameters where applicable1.4.2Minimum specificationsThe manufacturer shall provide the following specifications(see Clause3for definitions):a)Number of digitized bitsb)Range of allowable sample ratesc)Analog bandwidthd)Input signal full-scale range with nominal reference signal levelse)Input impedancef)Reference signal levels to be appliedg)Supply voltagesh)Supply currents(max,typ)i)Power dissipation(max,typ)1.4.3Additional specificationsa)Gain errorb)Offset errorc)Differential nonlinearityd)Harmonic distortion and spurious responsee)Integral nonlinearityf)Maximum static errorg)Signal-to-noise ratioh)Effective bitsi)Random noisej)Frequency responsek)Settling timel)Transition duration of step response(rise time)m)Slew rate limitn)Overshoot and precursorso)Aperture uncertainty(short-term time-base instability)p)Crosstalkq)Monotonicityr)Hysteresiss)Out-of-range recoveryt)Word error rateu)Common-mode rejection ratiov)Maximum common-mode signal levelw)Differential input impedancex)Intermodulation distortiony)Noise power ratioz)Differential gain and phase1.4.4Critical ADC parametersTable1is presented as a guide for many of the most common ADC applications.The wide range of ADC applications makes a comprehensive listing impossible.This table is intended to be a helpful starting point for users to apply this standard to their particular applications.Table1—Critical ADC parametersTypical applications Critical ADC parameters Performance issuesAudio SINAD,THD Power consumption.Crosstalk and gain matching.Automatic control MonotonicityShort-term settling,long-term stability Transfer function. Crosstalk and gain matching. Temperature stability.Digital oscilloscope/waveform recorder SINAD,ENOBBandwidthOut-of-range recoveryWord error rateSINAD for wide bandwidthamplitude resolution.Low thermal noise for repeatability.Bit error rate.Geophysical THD,SINAD,long-term stability Millihertz response.Image processing DNL,INL,SINAD,ENOBOut-of-range recoveryFull-scale step response DNL for sharp-edge detection. High-resolution at switching rate. Recovery for blooming.Radar and sonar SINAD,IMD,ENOBSFDROut-of-range recovery SINAD and IMD for clutter cancellation and Doppler processing.Spectrum analysis SINAD,ENOBSFDR SINAD and SFDR for high linear dynamic range measurements.Spread spectrum communication SINAD,IMD,ENOBSFDR,NPRNoise-to-distortion ratioIMD for quantization of smallsignals in a strong interferenceenvironment.SFDR for spatialfiltering.NPR for interchannel crosstalk.Telecommunication personal communications SINAD,NPR,SFDR,IMDBit error rateWord error rateWide input bandwidth channel bank.Interchannel crosstalk.Compression.Power consumption.Std1241-2000IEEE STANDARD FOR TERMINOLOGY AND TEST METHODS2.ReferencesThis standard shall be used in conjunction with the following publications.When the following specifications are superseded by an approved revision,the revision shall apply.IEC 60469-2(1987-12),Pulse measurement and analysis,general considerations.1IEEE Std 1057-1994,IEEE Standard for Digitizing Waveform Recorders.23.Definitions and symbolsFor the purposes of this standard,the following terms and definitions apply.The Authoritative Dictionary of IEEE Standards Terms [B15]should be referenced for terms not defined in this clause.3.1Definitions3.1.1AC-coupled analog-to-digital converter:An analog-to-digital converter utilizing a network which passes only the varying ac portion,not the static dc portion,of the analog input signal to the quantizer.3.1.2alternation band:The range of input levels which causes the converter output to alternate between two adjacent codes.A property of some analog-to-digital converters,it is the complement of the hysteresis property.3.1.3analog-to-digital converter (ADC):A device that converts a continuous time signal into a discrete-time discrete-amplitude signal.3.1.4aperture delay:The delay from a threshold crossing of the analog-to-digital converter clock which causes a sample of the analog input to be taken to the center of the aperture for that sample.COMINT ¼communications intelligence DNL ¼differential nonlinearity ENOB ¼effective number of bits ELINT ¼electronic intelligence NPR ¼noise power ratio INL ¼integral nonlinearity DG ¼differential gain errorSIGINT ¼signal intelligenceSINAD ¼signal-to-noise and distortion ratio THD ¼total harmonic distortion IMD ¼intermodulation distortion SFDR ¼spurious free dynamic range DP ¼differential phase errorTable 1—Critical ADC parameters (continued)Typical applicationsCritical ADC parametersPerformance issuesVideoDNL,SINAD,SFDR,DG,DP Differential gain and phase errors.Frequency response.Wideband digital receivers SIGINT,ELINT,COMINTSFDR,IMD SINADLinear dynamic range fordetection of low-level signals in a strong interference environment.Sampling frequency.1IEC publications are available from IEC Sales Department,Case Postale 131,3rue de Varemb,CH 1211,Gen ve 20,Switzerland/Suisse (http://www.iec.ch).IEC publications are also available in the United States from the Sales Department,American National Standards Institute,25W.43rd Street,Fourth Floor,New York,NY 10036,USA ().2IEEE publications are available from the Institute of Electrical and Electronics Engineers,445Hoes Lane,P.O.Box 1331,Piscataway,NJ 08855-1331,USA (/).。

EudraLexThe Rules Governing Medicinal Products in the European UnionVolume 4EU Guidelines toGood Manufacturing PracticeMedicinal Products for Human and Veterinary UsePart IChapter 1 Quality ManagementPrincipleThe holder of a Manufacturing Authorisation must manufacture medicinal products so as to ensure that they are fit for their intended use, comply with the requirements of the Marketing Authorisation and do not place patients at risk due to inadequate safety, quality or efficacy. The attainment of this quality objective is the responsibility of senior management and requires the participation and commitment by staff in many different departments and at all levels within the company, by the company‟s suppliers and by the distributors. To achiev e the quality objective reliably there must be a comprehensively designed and correctly implemented system of Quality Assurance incorporating Good Manufacturing Practice, Quality Control and Quality Risk Management. It should be fully documented and its effectiveness monitored. All parts of the Quality Assurance system should be adequately resourced with competent personnel, and suitable and sufficient premises, equipment and facilities. There are additional legal responsibilities for the holder of the Manufacturing Authorisation and for the Qualified Person(s).The basic concepts of Quality Assurance, Good Manufacturing Practice, Quality Control and Quality Risk Management are inter-related. They are described here in order to emphasise their relationships and their fundamental importance to the production and control of medicinal products.Quality Assurance1.1 Quality Assurance is a wide-ranging concept, which covers all matters, which individually or collectively influence the quality of a product. It is the sum total of the organised arrangements made with the objective of ensuring that medicinal products are of the quality required for their intended use. Quality Assurance therefore incorporates Good Manufacturing Practice plus other factors outside the scope of this Guide.The system of Quality Assurance appropriate for the manufacture of medicinal products should ensure that:(i) medicinal products are designed and developed in a way that takes account of the requirements of Good Manufacturing Practice;(ii) production and control operations are clearly specified and Good Manufacturing Practice adopted;(iii) managerial responsibilities are clearly specified;(iv) arrangements are made for the manufacture, supply and use of the correct starting and packaging materials;(v) all necessary controls on intermediate products, and any other in-process controls and validations are carried out;(vi) the finished product is correctly processed and checked, according to the defined procedures; (vii) medicinal products are not sold or supplied before a Qualified Person has certified that each production batch has been produced and controlled in accordance with the requirements of the Marketing Authorisation and any other regulations relevant to the production, control and release of medicinal products;(viii) satisfactory arrangements exist to ensure, as far as possible, that the medicinal products are stored, distributed and subsequently handled so that quality is maintained throughout their shelf life;(ix) there is a procedure for Self-Inspection and/or quality audit, which regularly appraises the effectiveness and applicability of the Quality Assurance system.Good Manufacturing Practice for Medicinal Products (GMP)1.2 Good Manufacturing Practice is that part of Quality Assurance which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the Marketing Authorisation or product specification.Good Manufacturing Practice is concerned with both production and quality control. The basic requirements of GMP are that:(i) all manufacturing processes are clearly defined, systematically reviewed in the light of experience and shown to be capable of consistently manufacturing medicinal products of the required quality and complying with their specifications;(ii) critical steps of manufacturing processes and significant changes to the process are validated; (iii) all necessary facilities for GMP are provided including:• a ppropriately qualified and trained personnel;• adequate premises and space;• suitable equipment and services;• correct materials, containers and labels;• approved procedures and instructions;• suitable storage and transport;(iv) instructions and procedures are written in an instructional form in clear and unambiguous language, specifically applicable to the facilities provided;(v) operators are trained to carry out procedures correctly;(vi) records are made, manually and/or by recording instruments, during manufacture which demonstrate that all the steps required by the defined procedures and instructions were in fact taken and that the quantity and quality of the product was as expected. Any significant deviations are fully recorded and investigated;(vii) records of manufacture including distribution which enable the complete history of a batch to be traced, are retained in a comprehensible and accessible form;(viii) the distribution (wholesaling) of the products minimises any risk to their quality;(ix) a system is available to recall any batch of product, from sale or supply;(x) complaints about marketed products are examined, the causes of quality defects investigated and appropriate measures taken in respect of the defective products and to prevent reoccurrence. Quality Control1.3 Quality Control is that part of Good Manufacturing Practice which is concerned with sampling, specifications and testing, and with the organisation, documentation and release procedures which ensure that the necessary and relevant tests are actually carried out and that materials are not released for use, nor products released for sale or supply, until their quality has been judged to be satisfactory.The basic requirements of Quality Control are that:(i) adequate facilities, trained personnel and approved procedures are available for sampling, inspecting and testing starting materials, packaging materials, intermediate, bulk, and finished products, and where appropriate for monitoring environmental conditions for GMP purposes; (ii) samples of starting materials, packaging materials, intermediate products, bulk products and finished products are taken by personnel and by methods approved by Quality Control;(iii) test methods are validated;(iv) records are made, manually and/or by recording instruments, which demonstrate that all the required sampling, inspecting and testing procedures were actually carried out. Any deviations are fully recorded and investigated;(v) the finished products contain active ingredients complying with the qualitative and quantitative composition of the Marketing Authorisation, are of the purity required, and are enclosed within their proper containers and correctly labelled;(vi) records are made of the results of inspection and that testing of materials, intermediate, bulk, and finished products is formally assessed against specification. Product assessment includes a review and evaluation of relevant production documentation and an assessment of deviations from specified procedures;(vii) no batch of product is released for sale or supply prior to certification by a Qualified Person that it is in accordance with the requirements of the relevant authorisations;(viii) sufficient reference samples of starting materials and products are retained to permit future examination of the product if necessary and that the product is retained in its final pack unless exceptionally large packs are produced.Product Quality Review1.4 Regular periodic or rolling quality reviews of all licensed medicinal products, including export only products, should be conducted with the objective of verifying the consistency of the existing process, the appropriateness of current specifications for both starting materials and finished product to highlight any trends and to identify product and process improvements. Such reviews should normally be conducted and documented annually, taking into account previous reviews, and should include at least:(i) A review of starting materials including packaging materials used in the product, especially those from new sources.(ii) A review of critical in-process controls and finished product results.(iii) A review of all batches that failed to meet established specification(s) and their investigation.(iv) A review of all significant deviations or non-conformances, their related investigations, and the effectiveness of resultant corrective and preventative actions taken.(v) A review of all changes carried out to the processes or analytical methods.(vi) A review of Marketing Authorisation variations submitted/granted/refused, including those for third country (export only) dossiers.(vii) A review of the results of the stability monitoring programme and any adverse trends. (viii) A review of all quality-related returns, complaints and recalls and the investigationsperformed at the time.(ix) A review of adequacy of any other previous product process or equipment corrective actions. (x) For new marketing authorisations and variations to marketing authorisations, a review of post-marketing commitments.(xi) The qualification status of relevant equipment and utilities, e.g. HV AC, water, compressed gases, etc.(xii) A review of any contractual arrangements as defined in Chapter 7 to ensure that they are up to date.The manufacturer and marketing authorisation holder should evaluate the results of this review, where different, and an assessment made of whether corrective and preventative action or any revalidation should be undertaken. Reasons for such corrective actions should be documented. Agreed corrective and preventative actions should be completed in a timely and effective manner. There should be management procedures for the ongoing management and review of these actions and the effectiveness of these procedures verified during self- inspection. Quality reviews may be grouped by product type, e.g. solid dosage forms, liquid dosage forms, sterile products, etc. where scientifically justified.Where the marketing authorisation holder is not the manufacturer, there should be a technical agreement in place between the various parties that defines their respective responsibilities in producing the quality review. The Qualified Person responsible for final batch certification together with the marketing authorisation holder should ensure that the quality review is performed in a timely manner and is accurate.Quality Risk Management1.5 Quality risk management is a systematic process for the assessment, control, communication and review of risks to the quality of the medicinal product. It can be applied both proactively and retrospectively.1.6 The quality risk management system should ensure that:- the evaluation of the risk to quality is based on scientific knowledge, experience with the process and ultimately links to the protection of the patient- the level of effort, formality and documentation of the quality risk management process is commensurate with the level of riskExamples of the processes and applications of quality risk management can be found inter alia in Annex 20.CHAPTER 2 PERSONNELPrincipleThe establishment and maintenance of a satisfactory system of quality assurance and the correct manufacture of medicinal products relies upon people. For this reason there must be sufficient qualified personnel to carry out all the tasks which are the responsibility of the manufacturer. Individual responsibilities should be clearly understood by the individuals and recorded. All personnel should be aware of the principles of Good Manufacturing Practice that affect them and receive initial and continuing training, including hygiene instructions, relevant to their needs. General2.1 The manufacturer should have an adequate number of personnel with the necessary qualifications and practical experience. The responsibilities placed on any one individual should not be so extensive as to present any risk to quality.2.2 The manufacturer must have an organisation chart. People in responsible positions should havespecific duties recorded in written job descriptions and adequate authority to carry out their responsibilities. Their duties may be delegated to designated deputies of a satisfactory qualification level. There should be no gaps or unexplained overlaps in the responsibilities of those personnel concerned with the application of Good Manufacturing Practice.Key Personnel2.3 Key Personnel include the head of Production, the head of Quality Control, and if at least one of 1 these persons is not responsible for the duties described in Article 51 of Directive 2001/83/EC , the Qualified Person(s) designated for the purpose. Normally key posts should be occupied by full-time personnel. The heads of Production and Quality Control must be independent from each other. In large organisations, it may be necessary to delegate some of the functions listed in 2.5, 2.6 and 2.7.2.4 The duties of the Qualified Person(s) are fully described in Article 51 of Directive 2001/83/EC, and can be summarised as follows:(a) for medicinal products manufactured within the European Community, a Qualified Person must ensure that each batch has been produced and tested/checked in accordance with the directives and the marketing authorisation ;(b) for medicinal products manufactured outside the European Community, a Qualified Person must ensure that each imported batch has undergone, in the importing country, the testing specified in paragraph 1 (b) of Article 51;(c) a Qualified Person must certify in a register or equivalent document, as operations are carried out and before any release, that each production batch satisfies the provisions of Article 51.The persons responsible for these duties must meet the qualification requirements laid down in Article 493 of the same Directive, they shall be permanently and continuously at the disposal of the holder of the Manufacturing Authorisation to carry out their responsibilities. Their responsibilities may be delegated, but only to other Qualified Person(s).2.5 The head of the Production Department generally has the following responsibilities:i. to ensure that products are produced and stored according to the appropriate documentation in order to obtain the required quality;ii. to approve the instructions relating to production operations and to ensure their strict implementation;iii. to ensure that the production records are evaluated and signed by an authorised person before they are sent to the Quality Control Department;iv. to check the maintenance of his department, premises and equipment;v. to ensure that the appropriate validations are done;vi. to ensure that the required initial and continuing training of his department personnel is carried out and adapted according to need.2.6 The head of the Quality Control Department generally has the following responsibilities:i. to approve or reject, as he sees fit, starting materials, packaging materials, and intermediate, bulk and finished products;ii. to evaluate batch records;iii. to ensure that all necessary testing is carried out;iv. to approve specifications, sampling instructions, test methods and other Quality Control procedures;v. to approve and monitor any contract analysts;vi. to check the maintenance of his department, premises and equipment;vii. to ensure that the appropriate validations are done;viii. to ensure that the required initial and continuing training of his department personnel is carried out and adapted according to need.Other duties of the Quality Control Department are summarised in Chapter 6.2.7 The heads of Production and Quality Control generally have some shared, or jointly exercised, responsibilities relating to quality. These may include, subject to any national regulations:— the authorisation of written procedures and other documents, including amendments;— the monitoring and control of the manufacturing environment;— plant hygiene;— process validation;— training;— the approval and monitoring of suppliers of materials;— the approval and monitoring of contract manufacturers;— the designation and monitoring of storage conditions for materials and products;— the retention of records;— the monitoring of compliance with the requirements of Good Manufacturing Practice;— the inspection, investigation, and taking of samples, in order to monitor factors which may affect product quality.Training2.8 The manufacturer should provide training for all the personnel whose duties take them into production areas or into control laboratories (including the technical, maintenance and cleaning personnel), and for other personnel whose activities could affect the quality of the product.2.9 Besides the basic training on the theory and practice of Good Manufacturing Practice, newly recruited personnel should receive training appropriate to the duties assigned to them. Continuing training should also be given, and its practical effectiveness should be periodically assessed. Training programmes should be available, approved by either the head of Production or the head of Quality Control, as appropriate. Training records should be kept.2.10 Personnel working in areas where contamination is a hazard, e.g. clean areas or areas where highly active, toxic, infectious or sensitising materials are handled, should be given specific training.2.11 Visitors or untrained personnel should, preferably, not be taken into the production and quality control areas. If this is unavoidable, they should be given information in advance, particularly about personal hygiene and the prescribed protective clothing. They should be closely supervised.2.12 The concept of Quality Assurance and all the measures capable of improving its understanding and implementation should be fully discussed during the training sessions. Personnel Hygiene2.13 Detailed hygiene programmes should be established and adapted to the different needs within the factory. They should include procedures relating to the health, hygiene practices and clothing of personnel. These procedures should be understood and followed in a very strict way by every person whose duties take him into the production and control areas. Hygiene programmes should be promoted by management and widely discussed during training sessions.2.14 All personnel should receive medical examination upon recruitment. It must be the manufacturer‟s responsibility t hat there are instructions ensuring that health conditions that can be of relevance to the quality of products come to the manufacturer‟s knowledge. After the first medical examination, examinations should be carried out when necessary for the work and personal health.2.15 Steps should be taken to ensure as far as is practicable that no person affected by an infectious disease or having open lesions on the exposed surface of the body is engaged in the manufacture of medicinal products.2.16 Every person entering the manufacturing areas should wear protective garments appropriate to the operations to be carried out.2.17 Eating, drinking, chewing or smoking, or the storage of food, drink, smoking materials or personal medication in the production and storage areas should be prohibited. In general, any unhygienic practice within the manufacturing areas or in any other area where the product might be adversely affected, should be forbidden.2.18 Direct contact should be avoided between the operator‟s hands and the exposed product as well as with any part of the equipment that comes into contact with the products.2.19 Personnel should be instructed to use the hand-washing facilities.2.20 Any specific requirements for the manufacture of special groups of products, for example sterile preparations, are covered in the annexes.CHAPTER 3 PREMISES AND EQUIPMENTPrinciplePremises and equipment must be located, designed, constructed, adapted and maintained to suit the operations to be carried out. Their layout and design must aim to minimise the risk of errors and permit effective cleaning and maintenance in order to avoid cross- contamination, build up of dust or dirt and, in general, any adverse effect on the quality of products.PremisesGeneral3.1 Premises should be situated in an environment which, when considered together with measures to protect the manufacture, presents minimal risk of causing contamination of materials or products.3.2 Premises should be carefully maintained, ensuring that repair and maintenance operations do not present any hazard to the quality of products. They should be cleaned and, where applicable, disinfected according to detailed written procedures.3.3 Lighting, temperature, humidity and ventilation should be appropriate and such that they do not adversely affect, directly or indirectly, either the medicinal products during their manufacture and storage, or the accurate functioning of equipment.3.4 Premises should be designed and equipped so as to afford maximum protection against the entry of insects or other animals.3.5 Steps should be taken in order to prevent the entry of unauthorised people. Production, storage and quality control areas should not be used as a right of way by personnel who do not work in them.Production Area3.6 In order to minimise the risk of a serious medical hazard due to cross-contamination, dedicated and self contained facilities must be available for the production of particular medicinal products, such as highly sensitising materials (e.g. penicillins) or biological preparations (e.g. from live micro-organisms). The production of certain additional products, such as certain antibiotics, certain hormones, certain cytotoxics, certain highly active drugs and non-medicinal products should not be conducted in the same facilities. For those products, in exceptional cases, the principle of campaign working in the same facilities can be accepted provided that specific precautions are taken and the necessary validations are made. The manufacture of technicalpoisons, such as pesticides and herbicides, should not be allowed in premises used for the manufacture of medicinal products.3.7 Premises should preferably be laid out in such a way as to allow the production to take place in areas connected in a logical order corresponding to the sequence of the operations and to the requisite cleanliness levels.3.8 The adequacy of the working and in-process storage space should permit the orderly and logical positioning of equipment and materials so as to minimise the risk of confusion between different medicinal products or their components, to avoid cross-contamination and to minimise the risk of omission or wrong application of any of the manufacturing or control steps.3.9 Where starting and primary packaging materials, intermediate or bulk products are exposed to the environment, interior surfaces (walls, floors and ceilings) should be smooth, free from cracks and open joints, and should not shed particulate matter and should permit easy and effective cleaning and, if necessary, disinfection.3.10 Pipework, light fittings, ventilation points and other services should be designed and sited to avoid the creation of recesses which are difficult to clean. As far as possible, for maintenance purposes, they should be accessible from outside the manufacturing areas.3.11 Drains should be of adequate size, and have trapped gullies. Open channels should be avoided where possible, but if necessary, they should be shallow to facilitate cleaning and disinfection.3.12 Production areas should be effectively ventilated, with air control facilities (including temperature and, where necessary, humidity and filtration) appropriate both to the products handled, to the operations undertaken within them and to the external environment.3.13 Weighing of starting materials usually should be carried out in a separate weighing room designed for that use.3.14 In cases where dust is generated (e.g. during sampling, weighing, mixing and processing operations, packaging of dry products), specific provisions should be taken to avoid cross- contamination and facilitate cleaning.3.15 Premises for the packaging of medicinal products should be specifically designed and laid out so as to avoid mix-ups or cross-contamination.3.16 Production areas should be well lit, particularly where visual on-line controls are carried out.3.17 In-process controls may be carried out within the production area provided they do not carry any risk for the production.Storage Areas3.18 Storage areas should be of sufficient capacity to allow orderly storage of the various categories of materials and products:starting and packaging materials, intermediate, bulk and finished products, products in quarantine, released, rejected, returned or recalled.3.19 Storage areas should be designed or adapted to ensure good storage conditions. In particular, they should be clean and dry and maintained within acceptable temperature limits. Where special storage conditions are required (e.g. temperature, humidity) these should be provided, checked and monitored.3.20 Receiving and dispatch bays should protect materials and products from the weather. Reception areas should be designed and equipped to allow containers of incoming materials to be cleaned where necessary before storage.3.21 Where quarantine status is ensured by storage in separate areas, these areas must be clearly marked and their access restricted to authorised personnel. Any system replacing the physicalquarantine should give equivalent security.3.22 There should normally be a separate sampling area for starting materials. If sampling is performed in the storage area, it should be conducted in such a way as to prevent contamination or cross-contamination.3.23 Segregated areas should be provided for the storage of rejected, recalled or returned materials or products.3.24 Highly active materials or products should be stored in safe and secure areas.3.25 Printed packaging materials are considered critical to the conformity of the medicinal product and special attention should be paid to the safe and secure storage of these materials.Quality Control Areas3.26 Normally, Quality Control laboratories should be separated from production areas. This is particularly important for laboratories for the control of biologicals, microbiologicals and radioisotopes, which should also be separated from each other.3.27 Control laboratories should be designed to suit the operations to be carried out in them. Sufficient space should be given to avoid mix-ups and cross-contamination. There should be adequate suitable storage space for samples and records.3.28 Separate rooms may be necessary to protect sensitive instruments from vibration, electrical interference, humidity, etc.3.29 Special requirements are needed in laboratories handling particular substances, such as biological or radioactive samples.Ancillary Areas3.30 Rest and refreshment rooms should be separate from other areas.3.31 Facilities for changing clothes, and for washing and toilet purposes should be easily accessible and appropriate for the number of users. Toilets should not directly communicate with production or storage areas.3.32 Maintenance workshops should as far as possible be separated from production areas. Whenever parts and tools are stored in the production area, they should be kept in rooms or lockers reserved for that use.3.33 Animal houses should be well isolated from other areas, with separate entrance (animal access) and air handling facilities.Equipment3.34 Manufacturing equipment should be designed, located and maintained to suit its intended purpose.3.35 Repair and maintenance operations should not present any hazard to the quality of the products.3.36 Manufacturing equipment should be designed so that it can be easily and thoroughly cleaned. It should be cleaned according to detailed and written procedures and stored only in a clean and dry condition.3.37 Washing and cleaning equipment should be chosen and used in order not to be a source of contamination.3.38 Equipment should be installed in such a way as to prevent any risk of error or of contamination.3.39 Production equipment should not present any hazard to the products. The parts of the production equipment that come into contact with the product must not be reactive, additive or absorptive to such an extent that it will affect the quality of the product and thus present any hazard.。

Drug SubstanceChemistry, Manufacturing, and Controls InformationDRAFT GUIDANCEThis guidance document is being distributed for comment purposes only. Comments and suggestions regarding this draft document should be submitted within 180 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit comments to Dockets Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register.For questions regarding this draft document contact (CDER) Stephen Miller (301) 827-2392, (CBER) Chris Joneckis (301) 435-5681, or (CVM) Dennis Bensley (301) 827-6956.U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Review (CBER)Center for Veterinary Medicine (CVM)January 2004CMCDrug Substance Chemistry, Manufacturing, and Controls InformationAdditional copies are available from:Office of Training and CommunicationDivision of Drug Information, HFD-240Center for Drug Evaluation and ResearchFood and Drug Administration5600 Fishers LaneRockville, MD 20857(Tel) 301-827-4573/cder/guidance/index.htmorOffice of Communication, Training andManufacturers Assistance, HFM-40Center for Biologics Evaluation and ResearchFood and Drug Administration1401 Rockville Pike, Rockville, MD 20852-1448/cber/guidelines.htm.(Tel) Voice Information System at 800-835-4709 or 301-827-1800orCommunications Staff, HFV-12Center for Veterinary MedicineFood and Drug Administration7519 Standish PlaceRockville, MD 20855(Tel) 301-827-3800/cvm/guidanc/published.htmU.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Review (CBER)Center for Veterinary Medicine (CVM)January 2004CMCTABLE OF CONTENTS1I. INTRODUCTION (1)II. BACKGROUND (3)A. The Common Technical Document — Quality (CTD-Q) Format (3)B. Content of an Application (4)C. Additional Guidance (4)D. References to Other Applications or Master Files (MFs) (5)1. Other Applications (5)2. Master Files (MFs) (6)III. GENERAL INFORMATION (S.1) (8)A. Nomenclature (S.1.1) (8)B. Structure (S.1.2) (8)C. General Properties (S.1.3) (9)IV. MANUFACTURE (S.2) (10)A. Manufacturers (S.2.1) (10)B. Description of Manufacturing Process and Process Controls (S.2.2) (10)1. Flow Diagram (11)2. Description of the Manufacturing Process and Process Controls (12)3. Reprocessing, Reworking, Recycling, Regeneration, and Other Operations (15)C. Control of Materials (S.2.3) (18)1. Starting Materials (18)2. Reagents, Solvents, and Auxiliary Materials (19)3. Diluents (20)D. Controls of Critical Steps and Intermediates (S.2.4) (20)E. Process Validation and/or Evaluation (S.2.5) (23)F. Manufacturing Process Development (S.2.6) (23)V. CHARACTERIZATION (S.3) (24)A. Elucidation of Structure and Other Characteristics (S.3.1) (24)1. Elucidation of Structure (24)2. Physicochemical Characterization (25)3. Biological and Other Relevant Characteristics (26)B. Impurities (S.3.2) (27)VI. CONTROL OF DRUG SUBSTANCE (S.4) (29)1 Alphanumeric designations in parentheses that follow headings show where information should be placed in applications that are submitted in Common Technical Document (CTD) format.A. Specification (S.4.1) (29)B. Analytical Procedures (S.4.2) (34)C. Validation of Analytical Procedures (S.4.3) (35)D. Batch Analyses (S.4.4) (35)1. Batch Analysis Reports (36)2. Collated Batch Analyses Data (36)E. Justification of Specification (S.4.5) (37)VII. REFERENCE STANDARDS OR MATERIALS (S.5) (40)VIII. CONTAINER CLOSURE SYSTEM (S.6) (40)IX. STABILITY (S.7) (41)A. Stability Summary and Conclusions (S.7.1) (41)B. Postapproval Stability Protocol and Stability Commitment (S.7.2) (41)C. Stability Data (S.7.3) (41)1. Primary Stability Studies (41)2. Supporting Stability Studies (42)3. Stress Studies (42)X. APPENDICES (A) (43)A. Facilities and Equipment (A.1) (43)B. Adventitious Agents Safety Evaluation (A.2) (44)1. Nonviral Adventitious Agents (45)2. Viral Adventitious Agents (45)XI. REGIONAL INFORMATION (R) (46)A. Executed Production Records (R.1.S) (46)B. Comparability Protocols (R.2.S) (46)C. Methods Validation Package (R.3.S) (46)XII. LITERATURE REFERENCES (3.3) (47)ATTACHMENT 1: (48)STARTING MATERIALS FOR SYNTHETIC DRUG SUBSTANCES (48)ATTACHMENT 2: (56)STARTING MATERIALS OF PLANT OR ANIMAL ORIGIN (56)GLOSSARY (59)GUIDANCE FOR INDUSTRY2Drug SubstanceChemistry, Manufacturing, and Controls Information12345678910111213If you plan to submit comments on this draft guidance, to expedite FDA review of your14comments, please:15∙Clearly explain each issue/concern and, when appropriate, include a proposed revision and the rationale and/or justification for the proposed revision.1617∙Identify specific comments by line numbers; use the pdf version of the document whenever 18possible.19∙If possible, e-mail an electronic copy (Word) of the comments you have submitted to the20docket to cummingsd@.212223I. INTRODUCTION2425Information on the chemistry, manufacturing, and controls (CMC) for the drug substance must 26be submitted to support the approval of original new drug applications (NDAs), abbreviated new 27drug applications (ANDAs), new animal drug applications (NADAs), and abbreviated new28animal drug applications (ANADAs).3 This guidance provides recommendations on the CMC 29information for drug substances that should be submitted to support these applications. The30guidance is structured to facilitate the preparation of applications submitted in Common31Technical Document (CTD) format.3233This guidance addresses the information to be submitted for drug substances to ensure continued 34drug substance and drug product quality (i.e., the identity, strength, quality, purity, and potency).2 This guidance has been prepared by Drug Substance Technical Subcommittee of the Chemistry Manufacturing andControls Coordinating Committee (CMC CC) in the Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluations and Research (CBER) and the Center for Veterinary Medicine (CVM) at the FDA.3 See 21 CFR 314.50(d)(1) and 514.1(b)This guidance provides recommendations on the information that should be included for the3536following topics:37∙Nomenclature, structure, and general drug substance properties3839∙Manufacture40∙Characterization41∙Control of drug substance42∙Reference standards or materials43∙Container closure system44∙Stability45The recommendations provided in this guidance apply to the following types of drug substances:464748∙Drug substances manufactured by chemical synthesis49∙Highly purified and well characterized drug substances derived from plants or animals 4 50∙Semisynthetic drug substances manufactured by the chemical modification of a highly 51purified and well characterized intermediate derived from plants or animals52∙The synthetic portion of the manufacturing process for semisynthetic drug substances53manufactured by the chemical modification of an intermediate produced by conventional 54fermentation.5556The guidance does not provide specific recommendations relating to the following:5758∙Monoclonal antibodies59∙Peptides60∙Oligonucleotides61∙Radiopharmaceuticals62∙Medical gases63∙Drug substances that are not well characterized (e.g., botanicals, some proteins) derived 64from plants or animals65∙Drug substances derived using transgenic technology66∙Drug substances derived directly from or manufacturing operations involving67fermentation (conventional fermentation or using rDNA technology) or tissue or cell68culture.6970More detailed guidance on the content of an application may be available in separate guidance 71documents for specific types of drug substances (see section II.C). Applicants with drug72substances not specifically covered by this (Drug Substance guidance) or another guidance can 73apply the content recommendations in this guidance, as scientifically appropriate, and/or can74contact the appropriate chemistry review teams for guidance.754 For purposes of this guidance, d rug substances derived from plants or animals does not include materials producedby plant cell fermentation, animal cell or tissue culture, or through use of transgenic technology (e.g.,biotechnology-derived protein drug products).FDA’s guidance docume nts, including this guidance, do not establish legally enforceable7677responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should 78be viewed only as recommendations, unless specific regulatory or statutory requirements arecited. The use of the word should in Agency guidances means that something is suggested or7980recommended, but not required.8182This guidance, when finalized, will replace the guidance entitled Submitting Supporting83Documentation in Drug Applications for the Manufacture of Drug Substances (February 1987).848586II. BACKGROUND8788A. The Common Technical Document — Quality (CTD-Q) Format89In November 2000, the International Conference on Harmonisation of Technical9091Requirements for Registration of Pharmaceuticals for Human Use (ICH) issued92harmonized guidance for the format of drug product applications (i.e., Common93Technical Document (CTD)). The CTD describes a format for applications that94(supplemented with regional information) can be used for submission to the regulatory 95authorities in the United States, European Union, and Japan. One focus of this effort was 96harmonizing the format for quality information (i.e., chemistry, manufacturing, and97controls) that will be submitted in an application. FDA’s guidance on M4Q: The CTD —98Quality describes the format for the quality information submitted in Module 3 of an99application and provides additional information on formatting aspects of an application. 100Applicants can submit NDAs, ANDAs, NADAs, and ANADAs using the CTD-Q101format.5Applicants should review FDA’s guidance on M4Q: The CTD — Quality and 102other related CTD guidance documents for detailed formatting recommendations on103preparing an application in CTD format.104105Module 3 of each NDA and ANDA should include the specified CTD sections: Drug 106Substance (3.2.S), Drug Product (3.2.P), Appendices (3.2.A), Regional Information107(3.2.R), and Literature References (3.3). In some cases, the majority of information to 108address the drug substance sections will be incorporated by reference from a master file 109(see section II.D.2). However, an applicant should still provide information to address 110some of the drug substance subsections. Recommendations on the content of the drug 111product section (3.2.P) of Module 3 will be the provided in the guidance Drug Product —112Chemistry, Manufacturing, and Controls Information (Drug Product guidance), when 113finalized.6 The Appendices, Regional Information, and Literature References sections 114include information for both drug substance and drug product, as appropriate.1155 The information in animal drug applications is commonly presented in the order of the required CMC informationspecified under section § 514.1(b)(4) and (5). Although the CTD-Q format was developed for human drugs, thedrug substance information to support NADAs and ANADAs can be formatted according to the CTD-Q format or any alternative format that provides the appropriate information to support the application.6 A draft version of this guidance published on January 28, 2003 (68 FR 4219).116This Drug Substance guidance has been organized in a format conforming to Module 3 of 117the CTD, and it provides CMC content recommendations specific to drug substance,118including recommendations for the Appendices, Regional Information, and Literature 119References sections. Alphanumeric designations in parentheses corresponding to the 120CTD format follow relevant headings and text to show where information is to be placed 121in the CTD.7 Recommendations specific to drug product, including recommendations for 122the Appendices, Regional Information and Literature References sections, will be123provided in the Drug Product guidance.124125Multiple Drug Substances in an Application126127When an application is submitted for a drug product involving two or more drug128substances (e.g., combination drug product, copackaged drug products), information for 129each drug substance should be presented separately in the application. Information130presented separately means one complete S section for one drug substance followed by 131other complete S sections for additional drug substances. All of the information pertinent 132to each one of the drug substances (general information, manufacture, characterization, 133control, standards, container closure system, and stability) should be provided in a single 134section.135136B. Content of an Application137The application should include information in every S subsection for each of the drug 138139substances and manufacturing schemes (e.g., alternative processes, manufacturing site) 140intended for approval under the application. Information should be provided in theAppendices, Regional Information, and Literature References sections for each of the 141142drug substances and manufacturing schemes, as appropriate. If an Appendices or143Regional Information subsection or the Literature References section is not applicable, 144this should be stated in the application.145146C. Additional Guidance147148This Drug Substance guidance and the Drug Product guidance, when finalized, will be 149the primary content guidances for NDA and ANDA applicants. For quality, the general 150format guidance is M4Q: The CTD — Quality. These are the first guidances an applicant 151should consider when preparing the quality section (i.e., chemistry, manufacturing, and 152controls) of an NDA or ANDA (Module 3).153This guidance references ICH guidance documents cited in the CTD-Q and FDA’s154155guidances on general technical topics (i.e., stability, container closure systems, analytical 156procedures and methods validation, sterilization process validation, drug master files, and7 Arabic numbers have been assigned to specific sections of the CTD. For example, the designation 3.2 before S, P,A, and R indicates Module 3, Body of Data section 2. Where this guidance discusses Module 3, Body of Datasection 2, for brevity, the initial designation 3.2 is not repeated throughout the rest of the guidance (e.g., 3.2.S.1.3reads S.1.3).157environmental assessments) rather than incorporating this detailed information. These 158guidances are referenced in the text and/or listed at the end of a section. An applicant159should refer to these guidances for recommendations on the detailed information that160should be included in the application to address the general technical topic.161162Finally, an applicant should consider guidances that are available for specific technical 163issues or type (e.g., synthetic peptides) of drug substance when preparing its application. 164These guidances provide additional recommendations on unique scientific and technical 165aspects of the topic. Some references to these types of guidances are included in this166guidance. However, the references are given only as examples, and the list is not meant 167to be all-inclusive. Some examples of these types of guidance include the following:168∙Submission of Chemistry, Manufacturing, and Controls Information for Synthetic 169170Peptide Substances171∙Submission of Chemistry, Manufacturing and Controls Information for a172Therapeutic Recombinant DNA-Derived Product or a Monoclonal Antibody173Product for In Vivo Use, CBER/CDER (under development)174∙Botanical Drug Products (under development)∙Fermentation Derived Drug Substances and Intermediates and Associated Drug 175176Products (under development)177∙Synthetic Oligonucleotides; Submission of Chemistry, Manufacturing, and178Controls Information (under development)179∙Radiopharmaceutical Drug Products: Chemistry, Manufacturing and ControlsInformation (under development)180181182FDA continues to update existing and publish new guidance documents. An applicant 183should use current guidance when preparing an NDA, ANDA, NADA or ANADA184submission.8185186D. References to Other Applications or Master Files (MFs)1871881. Other Applications189190In some cases, chemistry, manufacturing, and controls information about drug substances 191is provided in one application by reference to pertinent information in another application. 192This situation is less common than inclusion of information by reference to a MF and193usually occurs when the same firm submits both applications.194An applicant must identify in the application all other referenced applications, and each 195reference to information submitted in another application must identify where the196information can be found in the referenced application (21 CFR 314.50(a)(1) and197514.1(a)). If the referenced application was submitted by a firm other than the applicant,the referencing application must contain a written statement that authorizes the reference, 1988Current guidance documents are available on the Internet at /cder/guidance/index.htm,/cber/guidelines.htm, and /cvm/guidance/published.htm.199signed by the holder of the referenced application (21 CFR 314.50(g)(1), 314.420(b). and 200514.1(a)).9 Copies of letters of authorization (LOAs) should be submitted in Module 1 of 201the NDA or ANDA or in the appropriate section of an NADA or ANADA.2022032. Master Files (MFs)204205This guidance describes chemistry, manufacturing, and controls information for drug206substances that should be submitted to the Agency as part of the process of seeking theapproval of an NDA, ANDA, NADA, or ANADA. When a drug substance is207208manufactured by a firm other than the applicant, much of this information is frequently 209provided by reference to one or more Type II MFs rather than directly in an application. 210The CMC information in a Type II MF can be organized in CTD-Q format. Under FDA's 211regulations, an application can incorporate by reference all or part of the contents of any 212MF to address particular drug substance issues if the MF holder provides written213authorization (i.e., LOA) to the applicant and the authorization is included in the214application (Module 1 for an NDA or ANDA or in the appropriate section of an NADAor ANADA). The authorization must specifically identify the material being215216incorporated by reference (21 CFR 314.420 and 514.1(a)). The incorporated material217should be identified by name, reference number, volume and page number of the MF, anddate of submission. See 21 CFR 314.420, CDER’s guidance on Drug Master Files, and 218219CVM’s guidance on Preparation and Submission of Veterinary Master Files for moreinformation.220221222Both the applicant and the drug substance manufacturer (MF holder) contribute to223establishing and maintaining the identity, strength, quality, purity, and potency of the224applicant's drug products by manufacturing and controlling the drug substance in225accordance with the information submitted in the application and, by reference, in the MF. 226The following recommendations pertain to location of information in the MF and/or227application when an applicant and Type II MF holder are different firms.228229∙General Information (S.110): Both the MF and the application should include this 230information. These sections should contain similar, though not necessarily identical, 231information. For example, if an applicant performed screening studies and232established the existence of multiple polymorphs, information concerning these233polymorphs might be present in the application but not in the MF.234235∙Manufacture (S.2): The application should identify in S.2.1 the manufacturers of 236each drug substance with appropriate administrative information (see section IV.A). 237The MF should include this information for its manufacturing operations and any9 CVM discourages the reference of NDAs or ANDAs for drug substance information. In these instances, CVMrecommends that the drug substance information be included in a master file or incorporated in the applicant’sNADA or ANADA.10 Alphanumeric designations in parentheses that follow headings show where information should be placed inapplications that are submitted in Common Technical Document (CTD) format.238contract facilities that are used (e.g., intermediate manufacturers, laboratories). In239general, a MF can be referenced for the information recommended in S.2.2 through240S.2.6. However, the information should be augmented by the applicant, as241appropriate. For example, if the applicant micronizes drug substance purchased from242a MF holder the information on the micronization process should be included in the243application.244245∙Characterization (S.3): In general, a MF can be referenced for this information.However, the information should be augmented by the applicant, as appropriate. For 246247example, characterization information on physical properties critical to the applicant’s248product, such as solid state form or particle size distribution, should be included in249S.3.1 by the applicant under certain circumstances (e.g., applicant manipulates the250physical property (micronizes), the MF holder has not characterized the physical251property). Furthermore, information on an applicant’s studies to characterizeimpurities (S.3.2) can be warranted to support the applicant’s drug substance controls. 252253254∙Control of Drug Substance (S.4): In general, information recommended in S.4 should be provided in both the MF and the application. However, reference to an MF 255256can be appropriate for some of the information in S.4.2 through S.4.5 if the MF257holder and applicant are working together to develop the drug substance controls.Both the MF and the application should include a drug substance specification (S.4.1). 258259The MF could include more than one drug substance specification if the holder sellsdifferent technical grades of the drug substance (e.g., micronized and nonmicronized). 260261262∙Reference Standards (S.5): In general, information should be provided in both the 263MF and the application. However, reference to a MF can be appropriate for some of264the information if the MF holder and applicant are working together to develop the265reference standard.266267∙Container Closure System (S.6): In general, MFs can be referenced for this268information. However, the information should be augmented by the applicant, as269appropriate.270271∙Stability (S.7): In general, MFs can be referenced for this information. However, the information should be augmented by the applicant, as appropriate. For example, 272273an applicant might perform stress studies to support the analytical procedures it used274to control the drug substance.275276∙Appendices (A): In general, MFs can be referenced for this information. However, 277the information should be augmented by the applicant, as appropriate.278279∙Regional Information (R): Comparability protocols can be included in both the MF 280and application (R.2.S). A methods validation package should be included in theapplication (R.3.S).281282∙Literature References (3.3): Both the MF and the application should include283284literature references as warranted.285Type II MFs for drug substance intermediates can also be submitted in the CTD-Q format. 286287However, not all sections of the CTD-Q format would apply (e.g., S.4). The CMC288information provided to support an intermediate should be appropriate for the particularsituation (e.g., process, complexity of the molecule).289290291III. GENERAL INFORMATION (S.1)292293294General information on the nomenclature, structure, and general properties of the drug substance, should be provided in S.1.295296297A. Nomenclature (S.1.1)298299All appropriate names or designations for the drug substance should be provided in S.1.1. 300Any codes, abbreviations, or nicknames used in the application to identify the drug301substance should also be listed, including the following, if they exist or have been302proposed. A name that has not yet been finalized should be identified as proposed in the 303list.304305∙United States Adopted Name (USAN)∙Compendial name11306307∙Chemical names (e.g., Chemical Abstracts Service (CAS), International Union of 308Pure and Applied Chemistry (IUPAC))∙Company names or laboratory codes309310∙Other nonproprietary names (e.g., International Nonproprietary Name (INN),311British Approved Name (BAN), Japanese Accepted Name (JAN))312∙Chemical Abstracts Service (CAS) Registry Number313314B. Structure (S.1.2)315316Information on the chemical structure of the drug substance should be provided in S.1.2. 317This information should include:318319∙one or more drawings to show the overall chemical structure of the drug substance, 320including stereochemistry321∙molecular formula322∙molecular weight323324For a naturally derived protein drug substance, the information should include:11 A compendial name is a name that appears in an official compendium as defined in the Federal Food, Drug, andCosmetic Act (e.g., United States Pharmacopeia (USP)) (§ 201(j) (21 U.S.C. 32(i)).325326∙the schematic amino acid sequence indicating glycosylation sites or other327posttranslational modifications∙ a general description of the molecule (e.g., shape, disulfide bonds, subunit328329composition)330∙number of amino acid residues331∙molecular weight332333C. General Properties (S.1.3)334A list should be provided of the general physicochemical properties of the drug substance. 335336Other relevant properties of the drug substance should also be listed. Relevant properties 337are those physical, chemical, biological and microbiological attributes relating to theidentity, strength, quality, purity, and/or potency of the drug substance and, as338339appropriate, drug product. The information should include, as appropriate:340341∙ A general description (e.g., appearance, color, physical state)342∙Melting or boiling points343∙Optical rotation344∙Solubility profile (aqueous and nonaqueous, as applicable)345∙Solution pH346∙Partition coefficients347∙Dissociation constants348∙Identification of the physical form (e.g., polymorph, solvate, or hydrate) that will 349be used in the manufacture of the drug product350∙Biological activities351352For a naturally derived protein drug substance, additional information should be included, 353such as:354355∙Isoelectric point356∙Extinction coefficient357∙Any unique spectral characteristics358359If the drug substance can exist in more than one physical form, the information included 360in S.1.3 should be for the form (or forms) of the drug substance that will be used in the 361manufacture of the drug product. Detailed information on the characterization (e.g., X-362ray powder diffraction data, thermal analysis curves) of these and other physical forms 363and conditions required to produce one form or another should be provided in S.3.1.364。

RDF语义推荐标准TransWiki - 开放翻译计划（OTP）RDF 语义RDF SemanticsW3C 推荐标准2004年2月10日W3C Recommendation 10 February 2004当前版本:This Version:/TR/2004/REC-rdf-mt-20040210/最新版本:Latest Version:/TR/rdf-mt/前期版本:Previous Version:/TR/2003/PR-rdf-mt-20031215/编者:Editor:Patrick Hayes (IHMC)< phayes@>丛书编辑:Series EditorBrian McBride (Hewlett Packard Labs)<bwm@> Please refer to the errata for this document, which may include some normative corrections.See also translations.Copyright ? 2004 W3C? (MIT, ERCIM, Keio), All Rights Reserved. W3C liability, trademark, document use and software licensing rules apply.摘要[Abstract]这是一个RDF及RDF计划精确的语义说明书和相应完善推理法则系统。

This is a specification of a precise semantics, and corresponding complete systems of inference rules, for the Resource Description Framework (RDF) and RDF Schema (RDFS).Status of this Document 文件状态这篇文档已经由W3C成员和其他感兴趣的用户评审，并由指导者作为W3C 建议签署。

一、COS（Certificate of Suitability）指的是欧洲药典适用性认证，目的是考察欧洲药典是否能够有效地控制进口药品的质量，这是中国的原料药合法地被欧盟的最终用户使用的另一种注册方式。

这种注册途径的优点是不依赖于最终用户，可以由原料药生产厂商独立地提出申请。

中国的原料药生产厂商可以向欧盟药品质量指导委员会（EDQM）提交产品的COS认证文件（COS Dossier），申请COS证书，同时生产厂商必须要承诺产品生产的质量管理严格遵循GMP标准，在文件审查和可能的现场考察通过之后，EDQM会向原料药品的生产厂商颁发COS证书。

如果作为最终用户的欧盟成员国制剂生产企业准备采用中国生产的原料时，只要在注册文件或变更文件中附上该产品的COS证书复印件即可非常容易地获得批准。

COS认证是否需要现场检查，对企业的GMP管理水平有哪些要求？随着美国、欧盟和日本三方在药品注册程序和法规上的相互协调，欧盟在进口的原料药注册中逐步接近美国FDA的偏重现场GMP检查的办法，今后有可能对每一家提出COS认证的生产厂家进行现场的GMP检查。

自1999年开始，原料药生产企业在申请COS认证的技术文件后面必须要附加两封承诺信，一封信承诺说产品是按照GMP规范进行生产的，另一封信要承诺同意欧盟的相关审查机构进行现场检查。

如果欧盟EDQM的GMP审查越来越频繁，甚至最终变成为一种必要的审查手段，生产厂家就应当对此做出充分的准备，以使自身的GMP管理状况能够适应欧盟的检查。

欧盟的GMP检查与国内的GMP认证有以下差别：首先，欧盟的GMP检查依据的ICH Q7A的指导纲要，厂家要参照此指导进行自身检查；其次，所有的质量管理文件、操作规范（SOP）和各种生产管理表格、标牌、标签和生产记录都应当具备中英文对照，能够让国外的审查官员看懂；其三，要对员工进行GMP 的全员培训，了解并适应国外检查的特点。

COS认证过程对企业是有积极意义的，会使企业的GMP管理达到国际水平，而且随着美、欧、日三方协调的进一步发展，通过欧盟的GMP检查和COS认证最终有可能直接进入美国和日本市场，至少会使美国FDA的注册变得更为容易。

本体概念、描述语言和方法论方面的综述。

一、本体的概念Ontology 的概念最初起源于哲学领域，可以追溯到公元前古希腊哲学家亚里士多德（384-322 b.c.）。

它在哲学中的定义为“对世界上客观存在物的系统地描述，即存在论”，是客观存在的一个系统的解释或说明，关心的是客观现实的抽象本质[1]。

在人工智能界，最早给出Ontology定义的是Neches等人，他们将Ontology定义为“给出构成相关领域词汇的基本术语和关系，以及利用这些术语和关系构成的规定这些词汇外延的规则的定义”[1]。

Neches认为：“本体定义了组成主题领域的词汇表的基本术语及其关系，以及结合这些术语和关系来定义词汇表外延的规则。

”（“An ontology defines the basic terms and relations comprising the vocabulary of a topic area, as well as the rules for combining terms and relations to define extensions to the vocabulary.”）[6]。

后来在信息系统、知识系统等领域，越来越多的人研究Ontology，并给出了许多不同的定义。

其中最著名并被引用得最为广泛的定义是由Gruber提出的，“本体是概念化的明确的规范说明”，原文参见："An ontology is an explicit specification of a conceptualization. The term is borrowed from philosophy, where an Ontology is a systematic account of Existence. For AI systems, what "exists" is that which can be represented. When the knowledge of a domain is represented in a declarative formalism, the set of objects that can be represented is called the universe of discourse. This set of objects, and the describable relationships among them, are reflected in the representational vocabulary with which a knowledge-based program represents knowledge. Thus, in the context of AI, we can describe the ontology of a program by defining a set of representational terms. In such an ontology, definitions associate the names of entities in the universe of discourse (e.g., classes, relations, functions, or other objects) with human-readable text describing what the names mean, and formal axioms that constrain the interpretation and well-formed use of these terms. Formally, an ontology is the statement of a logical theory."[2, 3]。

医疗器械与体外诊断用品的良好生产技术规范TECHNICAL REGULATION OF GOOD MANUFACTURING PRACTICES FORMEDICAL DEVICES ANDPRODUCTS FOR IN VITRO DIAGNOSTIC USE注：参考葡萄牙语-英语翻译版本美国食品和药物管理局质量体系要求第21章第820节的基本术语。

Note: The translation from Portuguese to English used as refereneethe basic termi no logy of the FDA QSR 21 Part 820.巴西国家卫生监督局一一联合董事会决议第16号RDC2013年3月28日ANVISA - COLLEGIATE BOARD RESOLUTION RDC No.16 28 MAR 2013批准医疗用品与体外诊断用品的良好生产技术规范及其他措施。

Approves the Tech ni eal Regulati on of Good Manu faeturi ng Practice for Medical Products and Products for In Vitro Diag no stic Use and other measures.巴西国家卫生监督局在2013年3月7日召开的会议上，根据第1999年4月16日3029 号法令批准的规范的第11条第4款规定，以及根据巴西国家卫生监督局的第354号法令附录一批准的附则的第54条第1款与第3款规定获得授权行使权力，公布于2006年8月21 日的公报上。

参考1976年9月23 日生效的6360号法案及其规定，以及1977年1月5日的79094号法令；The Board of the National Health Surveillanee Agency, in exercise of the powers conferred upon him by section IV of article. 11 of the Regulation approved by Decree No. 3029 of April 16, 1999, and in view of the provisions of sect ion II and in 1 a§d § of art. 54 of the Bylaws approved in accorda nee with Annex I of Ordinance No. 354 of ANVISA, of August 11,2006, republished in the Official Gazette of August 21, 2006, at a meeting held March 7, 2013, considering the Law. 6360 of September 23, 1976 and its regulations, Decree No. 79094 of January 5, 1977;参考了内在化决议南美共同市场/GMC/RES的需要。

药物非临床研究质量管理规范英文Thirdly, it is necessary to strengthen the management of personnel and equipment involved in non-clinical research of pharmaceuticals. The personnel involved should be trained to be familiar with the quality management system and the relevant standards and procedures. At the same time, the equipment used in the research should also be inspected and maintained regularly to ensure the accuracy of the data.Fourthly, it is necessary to establish a system for monitoring and evaluating the quality of non-clinical research of pharmaceuticals. The system should include the evaluation of the research protocol, the monitoring of the process, the evaluation of the results and other aspects.Finally, it is necessary to establish a system for the feedback of the quality of non-clinical research of pharmaceuticals. This system should include the feedback of the quality of the research results, the feedback of the evaluation of the process, and the feedback of the evaluation of the personnel and equipment involved.The above is an introduction to the quality management guidelines for non-clinical research of pharmaceuticals. It is hoped that these guidelines can be used as a reference for enterprises to strengthen the management of non-clinical research of pharmaceuticals and lay a foundation for the research and development of new drugs.。

MHRA GMP Data Integrity Definitions and Guidance for Industry January 2015MHRA GMP 数据完整性定义和行业指导原则 1月 2015简述:Data integrity is fundamental in a pharmaceutical quality system which ensures that medicines are of the required quality. This document provides MHRA guidance on GMP data integrity expectations for the pharmaceutical industry. This guidance is intended to complement existing EU GMP, and should be read in conjunction with national medicines legislation and the GMP standards published in Eudralex volume 4.数据完整性是制药质量体系确保药品质量的基石。

本文提供了MHRA对制药行业GMP数据完整性的指导原则。

本指导原则旨在对现有EU GMP进行补充说明，需结合国家药品法规及GMP标准内Eudralex 第四册进行阅读理解。

The data governance system should be integral to the pharmaceutical quality system described in EU GMP chapter 1. The effort and resource assigned to data governance should be commensurate with the risk to product quality, and should also be balanced with other quality assurance resourcedemands. As such, manufacturers and analytical laboratories are not expected to implement a forensic approach to data checking, but instead design and operate a system which provides an acceptablestate of control based on the data integrity risk, and which is fully documented with supporting rationale. 数据管理体系需要结合在EU GMP第一章描所述的质量体系中。

Uniformance® FILEACCESS and FTP Real-Time Data InterfaceInstallation GuideR310Copyright, Notices, and Trademarks© Honeywell Inc. 2012. All Rights Reserved.While this information is presented in good faith and believed to be accurate, Honeywell disclaims the implied warranties of merchantability and fitness for a particular purpose and makes no express warranties except as may be stated in its written agreement with and for its customers.In no event is Honeywell liable to anyone for any indirect, special or consequential damages. The information and specifications in this document are subject to change without notice.Honeywell, Experion PKS, PlantScape, TotalPlant, Uniformance PHD, and Business FLEX are U.S. registered trademarks of Honeywell International Inc.Other brand or product names are trademarks of their respective owners.Release InformationUniformance 310Document Revision 10Document Revision Date: February, 2012Document ID : rdi3301Document Revisions :PAR DescriptionDocumentRevision9 n/a Revised the document for R300.10 n/a Revised the document for R310Honeywell Process Solutions1860 W. Rose Garden LnPhoenix, Arizona 85027-2708 USAii Uniformance - FILEACCESS and FTP RDI Installation GuideSupport and Other ContactsUnited States and CanadaC Contact: Honeywell Solution Support CenterPhone: 1-800 822-7673.Calls are answered by dispatcher between 6:00 A.M. and 4:00 P.M.Mountain Standard Time. Emergency calls outside normal working hoursare received by an answering service and returned within one hour.Mail: Honeywell HPS TAC, MS L171860 W Rose Garden LnPhoenix, Arizona 85027-2708EuropeContact: HoneywellTAC-EMEAPhone: +32-2-728-2732Facsimile: +32-2-728-2696Mail: TAC-BE02HermesPlaza1HHermeslaan,BelgiumDiegem,B-1831PacificContact: Honeywell Global TAC – PacificPhone: 1300-300-4822 (toll free within Australia)Australia)+61-8-9362-9559(outsideFacsimile: +61-8-9362-9564Mail: Honeywell Limited Australia5 Kitchener WayBurswood 6100, Western AustraliaEmail: GTAC@IndiaContact: Honeywell Global TAC – India66039400Phone: +91-20-Facsimile: +91-20- 66039800Mail: Honeywell Automation India Ltd.56 and 57, Hadapsar Industrial EstateHadapsar, Pune –411 013, IndiaEmail: Global-TAC-India@Uniformance - FILEACCESS and FTP RDI Installation Guide iiiSupport and Other Contactsiv Uniformance - FILEACCESS and FTP RDI Installation GuideKoreaContact: Honeywell Global TAC – KoreaPhone: +82-80-782-2255 (toll free within Korea)Facsimile: +82-2-792-9015Mail: Honeywell Co., Ltd4F, Sangam IT Tower B4-4 Block1590, DMC Sangam-dong, Mapo-gu,Seoul, 121-835, KoreaEmail: Global-TAC-Korea@People’s Republic of ChinaContact: Honeywell Global TAC – ChinaPhone: +86- 21-52574568Mail: Honeywell (China) Co., Ltd33/F, Tower A, City Center, 100 Zunyi Rd.Shanghai 200051, People’s Republic of ChinaEmail: Global-TAC-China@SingaporeContact: Global TAC – South East AsiaPhone: +65-6580-3500Facsimile: +65-6580-3501+65-6445-3033Mail: Honeywell Private LimitedHoneywell Building17, Changi Business Park Central 1Singapore 486073Email: GTAC-SEA@TaiwanContact: Global TAC – TaiwanPhone: +886- 7- 536 2567Facsimile: +886-7-536 2039Mail: Honeywell Taiwan Ltd.17F-1, No. 260, Jhongshan 2nd Road.Cianjhen DistrictKaohsiung, Taiwan, ROCEmail: Global-TAC-Taiwan@Support and Other ContactsUniformance - FILEACCESS and FTP RDI Installation Guide vJapanContact: Global TAC – JapanPhone: +81-3-6730-7160Facsimile: +81-3-6730-7228Mail: Honeywell Japan Inc.New Pier Takeshiba, South Tower Building,20th Floor, 1-16-1 Kaigan, Minato-ku,Tokyo 105-0022, JapanEmail: Global-TAC-JapanJA25@ElsewhereCall your nearest Honeywell office.World Wide WebHoneywell Solution Support Online: /psTraining ClassesHoneywell Automation College: Support and Other Contactsvi Uniformance - FILEACCESS and FTP RDI Installation GuideContents1.Introduction to FILEACCESS RDI and FTP RDI (9)1.1RDI Description (9)Tag Capacity Limitations (9)Concurrent Interface Limitations (10)Data Throughput and Constraints (10)Required Support Files (10)Required Hardware and Software (10)2.Installation of FILEACCESS RDI and FTP RDI (11)2.1Installation Checklist (11)2.2To Define Source System Tag Attributes and Data Types (13)2.3To Complete the RDI Parameter Configuration Form (14)2.4To Complete the Interfaces (RDI’s & Links) Form (15)RDIs participating in an RDC scheme (19)2.5To Increase the Maximum Tags (PhdParams.Dat) (20)2.6To Run RDISetup (21)Interfaces_CustomConfig.Dat (24)2.7To Define and Start RDIs on a Running PHD System (26)2.8Modify Registry Settings (27)To Set the Polled Mode Stamping Option (27)To Set the RDI Startup Option (28)To Prevent Duplicate Bad Tag Messages (31)3.Configure PHD Tags for FILEACCESS RDI (33)3.1Tag Field Usage (33)Tag Type and Tag Attribute (33)Source Index A (33)4.Configure PHD Tags for FTP RDI (35)4.1Tag Field Usage (35)Tag Type and Tag Attribute (35)Uniformance - FILEACCESS and FTP RDI Installation Guide viiContents4.2Values for ST Type Tags (36)5.Format of Configuration File and Input Data File for FILEACCESS RDI (41)5.1Input Data File Format – Exception Mode Tags (41)5.2Configuration File Format – Exception Mode Tags (42)Additional Considerations (45)Warnings (46)Comment Lines (46)6.Format of Configuration File and Input Data File for FTP RDI (47)6.1Input Data File Format – Polled Mode Tags (47)6.2Configuration File – Polled Mode Tags (48)6.3Line Formatting Option (51)6.4Comment Lines (52)7.TCP/IP Configuration File Format (53)8.Troubleshoot RDI (55)8.1Common Installation Problems (55)8.2Problem Diagnosis (55)Glossary (57)Index 59viii Uniformance - FILEACCESS and FTP RDI Installation Guide1. Introduction to FILEACCESS RDI and FTP RDI 1.1 RDI DescriptionThe FILEACCESS RDI and the FTP RDI are used to read data from text files eitherdropped at a local directory or pulled from an FTP server on the network.RDI Type RDI Mode RDI FunctionFILEACCESS RDI Exception Reads files on the local system. Each filehas one or more lines and each linerepresents a single value for a different tag.The files can be:∙Placed in the directory by a remote system,∙Pulled from an FTP server, or∙Pulled from a mapped network drive.FTP RDI Polled Pulls a different file for each tag (as specifiedin the 'Source Tag Name' field), Each filecontains one or more lines, representing thecurrent value and some history.The system uses standard file I/O to read the files associated with each tag, and standardTCP/IP using the FTP protocol. Standard file I/O and TCP/IP sockets provide thefunctionality of the RDIs.You configure each RDI in the Interfaces (RDI’s & Links) form through the PHDConfiguration Tool (previously named TPI).Tag Capacity LimitationsFILEACCESS RDIThe capacity of the RDI is limited by access speed of the file system.FTP RDIThe capacity of the system is limited by the access speed of the network. File retrievalfrom the FTP Server by the FTP RDI can take anywhere from a few seconds to a numberof minutes using FTP. This can put a severe limit on the RDI throughput. As long asFTP requests are not too frequent, then the number of tags is not limited; however, therate of input is limited.Uniformance - FILEACCESS and FTP RDI Installation Guide ∙ 91 Introduction to FILEACCESS RDI and FTP RDI1.1 RDI DescriptionConcurrent Interface LimitationsThere are no concurrent interface limitations for these interfaces.Data Throughput and ConstraintsData throughput is governed by the transfer times of the FTP access or networkconnection.Required Support FilesThe following items are delivered as part of the interface:∙RDIFTP.DLL∙RDITCPIP.DLL∙RDIUTILS.DLLThe FTP RDI and the FILEACCESS RDI use the same .dll files.Required Hardware and SoftwareA hardware connection must exist in the form of a LAN connection providing file access.If access to remote FTP sites is required, then the necessary network access must beavailable.For the FILEACCESS RDI, the default is to just read the files from the local directory;however, the RDI can be configured to pull files from an FTP server or a mappednetwork drive, and place the files into the local directory.10 ∙ Uniformance - FILEACCESS and FTP RDI Installation Guide2. Installation of FILEACCESS RDI and FTP RDI 2.1 Installation ChecklistTask GotoNotes1. Prepare the System EnvironmentTCP/IP must be configured. This guide – sectionRequired Hardware andSoftware2. Enter Database DataIn the PHD Configuration Tool, modify the Tag Source Configuration form, if necessary. This guide – section ToDefine Source SystemTag Attributes and DataTypesIf parameters to behistorized by PHD are notspecified in the standard list(such as parameters withlarger fields), then you mustadd them to this form.In the PHD Configuration Tool, complete the RDI Parameter Configuration form, if necessary This guide – section ToComplete the RDIParameter ConfigurationFormNo modifications to thisform are required.In the PHD Configuration Tool, complete the Interfaces (RDI’s & Links) form. This guide – section To Complete the Interfaces (RDI’s & Links) Form(Optional) In the PHD Configuration Tool, configure additional copies of the Interfaces (RDI’s & Links) form if the RDI is to participate in a Robust Data Collection scheme. Robust Data CollectionUser Guide (pim3501)To support RDC, two orthree copies of each RDImust be configured,depending on the RDCmode of the RDI.(Optional) In the PHD Configuration Tool, complete the RDC Configuration form if the RDI is to participate in a Robust Data Collection scheme. Robust Data CollectionUser Guide (pim3501)Port numbers must beassigned to each RDI thatis to participate in an RDCscheme.Uniformance - FILEACCESS and FTP RDI Installation Guide 112 Installation of FILEACCESS RDI and FTP RDI 2.1 Installation Checklist12 Uniformance - FILEACCESS and FTP RDI Installation GuideTask Go to Notes3. Verify PHD System Configuration Modify the PhdParams.Dat file,if necessary, to ensure that tags to be built against the new RDI will not exceed the specified maximum. This guide – section To Increase the Maximum Tags (PhdParams.Dat)MAX_TAGS and MAX_TAGNO4. Create RDIRun RDISetup to create the appropriate RDI files. This guide – section To Run RDISetupStart>Programs>Uniforman ce>PHD Server>PHD RDI Configuration In a running PHD system, use PHDMAN to define and start the RDI.This guide – section To Define and Start RDIs on a Running PHD SystemPHDMAN EXECUTE Interfaces.Dat PHDMAN STA INT5. Modify Registry Settings (Optional) If appropriate, add the "NewPolledModeStamping" parameter to the registry for the new RDI.This guide – section To Set the Polled Mode Stamping OptionEnable this option if you want the RDI to defer its next scan if it falls behind, instead of starting it immediately after the current scan.(Optional) If appropriate, add the RDIDependency parameter to the registry for the new RDI. This guide – section To Set the RDI Startup OptionEnable this option if you want to startup RDIs in dependency order. (Optional) If appropriate, add the PreventBadTagMessages parameter to the registry for the new RDI.This guide – section To Prevent Duplicate Bad Tag MessagesEnable this option if you want only one record for a tag's bad value to be output to the PHD_EVENT.log.6. Configure PHD Tags In the PHD Configuration Tool, configure PHD tags.This guide – section Configure PHD TagsPHD ConfigurationTool>Tag Configuration form2 Installation of FILEACCESS RDI and FTP RDI2.2 To Define Source System Tag Attributes and Data Types 2.2 To Define Source System Tag Attributes and Data TypesThe Tag Source Configuration form defines the data mapping between a source systemand PHD. Perform the following steps to add attributes for the source system type to theTag Source Configuration form, if necessary.Perform the following procedure only if parameters to be historized are not alreadyspecified in the RDBMS, such as user-defined parameters.Step Action1 Open the PHD Configuration Tool.2 Under Interfaces menu select ‘Source Systems’.3 Select FILEACCESS or FTP in the ‘Current list of Source System records’window.4 In an empty record at the bottom of the form, add the information foradditional parameter(s), as necessary and click the ‘Save’ button.REFERENCE: For definitions of the PHD data types, refer to the PHD System Manual(pim0301), section Understanding the Tag Source Definitions.Uniformance - FILEACCESS and FTP RDI Installation Guide 132 Installation of FILEACCESS RDI and FTP RDI2.3 To Complete the RDI Parameter Configuration Form14 Uniformance - FILEACCESS and FTP RDI Installation Guide2.3 To Complete the RDI Parameter Configuration FormNo modifications are required to the RDI Parameter Configuration form. Perform the following steps to view the form.Step Action 1 Open the PHD Configuration Tool.2 Under Interfaces menu select ‘RDI Types ’.3 Select FILEACCESS or FTP in the ‘Current list of RDI Type records ’ window.4 See Table 1 for the description of each field. 5Close the form.Table 1 – RDI Parameter Configuration FormFieldDescriptionRDI Type Name FILEACCESS or FTP Description Description of the RDI Type Parameter NameName of the parameterFor definitions of the parameters:See Table 3 for FILEACCESS RDI See Table 4 for FTP RDI SeqThe position of the parameter in the RDI program command line.Mandatory Parameter Designates whether parameter is always required. Default Include Specifies that for new RDI’s that this parameter should be included by default.Command Line Prefix The prefix text for the specific parameter. This is usually the fixed portion of a parameter.Default Value Specifies the default value to be transferred to the Interfaces (RDI’s & Links) form Description Description of the parameter.Validation TextThe validation to apply when a value is entered in2 Installation of FILEACCESS RDI and FTP RDI2.4 To Complete the Interfaces (RDI’s & Links) FormField Descriptionthe Interfaces (RDI’s & Links) form.2.4 To Complete the Interfaces (RDI’s & Links) FormThe File Access and FTP RDIs require the activation mode and, conditionally, a path,search mask, and file deletion command specified in the Interfaces (RDI’s & Links)form.Perform the following steps to configure a specific RDI.Step Action1 Open the PHD Configuration Tool.2 Under Interfaces menu select ‘Interfaces (RDI’s and Links)’.3 Fill in the RDI Name, Hostname, Description, and select the Enabled checkbox.4 Select FILEACCESS or FTP as the Source System and then click the‘Retrieve Parameters’ button.The parameters for the RDI will be populated in the table at the bottom of thedisplay.5 After entering the required data, close the form.Table 2 – Interfaces (RDI’s & Links) Form – FILEACCESS and FTP RDIsField Description *RDI/Link Name Enter the PHD Real-time Data Interface name (interfaceinstance name).The RDI Name and Hostname combination must be aunique identifier that will be used to identify data parametersto be collected from the interface.*Host Name Enter the name of the host on which the interface executes.When the user runs RDISetup, the utility only processes theinterfaces defined in the database for the host on whichRDISetup is executing.For PHD systems with buffered PHD Servers, the sameinterface name can be defined on two different hosts.Uniformance - FILEACCESS and FTP RDI Installation Guide 152 Installation of FILEACCESS RDI and FTP RDI 2.4 To Complete the Interfaces (RDI’s & Links) Form16 Uniformance - FILEACCESS and FTP RDI Installation GuideField DescriptionPrimary TDA HostSpecifies that the host running this RDI acts as the primary system that should be queried by other PHD Servers using Transparent Data Access (TDA). *Description Enter the description of the RDI.Enabled Select whether the interface is enabled. If this flag is not set, the RDISetup utility does not process this interface. *RDI Type Name Set to FILEACCESS or FTP *Remote RDI Type NameLeave blankSource System Select FILEACCESS or FTP . Parameter Name ValueFor FILEACCESS RDI parameters, refer to Table 3. For FTP RDI parameters, refer to Table 4.Table 3 – RDI Parameters – FILEACCESS RDIParameter NameValueDescription*MODE SERVER SERVER specifies that the RDI is toexecute in FILE ACCESS mode.Tip:FILEACCESS mode expects files to be placed on its local drives, and FTP mode fetches the files. Since the FILEACCESS RDI expects others to place the files, Honeywell named itSERVER mode; and since the FTP RDI retrieves the files, Honeywell named it CLIENT mode.*CONFIGFILE /c<ConfigFile> Specifies the file that details theconfiguration information. HISTORYMODE /h/h enables history recovery. This can cause excess memory usage and file I/O if many files are being read.2 Installation of FILEACCESS RDI and FTP RDI 2.4 To Complete the Interfaces (RDI’s & Links) FormUniformance - FILEACCESS and FTP RDI Installation Guide ∙ 17Parameter Name Value DescriptionNOINITTAG/i/i disables the insertion of a zero (0) value with –1 confidence at RDI startup, shutdown, or every 24 hours when the RDI resynchronizes its clock.TAGLOOKUP /n<TagFile> Specifies a file containing a list ofnames that will be received as theincoming tag name and the name that is to be checked against the source tagname configured in PHD. Thisallows longer incoming tag names to be matched against shorter PHD tag names. Tag names are matched on a case-insensitive basis.Tag Lookup File Format:<LongTagName> = <ShortTagName>VALUELOOKUP /m<MacroFile> Specifies the name of a file thatcontains a list of replacements for received values.For example, if a value of ‘TRUE’ is received, it needs to be replaced with ‘1’.The macro file can contain many lines. Each line contains a lookup value (case-insensitive) and a replacement value. Examples:∙ TRUE = 1 ∙ YES = 1 ∙ FALSE = 0 ∙ NO = 0TRANSFERMODE /t<mode> Specifies whether to transfer the file inBINARY or ASCII mode during FTP transfers.Where <mode > is BINARY or ASCII. Default is BINARY.2 Installation of FILEACCESS RDI and FTP RDI 2.4 To Complete the Interfaces (RDI’s & Links) Form18 ∙ Uniformance - FILEACCESS and FTP RDI Installation GuideTable 4 – RDI Parameters – FTP RDIParameter NameValueDescription*MODE CLIENT CLIENT specifies that the RDI is to executein FTP mode.Tip:FILEACCESS mode expects files to be placed on its local drives, and FTP mode fetches the files. Since the FILEACCESS RDI expects others to place the files, Honeywell named it SERVER mode; and since the FTP RDI retrieves the files, Honeywell named it CLIENT mode.DEBUGLEVEL/v<number> or VERBOSE/V<number> or VERBOSE sets the tracing information level for client mode. Where <number> is a value from 0 to 2: 0 = None 2 = Full Default is 0.NOINITTAG /i/i disables the insertion of a zero (0) value with –1 confidence at RDI startup,shutdown, or every 24 hours when the RDI resynchronizes its clock.VALUELOOKUP /m<MacroFile> Specifies the name of a file that contains alist of replacements for received values.For example, if a value of ‘TRUE’ isreceived, it needs to be replaced with ‘1’. The macro file can contain many lines. Each line contains a lookup value (case-insensitive) and a replacement value. Examples:∙ TRUE = 1 ∙ YES = 1 ∙ FALSE = 0 ∙ NO = 02 Installation of FILEACCESS RDI and FTP RDI2.4 To Complete the Interfaces (RDI’s & Links) FormParameter Name Value DescriptionTRANSFERMODE /t<mode> Specifies to transfer file in BINARY orASCII mode during FTP transfers.Where <mode > is BINARY or ASCII.Default is BINARY.RDIs participating in an RDC schemeIf the RDI is to participate in a Robust Data Collection (RDC) scheme, then two or threecopies of the Interfaces (RDI’s & Links) form must be configured, depending on whether the RDC scheme is for a single or dual buffer system.In addition, after the Interfaces (RDI’s & Links) forms are completed, the RDCConfiguration form must be completed.REFERENCE: For RDC configuration details refer to the Robust Data Collection UserGuide (pim3501).Uniformance - FILEACCESS and FTP RDI Installation Guide 192 Installation of FILEACCESS RDI and FTP RDI2.5 To Increase the Maximum Tags (PhdParams.Dat)2.5 To Increase the Maximum Tags (PhdParams.Dat)Perform the following steps to view or modify the maximum number of tags configuredfor the PHD System, to ensure that tags built against the new RDI do not exceed thespecified maximum.Step Action1 Open the file <install directory>PHDServer\NtSite\PhdParams.Dat.2 If necessary, increase the values of the following parameters:∙MAX_TAGS - Maximum number of defined tags.∙MAX_TAGNO - Maximum possible tag numbers.3 Save the file.4 If you modified the above parameters, then you need to Stop and Cold Startthe PHD Server in order to resize its global memory sections.To restart the PHD Server, execute the following commands at a commandprompt:PHDCTL STOPPHDCTL START COLD20 ∙ Uniformance - FILEACCESS and FTP RDI Installation Guide2 Installation of FILEACCESS RDI and FTP RDI2.6 To Run RDISetupUniformance - FILEACCESS and FTP RDI Installation Guide 212.6 To Run RDISetupPerform the following steps to run the RDISetup utility, which creates the files for aparticular RDI.REFERENCE: For more information about how RDISetup works, refer to the Basic RDI Installation Guid e (in0701).Attention: The following steps must be performed on the PHD Server machine onwhich the RDI is to run.Attention: Do NOT delete "127.0.0.1 localhost" from the Hosts file. This entry (which is created when Windows is installed) is used by PHD functions. If it is deleted, PHD will not function properly.Prerequisite: Log on to the operating system as a user that is member of the Product Administrators group. Tip: If you change local rights, you must logon again to establish the change.Step Action 1 Make a backup copy of the following files located at <install directory>\PHDServer\NtSite\:Interfaces.Dat and Start_Interfaces.Dat .2 If the RDI was previously created in error, execute the PHDMAN command tostop the interface.PHDMAN SHUT INT <rdiname >TIP:Later, when you execute the 'Save RDI/Link Configuration' command throughRDISetup, the utility may attempt to copy new dlls for every interfaceconfigured for this node. If you choose to leave any existing interfacesrunning on this node, then when RDISetup attempts to copy the dll for arunning interface, the copy fails and an error message is output.3 On the PHD Server where the RDI is to run, open the RDISetup utility:Start>Programs>Uniformance>PHD Server>PHD RDI Configuration4Select the RDI of interest in the left pane.RESULT: The RDI parameters appear in the right pane.5 Verify/modify the values of the items listed Table 5, as needed.2 Installation of FILEACCESS RDI and FTP RDI2.6 To Run RDISetup22 ∙ Uniformance - FILEACCESS and FTP RDI Installation Guide Step Action 6To run RDISetup, select File and choose Save RDI/Link Configuration . 7 Verify that RDISetup accomplished the following for the new RDI:∙ Rewrote the Interfaces.Dat file to add commands that define the new RDI.∙ Rewrote the Start_Interfaces.Dat file to add commands for starting the newRDI.∙ It may have copied the DLL for the interface type as RDI<rdiname>.DLL tothe RDI directory. This will NOT occur for those RDI’s distributed with thePHD Server.Note: RDISetup never writes data to the database.8Verify that the Interfaces.Dat and the Start_Interfaces.Dat files contain the appropriate parameters. 9 Verify that the GO file or registry reflects the correct RDI parameters enteredthrough the Interfaces (RDI’s & Links) form.Registry location: HKLM \ SYSTEM \ CurrentControlSet \ Services\ <RDIServer> \ Parameters \ RDIList \ <rdiname >Table 5 – Parameters Entered Through the RDISetupThis parameter…Sets this… RDIServer Instance If the PHD Server has more than one RDIServer, then thisparameter represents the RDIServer to which this RDI is associated.RDIServer Port If the PHD Server has more than one RDIServer, then thisparameter represents the port number of the RDIServer towhich this RDI is associated.MIN_HISTRECMNAttention: The meaning of the history recovery limitvalues is different for RDIs participating in an RDCscheme than it is for normal RDIs. Normal RDIs (D) This is the minimum duration (minutes)of system outage for invocation of history recovery fromthe real-time system. No history recovery is performed ifthis value and the MAX_HISTRECMN are set to zero (0).Note: For the FILEACCESS RDI and the FTP RDI, theMIN_HISTRECMN value is usually set to 0 for historyrecovery.2 Installation of FILEACCESS RDI and FTP RDI2.6 To Run RDISetupUniformance - FILEACCESS and FTP RDI Installation Guide 23This parameter… Sets this… RDC RDIs (D) The following table shows the meaning ofthe limit values for RDC RDIs. REFERENCE: RobustData Collection Configuration Guide (pim3501).If <limit > is…Then… Both 0 (zero) All history is recovered.Note: The opposite is true for non-RDC RDIs, where no history isrecovered if both parameters are set to zero.Both 1 History recovery is disabled.This setting applies only to RDIsrunning on Shadow RDC nodes.Note: If MIN_HISTRECMN is set toany non-zero value greater than orequal to MAX_HISTRECMN, thenRDC history recovery is disabled.MIN_HISTRECMN 0MAX_HISTRECMN 2 History recovery is minimized (limited to one minute of history). MAX_HISTRECMN For normal RDIs: (D) This is the maximum recoverablehistory duration (minutes).Note: For the FILEACCESS RDI and the FTP RDI, theMAX_HISTRECMN value can be set to a value thatspecifies the maximum amount of history to be recoveredfrom an input file. For RDC RDIs: Refer to the previous table forMIN_HISTRECMN.XSCANSECS (D) Exception interface scan wait interval (scan interval inexception mode). The real-time system will be queried forvalues at this interval (seconds).Use Remote ClockREMCLOCK(D) For the FTP RDI to pass the time from the input file into the tag queue, the REMCLOCK value must be set to 1.The FILEACCESS RDI does not use this parameter.REMSYNCH The FILEACCESS RDI and the FTP RDI do not use thisparameter.。

Date of implementation: 1 March 2010Introduction:The holder of a Certificate of suitability shall inform the EDQM of any change to the information in the certification dossier by sending an application form and all necessary documents demonstrating that the conditions laid down in the present guideline are met.Classification of changesThe changes have been classified in three categories (notification/minor/major) depending on the potential impact of the change on the quality of the final substance. These three categories are based on those (IA-IAIN/IB/II) of the Commission Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisation for medicinal products for human use and veterinary medicinal products.Any change not classified as a notification or a major change should be classified as a minor change except in the following cases where a new application should be submitted:- addition of a new route of synthesis and/or a new manufacturing site where the specifications of the final substance are different from the one already approved- transfer to a new holder that is not the same legal entity as the approved one, where the transfer does not occur because of a merger or because the company is sold, and where the manufacturer does not take out the Certificate of suitability in their own name.The changes related to Ph. Eur. monograph revisions or any other regulatory requirements are treated separately and generally initiated by the EDQM.执行日期：2010年3月1日介绍：欧洲药典适用性证书持有人必须向EDQM报告所有与申报文件有关的变更，申报时应填写申请表格和所有必要的资料，证明变更符合现行指南的规定。