The RDF Schema Specification Revisited

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FDA检验方法验证指南中英文

美国FDA分析方法验证指南中英文对照Guide to the U.S. FDA method validation Chinese and English目录ContentsI. INTRODUCTION (3)II. BACKGROUND (4)III. TYPES OF ANALYTICAL PROCEDURES (6)IV. REFERENCE STANDARDS (7)V. METHODS VALIDATION FOR INDs (10)VI. CONTENT AND FORMAT OF ANALYTICAL PROCEDURES FOR NDAs, 230ANDAs, BLAs, AND PLAs (11)VII. METHODS VALIDATION FOR NDAs, ANDAs, BLAs, AND PLAs (15)VIII. STATISTICAL ANALYSIS (23)IX. REVALIDATION (24)X. METHODS VALIDATION PACKAGE: CONTENTS AND PROCESSING (25)XI. METHODOLOGY (30)ATTACHMENT ANDA, ANDA, BLA, AND PLA SUBMISSION CONTENTS (40)ATTACHMENT BMETHODS VALIDATION PROBLEMS AND DELAY (41)GLOSSARY (42)美国FDA分析方法验证指南中英文对照I. INTRODUCTIONThis guidance provides recommendations to applicants on submittinganalytical procedures, validation data, and samples to support thedocumentation of the identity, strength, quality, purity, and potencyof drug substances and drug products.1. 绪论本指南旨在为申请者提供建议，以帮助其提交分析方法，方法验证资料和样品用于支持原料药和制剂的认定，剂量，质量，纯度和效力方面的文件。

欧洲药物管理EDMF和CTD基本介绍

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。

20140219_Analytical_Procedures_and_Methods_Validation_for_Drugs_and_Biologics

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Procedures and Methods Validation for Drugsand BiologicsDRAFT GUIDANCEThis guidance document is being distributed for comment purposes only.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be submitted within 90 days of publication in the Federal Register of the notice announcing the availability of the draft guidance.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.。

AMS2241S

__________________________________________________________________________________________________________________________________________ SAE Technical Standards Board Rules provide that: “This report is published by SAE to advance the state of technical and engineering sciences. The use of this report is entirely voluntary, and its applicability and suitability for any particular use, including any patent infringement arising therefrom, is the sole responsibility of the user.”SAE reviews each technical report at least every five years at which time it may be revised, reaffirmed, stabilized, or cancelled. SAE invites your written comments and suggestions.Copyright © 2016 SAE InternationalAll rights reserved. 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”。

欧盟GMP附录15：确认与验证(修订版英文+中文)

1.1.所有的确认和验证都应当被计划，并考虑到设施、设备、公用系统、工艺和产品的生命周期。
1.2.Qualification and validation activities should only be performed by suitably trained personnel who follow approved procedures.
概述
质量风险管理的方法应作为质量风险管理系统的一部分贯穿于药品的整个生命周期，应基于对设施、设备、公用系统和工艺的论证和书面风险评估决定确认和验证的范围和程度。回顾性验证不再被认为是可接受的方式。如果方法经过论证，并且获取数据的整个过程中有足够的保证性控制措施，也可以使用从生产商自身程序以外获得的用于支持确认和/或验证研究的数据。
1.2.确认和验证活动应只能由经过培训合格的人员严格按照批准的程序实施。
1.3.Qualification/validation personnel should report as defined in the pharmaceutical quality system although this may not necessarily be to a quality management or a quality assurance function. However, there should be appropriate quality oversight over the whole validation life cycle.
1.4.应当在验证主计划（VMP）或其等同文件中，清晰地界定和记录现场确认与验证程序的关键性要素。
1.5. The VMP or equivalent document should define the qualification/validation system and include or reference information on at least the following:

语义网

【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。

EDMF、CEP、FDA认证及GMP基础知识

2、EDMF：
欧盟药品主文件（European Drug Master File），由欧盟的药品注册当局进行审查。
3、DMF：
美国药物主文件档案（Drug master File），由美国FDA进行认证。
二、CEP认证和EDMF的区别
❖ 是评审方式上的不同； ❖ 针对的情况不同； ❖ 适用的范围不同； ❖ 所要求提供的资料不同； ❖ 申请的结果不同；
GMP内容
❖ GMP要求在机构、人员、厂房、设施设备、卫生、验证、文件、生产管理、质量管理、产品销售与回收、投诉与不良反应报告、自检等方面都必须制订系统的、规范化的规程，通过执行这一系列的规程，藉以达到一个共同的目的：
共同的目的
❖ 防止不同药物或其成份之间发生混杂； ❖ 防止由其它药物或其它物质带来的交叉污染； ❖ 防止差错与计量传递和信息传递失真； ❖ 防止遗漏任何生产和检验步骤的事故发生； ❖ 防止任意操作及不执行标准与低限投料等违
所要求提供的资料不同edmf文件必须包括药物的稳定性研究资料而cos证书的申请文件并不强求这些资料申请的结果不同申请cos证书的结果是直接颁发给原料药的生产厂家一个证书只要将这个证书的复印件提供给欧洲方面的中间商或终端用户对方就可以购买我们的原料药而edmf文件登记的结果是只告诉制剂生产厂家一个edmf文件的登记号欧洲评审机构不会将这个登记号告诉原料药的生产厂家原料药的生产厂家只能从负责申请登记的欧洲药品制剂的生产厂家那儿查询这个登记号三dmf和edmf的区别原料药生产厂家和申请人是两个概念保密问题递交程序原料药生产厂家和申请人是两个概念usdmf可以直接递交但是要通过你指定的美国代理交给fda而不是生产厂家直接给fdadmf可以单独递交但如果没有客户提出申请fda不会进行审查

IEEE standard for Terminology and Test methods for ADC Std 1241-2000

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. Printed in the United States of America.Print:ISBN0-7381-2724-8SH94902PDF:ISBN0-7381-2725-6SS94902No part of this publication may be reproduced in any form,in an electronic retrieval system or otherwise,without the prior written permission of the publisher.IEEE Standards documents are developed within the IEEE Societies and the Standards Coordinating Committees of the IEEE Standards Association(IEEE-SA)Standards Board.The IEEE develops its standards through a consensus development process,approved by the American National Standards Institute,which brings together volunteers representing varied viewpoints and interests to achieve theﬁnal product.Volunteers are not necessarily members of the Institute and serve without compensation.While the IEEE administers the process and establishes rules to promote fairness in the consensus development process,the IEEE does not independently evaluate,test,or verify the accuracy of any of the information contained in its standards.Use of an IEEE Standard is wholly voluntary.The IEEE disclaims liability for any personal injury,property or other damage,of any nature whatsoever,whether special,indirect,consequential,or compensatory,directly or indirectly resulting from the publication,use of,or reliance upon this,or any other IEEE Standard document.The IEEE does not warrant or represent the accuracy or content of the material contained herein,and expressly disclaims any express or implied warranty,including any implied warranty of merchantability orﬁtness for a speciﬁc purpose,or that the use of the material contained herein is free from patent infringement.IEEE Standards documents are supplied‘‘AS IS.’’The existence of an IEEE Standard does not imply that there are no other ways to produce,test,measure,purchase, market,or provide other goods and services related to the scope of the IEEE Standard.Furthermore,the viewpoint expressed at the time a standard is approved and issued is subject to change brought about through developments in the state of the art and comments received from users of the standard.Every IEEE Standard is subjected to review at least everyﬁve years for revision or reaﬃrmation.When a document is more thanﬁve years old and has not been reaﬃrmed,it is reasonable to conclude that its contents,although still of some value,do not wholly reﬂect the present state of the art. Users are cautioned to check to determine that they have the latest edition of any IEEE Standard.In publishing and making this document available,the IEEE is not suggesting or rendering professional or other services for,or on behalf of,any person or entity.Nor is the IEEE undertaking to perform any duty owed by any other person or entity to another.Any person utilizing this,and any other IEEE Standards document,should rely upon the advice of a competent professional in determining the exercise of reasonable care in any given circumstances.Interpretations:Occasionally questions may arise regarding the meaning of portions of standards as they relate to speciﬁc applications.When the need for interpretations is brought to the attention of IEEE,the Institute will initiate action to prepare appropriate responses.Since IEEE Standards represent a consensus of concerned interests,it is important to ensure that any interpretation has also received the concurrence of a balance of interests.For this reason, IEEE and the members of its societies and Standards Coordinating Committees are not able to provide an instant response to interpretation requests except in those cases where the matter has previously received formal consideration. Comments for revision of IEEE Standards are welcome from any interested party,regardless of membership aﬃliation with IEEE.Suggestions for changes in documents should be in the form of a proposed change of text,together with appropriate supporting ments on standards and requests for interpretations should be addressed to:Secretary,IEEE-SA Standards Board445Hoes LaneP.O.Box1331Piscataway,NJ08855-1331USANote:Attention is called to the possibility that implementation of this standard may require use of subjectmatter covered by patent rights.By publication of this standard,no position is taken with respect to theexistence or validity of any patent rights in connection therewith.The IEEE shall not be responsible foridentifying patents for which a license may be required by an IEEE standard or for conducting inquiriesinto the legal validity or scope of those patents that are brought to its attention.IEEE is the sole entity that may authorize the use of certiﬁcation marks,trademarks,or other designations to indicate compliance with the materials set forth herein.Authorization to photocopy portions of any individual standard for internal or personal use is granted by the Institute of Electrical and Electronics Engineers,Inc.,provided that the appropriate fee is paid to Copyright Clearance Center. 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 (/).。

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The RDF Schema Specification RevisitedWolfgang Nejdl and Martin Wolpers and Christian CapelleInstitut für Technische InformatikRechnergestützte WissensverarbeitungUniversität HannoverAppelstraße 4, 30167 Hannover{nejdl,wolpers,capelle}@kbs.uni-hannover.de1AbstractIn this paper, we will discuss the proposed recommendation (March 1999) for an RDF Schema Specification and compare the approach taken in this specification to conventional meta data models. We will point out several pecularities in the RDF schema specification compared to more conventional approaches, which are basically due to the dual role of properties such as subclass and domain both as primitive constructs used in the definition of the RDF schema specification and as specific instances of RDF properties. We then discuss an approach for specifying RDF schemas, which distinguishes between a set of specific properties, which are needed in the RDF meta model itself, and conventional properties. Finally we show how we use this modified RDF meta model in a structured hypertext system (the KBS Hyperbook System), which uses RDF annotations not only for informational purposes, but also for structuring hypertext according to the semantic relationships recorded by these RDF annotations.2IntroductionSemantic annotations and metadata are seen as a crucial technique for transforming the World Wide Web from a huge set of amorphous pages interlinked with each other to a semantic web, which uses semantic annotations in order to give meaning to these pages and their relationships [Lass 1998]. This is in line with the development in other disciplines such as database and software engineering, which use semantic data models and schemas to define and give meaning to data and parts of programs (e.g.[CJB 1998, Guar 1998]).The standard for initiating this transformation is the RDF (Resource Description Framework) Standard [W3C 1998], which has been defined in a set of two documents defining the syntax and semantics of RDF annotations and of RDF schemas. Using RDF, WWW resources are annotated with semantical information, which uses underlying conceptual models (schemas) to define the classes and properties used for these semantic annotations. The shared use of such a schema makes it possible for a group of people to use semantic annotations, which are comparable with each other, because they use the same set of concepts and properties to describe their WWW pages. In this paper, we will discuss the proposed recommendation (March 1999) for an RDF Schema Specification [W3C 1999b]. We will point out several pecularities in the RDFModellierung 2000 schema specification compared to more conventional meta data models, which are basically due to the dual role of the properties rdfs:subClassOf, rdf:type, rdfs:domain and rdfs:range, which are used both as primitive constructs in the definition of the RDF schema specification and as specific instances of RDF properties. This dual role makes it possible to view e.g. rdfs:subClassOf as an RDF property just like other predefined or newly introduced RDF properties, but introduces a self referentiality into the RDF schema definition, which makes it rather unique when compared to conventional model and meta modeling approaches, and makes the RDF schema specification very difficult to read and to formalize.Based on this observation, we discuss an alternative approach for specifying RDF schemas, which distinguishes between primitive properties such as rdfs:subClassOf, which are needed in the RDF meta model itself, and conventional properties. This alternative meta model separates clearly between meta modeling constructs and their instantiations and avoids any self referentiality for these constructs, making it similar to more conventional meta modeling approaches such as IRDS [IRDS 1990].Finally we use this modified RDF meta model in a structured hypertext system (the KBS Hyperbook System [FHN 1997, FNW 1998, NeWo 1998, HeNe 1999]), which uses RDF annotations not only for informational purposes, but also for structuring hypertext according to the semantic relationships recorded by these RDF annotations. Using this meta model, the KBS Hyperbook System can display both conventional metadata information for WWW pages, as well as use metadata information concerning semantical relationships to connect semantically related pages based on these relationships.After discussing the RDF schema specification in Section 2, we introduce and discuss an alternative RDF schema specification in Section 3. The main goal of this alternative model is to make explicit the different meanings of the original RDF schema constructs. We therefore concentrate on the main RDF constructs in order not to complicate our presentation and ignore in this paper some RDF constructs like rdfs:ConstraintProperty or rdfs:ConstraintResource. Finally, Section 4 gives a short introduction to the KBS Hyperbook System as discussed in [NeWo 1999] and uses our alternative RDF schema specification as a basis for connecting semantically related WWW pages based on semantic relationships expressed by RDF annotations.3The RDF Schema SpecificationFirst, let us describe the RDF Schema Specification, based on [W3C 1999b], in order to discuss and point out some unconventional design decisions taken in this specification. We will try to make this chapter self-contained, but a working knowledge of [W3C 1999b] will help to understand the discussion in this section. The prefixes rdf: and rdfs: indicate, whether a resource is part of the RDF Data Model [W3C 1999a] or the RDF Schema Specification [W3C 1999b].RDF schemas are used to define the structure of the metadata that are used to describe WWW resources (i.e. WWW pages or parts of WWW pages, referenced by an URL). The RDF Schema Specification consists of some basic classes and properties, and can be extended by others to fit possibly any given domain. Classes are arranged hierarchically, and the use of properties can be constrained to members of certain classes. The root of the class hierarchy is rdfs:Resource, rdfs:Class is subclass of rdfs:Resource.The RDF Schema Specification RevisitedFigure 1: RDF Classes and Resources as Sets and Elements Properties are defined by the rdf:Property class and can be seen as attributes, that are used to describe resources by assigning values to them. Properties are resources themselves. The RDF Schema Specification defines four specific properties (rdfs:subClassOf, rdf:type, rdfs:range, rdfs:domain) that have, unlike other predefined or self-defined properties, certain constraints. These four properties are both used to define the other RDF schema constructs and also as constructs defined in the RDF schema. Additional predefined properties such as rdfs:seeAlso and rdfs:comment are used to specify resources with related subjects, or to give a human readable description of a resource. The fact, that these properties are predefined can be seen as a convenience, they are not needed for the definition of other properties.Figure 1, 2 and 3 (which we have reproduced from [W3C 1999b]) show the RDF schema specification as a set of pictures. We will use an abbreviated description of these pictures based on the text in [W3C 1999b] and discuss the design issues we want to address in our alternative RDF schema specification model. Figure 1 shows RDF classes, subclasses and resources as sets, subsets and elements. A class is depicted by a rounded rectangle, a resource is depicted by a large dot. Arrows are drawn from a resource to the class it defines. A sub-class is shown by having a rounded rectangle (the sub-class) completely enclosed by another (the super-class). If a resource is inside a class, then there exists either an explicit or implicit rdf:type property of that resource whose value is the resource defining the containing class.The constraint properties rdfs:range and rdfs:domain are distinguished from the other predefined properties. The property rdf:type is present both as a specific property and depicted as an arrow, rdfs:subClassOf both as a specific property and depicted as set containment.Figure 2 shows the same information about the class hierarchy as in figure Figure 1, but does so using a …nodes and arcs“ graph representation of the RDF data model. If a class is a subset of another, then there is an rdfs:subClassOf arc from the node representing the first class to the node representing the second. Similarly, if a Resource is an instanceModellierung 2000 of a Class, then there is an rdf:type arc from the resource to the node representing theclass.Figure 2: Class Hierarchy for the RDF SchemaAgain, rdfs:subClassOf is present both as a specific property and a primitive construct (an arrow labelled with …s“), rdf:type as specific instance of property and as primitive construct (an arrow labelled with …t“).Figure 3: Constraints in the RDF SchemaFigure 3 takes a different view compared to the previous two figures, and uses rdfs:range and rdfs:domain as primitive constructs to constrain the relationship between RDF classes and properties. Now, rdfs:range and rdfs:domain occur both as primitive constructs and as explicit properties.The RDF Schema Specification Revisited4An Alternative Approach to the RDF Schema SpecificationAs discussed in the previous section, the properties rdfs:subClassOf, rdf:type, rdfs:range and rdfs:domain are used both as primitive constructs for specifying RDF schemas and also as specific properties defined by RDF. This is probably at least partially motivated by the goal to make the RDF schemas and all their constructs themselves available as explicit metadata about the RDF schemas.However, this makes it very difficult to formalize the RDF schema specfication as described in [W3C 1999b] (or even impossible). We are currently exploring this issue in more detail.In the following, we will therefore distinguish between the specification for RDF schemas (i.e. how RDF annotations are structured and used) and the view, that RDF schemas (and their parts) are themselves data, which are defined by specific WWW resources. Additionally, we will distinguish between the different uses of rdfs:subClassOf, rdf:type, rdfs:range and rdfs:domain, and introduce different constructs whenever they are used in different contexts or represent them by primitive constructs from the modeling language.As modeling language we will use O-Telos [MBJ+ 1990, SJJ 1996], which is a language very suitable for modeling and meta modeling tasks. The main constructs in O-Telos are Class and Relation (resp. Attribute). Predefined relations are the …isA“-Relation (denoting a class - subclass relationship) and the …in“-Relation (denoting the relationship between a class and its instances). The original RDF schema specification is not expressible in O-Telos, as this would lead to constructs like …type type property“, where the first …type“ is the RDF property with this name, and the second …type“ is the modeling language construct expressing instantiation (i.e. …type“ is a …type“ (an instance) of property).Figure 4 represents the part of the RDF schema specification, which defines the main RDF constructs used for constructing RDF schemas and how these constructs are used for annotating WWW resources. We have decided not to include a few RDF constructs like rdfs:ConstraintProperty or rdfs:ConstraintResource, as they are not relevant to our discussion. Figure 4 shows the familiar constructs of RDF_Class and RDF_Property. They are related through the relationships RDF_Domain and RDF_Range, which correspond to rdfs:domain and rdfs:range. However, RDF_Domain and RDF_Range are specific relationships defined by this specification, and are therefore no instances of RDF_Property.rdfs:subClassOf and rdf:subPropertyOf are substituted similarly by the two relationships RDF_Subclass and RDF_Subproperty, which have the same semantics as the metalanguage construct …isA“ in O-Telos, and allow the definition of class - subclass and property - subproperty relationships. rdf:type is used in different meanings in the RDF Schema specification. In case it is used to express the relationship between RDF metadata and a conventional WWW resource, we introduce the corresponding relations of …RDF_Annotates“ and …RDF_Defined_By“. In case it is used as conventional instantiation (needed in our model only for instantiating the RDFModellierung 2000Figure 4: Main Constructs of the Alternative RDF Schema Specification schema to get the actual RDF annotations, as discussed below), we substitute it by the corresponding construct …in“ from O-Telos, which denotes instantiation.We distinguish between two subclasses of RDF_Class, namely RDF_Annotation_Class and RDF_Primitive_Type. RDF_Annotation_Class (plus subclasses like RDF_SeeAlso) has as instances what we might call RDF_Annotation_Objects, which (together with their instantiated properties) basically correspond to RDF statements and are used to annotate WWW resources. RDF_Primitive_Type with subclasses like String, etc. has as instances specific values for RDF properties (of type String, Integer, etc.) An RDF_WWW_Resource can be annotated by more than one RDF_Annotation_Object (i.e. when different RDF schemas are used to define the metadata for a specific WWW resource).Figure 5: Predefined properties and types of the alternative RDF Schema Specification If we look at the class hierarchy in Figure 2 and compare it to our alternative specification, we have the following additional differences:•We have not modelled, that an rdfs:Class can be instance of itself. It is not quite clear from the RDF Schema Specification, in which circumstances this additional possibility should be used, and also is suspiciously close to Russels paradox (no set can be element of itself).•The rdfs:subClassOf relationship between rdfs:Resource and rdfs:Class and rdfs:Property is not modelled. As it is used in the RDF Schema Specification only when specifying domains and ranges (as rdfs:Resource), we have substituted rdfs:Resource in these cases with more specific classes (RDF_Class etc.)The RDF Schema Specification Revisited•We have substituted the rdf:type relationship between rdfs:Class and rdfs:Resource with RDF_Annotates and RDF_Defined_By.Specific types and properties defined in an RDF schema are subclasses and subproperties of RDF_Class and RDF_Property, so more specific properties have more specific classes for their RDF_Range and RDF_Domain attributes.Figure 5 shows several predefined properties and types, which can be used in RDF schemas. These are subclasses of RDF_Relational_Property, RDF_Primitive_Property and RDF_Primitive_Type. Additional subclasses can be defined as needed (as will be seen in Section 4).Figure 6: Basic RDF Constructs as Instances of RDF_DefinitionFigure 6 shows, that RDF schema constructs (RDF_Class, RDF_Property, etc.) are instances of the class …RDF_Definition“, which is connected to the class RDF_WWW_Resource by the specific relation RDF_Defined_By (i.e. each RDF_Definition is itself defined by a WWW resource).We think, that this alternative RDF schema specification achieves basically the same goals as the original specification, but makes it much easier to read and to formalize the RDF meta model because of its clear distinction between primitive constructs used for specifying this meta model and other …conventional“ properties, and its use of different relations, whenever different meanings have to be represented.5Using the KBS Hyperbook for Visualizing Semantic RelationshipsFinally, we show how we visualize semantic relationships expressed as RDF-like metadata specified according to our alternative specification described in the previous chapters using the KBS Hyperbook System [NeWo 1999, HNN+ 1999]. Such a hyperbook [HNN+ 1999] is defined as follows:A Hyperbook is an information repository, which integrates a set of (possiblydistributed) information sources using explicit semantic models and metadata. Following this definition a Hyperbook uses semantic models and meta data to structure the documents. The KBS Hyperbook (as described in [HNN+ 1999]) employs a general representation model which defines the basic constructs of each hyperbookModellierung 2000 Additional presentation classes govern the document layout. Semantic relationships between WWW pages can be modeled according to the representation model and displayed as indices, links or sequences, together with the corresponding WWW page.Figure 7: The KBS Hyperbook using our RDF Schema SpecificationThe alternative RDF Schema definition introduced in the previous sections states such a general representation model. It is therefore possible to use our RDF Schema definition as representation model and display the semantic relationships represented byFigure 8: Part of data model representing part of figure 7The RDF Schema Specification Revisitedinstancesof RDF_Relational_Property or subclasses thereof. RDF_Relational_Property and its subclasses thus serve as a document structure, which is explicitly modeled by RDF like statements. RDF_Annotation_Class and its subclasses describe the content of the documents. The document itself consists of RDF_WWW_Resources, which reference the documents’ content via an URL.In order to display the documents content as well as the underlying structure in a browser window, the KBS Hyperbook displays in a right frame the documents content and in a left frame the semantical relationships for this current page. Figure 7 shows an example (part of our CS1 lecture material). The lecture material displayed is used for a joint CS1 course in cooperation with the Free University of Bozen in Italy (and in similar form for the corresponding CS1 course in Hannover).Figure 8 shows part of the underlying metadata and schema for figure 7 in O-Telos graphical notation. The model represents the necessary concepts for displaying the document content as well as the uppermost relation (named …Kurseinheiten der aktuellen Vorlesung“) and its first link (named …Kurseinheit (Bozen) vom 7. Oktober 1999“). The figure shows, how our alternative RDF schema specification is used as part of the schema definition for our hypermedia document. As we will see in the following, in the current KBS Hyperbook System we have substituted several constructs (for subclass, primitive property and primitive type) by the corresponding constructs in O-Telos. Other than that, the schema definition used in the hyperbook system is equivalent to the RDF specification model we have proposed in the previous section.For our CS1 course we have defined additional subclasses of RDF_Annotation_Class like Vorlesungsgruppe (course group), Vorlesung (course) and Vorlesungseinheit (course unit) and subclasses of RDF_Relational_Property like Vorlesungs-gruppe_beinhaltet_Vorlesungen (course group contains courses) and Vorlesung_ent-haelt_Vorlesungseinheiten (course includes course units). Subclasses and subproperties are both defined using the O-Telos language construct …isA“. These subclasses of RDF_Relational_Property structure the (shared) documents used in these courses. Several courses of the same type (in our example the CS1 course held at different universities) reside in the same group (using the …course group contains course“property). A course itself consists of several course units which themselves contain the appropriate text units.RDF_Primitive_Type and its subclasses are not represented in the figure because the current KBS Hyperbook System uses the primitive types of O-Telos (like String) instead. Additionally, it uses the O-Telos-Class Attribute instead of RDF_Primitive_Property, so primitive attributes are displayed as links in Figure 8. Thus we are able to use the constraint facilities of O-Telos for integrity insurance. The name attribute for relations is instantiated from an additional presentation class …KBS_Displayed_Relation“ (specific to the KBS Hyperbook System) and is used for displaying the name of the semantic relationship. We have not included this concept in Figure 8 as it has no corresponding concept in RDF.Using this schema we are now able to specify the appropriate metadata for our lectures. The figure shows how we group various courses of the same topic, here with the instance …Info1“ of …course group“. The courses held in Bozen as well as in Hannover are included in this course group. From …Info1“ the instantiated relationship …Info1_Vorlesungen“ (CS1 courses) connects to the specific course …Vorlesung_Bozen“(course Bozen), and then connect the various course units (here for exampleModellierung 2000…Vorlesung_10_07“ (course from 10/7/99)) via the relation …Vorlesungs-einheiten_Bozen“ (course units Bozen) as shown in figure 7, which is a snapshot from the ConceptBase Browser. Note that the same course units can be used in different courses (e.g. the course units used in the CS1 course in Bozen are partly the same that are used in the CS1 course in Hannover). The instances connected by the name1 relation to the various classes and instances represent the Strings displayed in the browser. id1 is an instantiation of RDF_Annotates.The current KBS Hyperbook System only supports the display of selected primitive attributes (like name). We are working on an extended version, which also displays the RDF_Primitive_Property instances as an alternative view in the right browser frame.6Conclusion and Further WorkIn this paper we discussed the proposed RDF Schema Specification from March 1999, and pointed out several pecularities in the RDF schema specification compared to more conventional meta data models, which are basically due to the dual role of the properties rdfs:subclass, rdf:type, rdfs:domain and rdfs:range (used both as primitive constructs in the definition of the RDF schema specification and as specific instances of RDF properties). We then introduced an alternative specification which allowed us to distinguish between modeling and meta modeling features, and make the different meanings of constructs like rdf:type explicit. We specified this alternative using the modeling language O-Telos, and used the KBS Hyperbook system in order to display semantical relationships specified by RDF-like metadata.We are currently extending the capabilities of the KBS Hyperbook System to visualize these semantical relationships also graphically and to view arbitrary metadata (whose values are not WWW resources, but instances of primitive types like String, Integer, etc).Bibliography[CJB 1998] Chandrasekaran, B.; Josephson, J. R.; Benjamins, V. R.: The ontology of tasks and methods. In Proceedings of the 11th Workshop onKnowledge Acquisition, Modeling and Management, Banff, Alberta,Canada, April 1998.[FHN 1997] Fröhlich, P.; Henze, N.; Nejdl, W.: Meta-modeling for hypermedia design. 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