chapter2.6
英文论文提纲的格式范文_论文格式_
英文论文提纲的格式范文chapter i introduction 11.1 research background 11.2 significance and objectives of the research 21.2.1 the significance of the research 21.2.2 the objectives of the research 21.2.3 summary 31.3 studies of fossilization both home and abroad 31.3.1 studies of fossilization abroad 41.3.2 studies of fossilization in china 51.3.3 summary 61.4 organization of the thesis 7chapter ii literature review 72.1 interlanguage 82.2 the definitions of fossilization 92.3 the classification of fossilization : :. 132.3.1 individual fossilization vs. group fossilization 132.3.2 temporary fossilization vs. permanent fossilization 14 2.3.3 how to identify fossilization 152.4 possible factors of fossilization 172.4.1 internal factors 182.4.2 external factors 202.5 error analysis 222.5.1 the background of error analysis 222.5.2 procedures of error analysis 232.5.3 classification of errors 242.5.4 the significance of error analysis 262.6 summary 26chapter iii design of the research 273.1 research questions 273.2 subjects 283.3 method 283.4 instruments 293.5 procedures 293.6 summary 30chapter iv result and discussion 314.1 data analysis 314.1.1 classification of errors 314.1.2 analysis of the errors 314.2 the design of the questionnaires 374.3 the analysis of the questionnaires 384.4 analysis of causes of fossilized errors in writing 40 4.5 summary 42chapter v strategies for fossilization avoidance 435.1 to take a good attitude to the interference of li 43 5.2 to enhance the learners' motivationr445.3 to guarantee the quality and quantity of l2 input 46 5.4 to provide effective feedback 485.5 to attach more importance to grammar teaching 49 5.6 to apply more effective learning strategies 495.7 summary 50chapter vi conclusion 516.1 a brief review of the study 516.2 major findings 526.3 limitations of this study 536.4 suggestions 54bibliography 55。
Chapter 词汇学
2.2 Three Phases of the Historical Development
• For each phase of the development, the following points must be made clear:
– Time range – Features of English – Social and historical events that influenced English greatly
1. The first peoples known to inhabit the land were Celts. 2. The Germanic tribes include Angles, Saxons, and Jutes. They were first allies of Celts to fight against Picts and Scots, but then they became new conquerors. 3. Angles, Saxons and Jutes all have their dialects. The Saxons were numerically superior to the Angles, but the latter were influential enough to impose their name on the whole. 4. Old English was almost monogeneous and entirely Germanic with only a few borrowings from Latin and Scandinavian. It was a highly inflected language, of which nouns, pronouns, adjectives, verbs, and adverbs had complex systems of endings or vowel changes or both.
2.6.3 error control
2.6.3 Error Control
We can represent transmission errors by a binary word E whose 1s indicate which bits the transmission corrupts.
With this representation the packet that the receiver gets is A.G + E. This received packet is a multiple of G, and the receiver does not detect the errors if and only if E is a multiple of G. Thus to be a robust error-detection code, the CRC should use a binary word G that is not likely to divide an error world E.
Chapter 2 Network services and Layered Architectures
2.6 Basic Network Mechanisms
Multiplexing Switching
Error control
Flow control Congestion control Resource allocation
Typical implementation
Before sending a packet, the transmitter makes a copy that it keeps. The transmitter then sets a count-down timer 倒计时器 to specific value and sends the packet. We say that the packet times out 超时 when the count-down timer reaches the value 0. If the receiver gets the intact packet, then it sends back an acknowledgment to the transmitter. If the transmitter gets the acknowledgment of the packet before the packet times out, then the transmitter knows that receiver got the packet. In that case, the transmitter discards its copy of the packet and repeats the procedure with the next packet.
第二章 压力容器应力分析2.5-2.6
长圆筒
短圆筒
刚性圆筒 L/Do和Do/t很小时，壳体的刚性很大，此时圆柱 壳体的失效形式已经不是失稳，而是压缩强度破 坏。
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2.5.2 外压薄壁圆柱壳弹性失稳分析
过程设备设计
长圆筒和短圆筒失稳时临界压力计算方法： 一、受均布周向外压的长圆筒的临界压力
二、受均布周向外压的短圆筒的临界压力 三、临界长度 四、周向外压及轴向载荷联合作用下的失稳 五、形状缺陷对圆筒稳定性的影响
10
2.5.1 概述
过程设备设计
3. 影响Pcr的因素：
对于给定外直径Do和厚度t Pcr与圆柱壳端部约束之间距离和圆柱壳上两个刚性元件 之间距离L有关； Pcr随着壳体材料的弹性模量E、泊松比μ的增大而增加； 非弹性失稳的Pcr还与材料的屈服点有关。
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2.5.2 外压薄壁圆柱壳弹性失稳分析
过程设备设计
c、圆环的挠曲微分 方程2-87式
M M O pRwo w
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2.5.2 外压薄壁圆柱壳弹性失稳分析
过程设备设计
图2-39 圆环变形的几何关系
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2.5.2 外压薄壁圆柱壳弹性失稳分析
pR3 RM pR w d 2w 1 c. 圆环的挠曲微分方程：2-87式 2 w d EJ EJ
对圆筒的初始不圆度严格限制
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2.5.3 其他回转薄的的临界压力
过程设备设计
2.5.3 其他回转薄壳的的临界压力
半球壳 椭球壳 碟形壳 锥壳
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2.5.3 其他回转薄壳的的临界压力
过程设备设计
1、半球壳
临界应力经典公式
pcr
3 1 2
0.3
2E
国际危规 IMDG
国际危规IMDG code (Amdt.35-10)Foreword...Preamble…Part 1 – general provisions, definitions and trainingChapter 1.1 general provisions1.1.0 introductory notes1.1.1 application and implementation of the code1.1.2 conventions1.1.3 dangerous goods forbidden from transportChapter 1.2 definitions, units of measurement and abbreviations1.2.1 definitions1.2.2 units of measurement1.2.3 list of abbreviationsChapter 1.3 training1.3.0 introductory note1.3.1 training of shore-side personnelChapter 1.4 security provisions1.4.0 introductory note1.4.1 general provisions for companies, ships and port facilities1.4.2 general provision for shore-side personnel1.4.3 provisions for high consequence dangerous goodsChapter 1.5 general provisions concerning class 71.5.1 scope and application1.5.2 radiation protection program1.5.3 quality assurance1.5.4 special arrangement1.5.5 radioactive material possessing other dangerous properties1.5.6 non-compliancePart 2 – classificationChapter 2.0 introduction2.0.0 responsibilities2.0.1 classes, divisions, packing groups2.0.2 UN numbers and proper shipping names2.0.3 classification of substances, mixtures and solutions with multiple hazards (precedence of hazard characteristics)2.0.4 transport of samplesChapter 2.1 class 1 – explosives2.1.0 introductory notes2.1.1 definition and general provisions2.1.2 compatibility groups and classification codes2.1.3 classification procedureChapter 2.2 class 2 – gases2.2.0 introductory note2.2.1 definitions and general provisions2.2.2 class subdivisions2.2.3 mixtures of gasesChapter 2.3 class 3 – flammable liquids2.3.0 introductory note2.3.1 definitions and general provisions2.3.2 assignment of packing group2.3.3 determination of flashpoint2.3.4 determination of initial boiling pointChapter 2.4 class 4 – flammable solids; substances liable to spontaneous combustion; substances which, in contact with water, emit flammable gases2.4.0 introductory note2.4.1 definition and general provisions2.4.2 class 4.1 – flammable solids, self-reactive substances and solid desensitized explosives 2.4.3 class 4.2 – substances liable to spontaneous combustion2.4.4 class 4.3 – substances which, in contact with water, emit flammable gases2.4.5 classification of organometallic substancesChapter 2.5 class – oxidizing substances and organic peroxides2.5.0 introductory note2.5.1 definitions and general provisions2.5.2 class 5.1 – oxidizing substances2.5.3 class 5.2 – organic peroxidesChapter 2.6 class 6 – toxic and infectious substances2.6.0 introductory notes2.6.1 definitions2.6.2 class 6.1 – toxic substances2.6.3 class 6.2 – infectious substancesChapter 2.7 class 7 – radioactive material2.7.1 definitions2.7.2 classificationChapter 2.8 class 8 – corrosive substances2.8.1 definitions and properties2.8.2 assignment of packing groupsChapter 2.9 miscellaneous dangerous substances and articles (class 9) and environmentally hazardous substances2.9.1 definitions2.9.2 assignment to class 92.9.3 environmentally hazardous substances (aquatic environment)Chapter 2.10 marine pollutants2.10.1 definition2.10.2 general provisions2.10.3 classificationPart 3 – dangerous goods list, special provisions and exceptions~ ···········Part 4 – packing and tank provisionsChapter 4.1 use of packaging, including intermediate bulk containers (IBCs) and large packaging4.1.0 definitions4.1.1 general provisions for the packing of dangerous goods in packings, including IBCs and large packaging4.1.2 additional general provisions for the use of IBCs4.1.3 general provisions concerning packing instructions4.1.4 list of packing instructionspacking instructions concerning the use of packaging (except IBCs and large packaging)packing instructions concerning the use of IBCspacking instructions concerning the use of large packaging4.1.5 special packing provisions for goods of class 14.1.6 special packing provisions for goods of class 24.1.7 special packing provisions for organic peroxides (class5.2) and self-reactive substances of class 4.14.1.8 special packing provisions for infectious substances of category A (class 6.2, UN 2814 and UN 2900)4.1.9 special packing provisions for class 7。
材料化学第2章高分子材料的结构
X
CH2
C n
H
有不对称碳原子，所以有旋光异构。
注：对高分子来说，关心不是具体构型（左旋或 右旋），而是构型在分子链中的异同，即：
全同（等规）、间同或无规。
34
c
aC b
高分子链上有 取代基的碳原子 可以看成是不对
d
R RR R R
称碳原子
HHHH
将锯齿形碳链 H 排在一个平面上，
RH
RH
取代基在空间有 不同的排列方式。
以大分子链中的重复单元数目表示，记作 DP
注：重复单元与结构单元的异同：
5
(1) 由一种结构单元组成的高分子
一个高分子如果是由一种单体聚合而成，其重复单 元与结构单元相同。
例如：聚苯乙烯
n CH2 CH 聚合
CH2-CH-CH2-CH-CH2-CH
缩写成
CH2 CH n
n 表示重复单元数，也称为链节数, 在此等于聚合度
(6) 单体单元（monomer unit）: 与单体的化学组成完全相同只是化学结构不同的 结构单元。
4
(7) 聚合度(degree of polymerization): 聚合物分子中，结构单元的数目叫聚合度。 聚合度是衡量高分子大小的一个指标。
有两种表示法：
以大分子链中的结构单元数目表示，记作 xn
2.6 高分子材料的结构
前言 一、定义
1. 高分子化合物 是指分子量很高并由共价键连接的一类化合物 . 又称：高分子化合物、大分子化合物、高分子、
大分子、高聚物、聚合物 Macromolecules, High Polymer, Polymer
分子量：一般高达几万、几十万，甚至上百万， 范围在104～106
托马斯微积分课件2.6 Implicit Differentiation
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p 1 p q q 1
qy
q 1
y px
p 1
p 1 q 1 y px qy
p x q
p p 1 p q
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Exercises
P204 19, 20, 32, 33, 40, 43. P205 46. P206 56.
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2.6
Implicit Differentiation
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2.6.1 Implicitly Defined Functions 2.6.2 Derivatives of Higher Order 2.6.3 Rational Powers of Differentiable Functions
12 x 6 y y y y 0
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2.6.3
Rational Powers of Differentiable Functions
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பைடு நூலகம்
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Let y x p q , we have
yq x p .
px q x p p 1 p q 1 q x x q
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隐函数求导方法
两边对 x 求导( 注意 y = y(x) ) (含导数 y 的方程)
VDA_Structure_Component_Requirement_Specification_module_I
VDA Structure Component Requirement SpecificationModule ICRS Universal Requirements<Title><Number>Version 1.0ReleaseTechnical depart-ment/functionName Date SignatureCRS authorTechnical departmentProject managementDevelopmentTable of Contents0Change History 8-4 1Foreword 8-5 2General Project Guidelines 8-6 2.1Objective 8-6 2.2Organisation 8-6 2.3Sub-Supplier Management 8-6 2.4Production Process Release and Product Release 8-7 2.5Performance Specification 8-7 2.6Variant Management 8-7 2.7Test Management 8-8 2.8Change Management 8-8 2.9General Development and Supply Scope 8-8 2.10Content Amendments 8-8 3Scheduling in the Project 8-9 4Reporting and Documentation 8-10 4.1Information Exchange 8-10 4.2Documentation and Archiving Obligations 8-10 4.3Priority and Up-to-Dateness of Documents 8-10 4.4Change Documentation and Part History Documentation 8-11 4.5Vehicle Documentation 8-11 4.6Traceability 8-11 4.7Labelling of Parts 8-11 4.8Content Amendments 8-12 5Quality Requirements on the Product Design 8-13 5.1Quality Contribution 8-13 5.2Quality Management System 8-13 5.3Preventive QM Methods and Safeguarding Against Risk 8-13 5.4Maturity Level Assurance in the Supply Chain 8-13 5.5Requalification 8-14 5.6Complaint Processing 8-14 5.7Error Management 8-14 5.8Content Amendments 8-14 6Nondisclosure 8-157Product Data Management 8-16 7.1CAx and EDM Supplier Integration 8-16 7.1.1Qualification of the Suppliers 8-16 7.1.2Data Exchange Agreement 8-16 7.2CAD Requirements 8-16 7.3DMU Requirements 8-17 7.4Parts List and Documentation Method 8-17 7.5Reference Point System and Functional Dimensions 8-17 7.6Requirements on the Creation of Drawings 8-17 7.7Content Amendments 8-17 8Environmental Compatibility 8-18 8.1Recycling Scheme 8-18 8.2Environmental Characteristics of the Materials 8-18 8.3Dismantling Scheme 8-18 8.4Content Amendments 8-18 9Material Specification and Surfaces 8-19 9.1Material Directives and Prohibitions 8-19 9.2Universal Material Requirements 8-19 9.3Requirements on the Weather Resistance 8-19 9.4Requirements on Electrical Components 8-19 9.5Surface Protection, Surfaces, Edges 8-20 9.6Corrosion Protection 8-20 10Logistic Requirements 8-21 11Customer Service and other Service Requirements 8-22 12Requirements on Test and Prototype Tools 8-23 13Standard and Repeat Parts 8-24 14Content Amendments to Module I 8-25 15Definitions, Terms, Acronyms 8-26 16Further Applicable Documents 8-270 Change HistoryEdited (date) Approved by No. Amendment DescriptionOEM OEM1 ForewordEditor comments (delete in the final version)This chapter is an informative introductory element that gives certain information or commentaries about the purpose of the requirementspecification (e.g. that the requirement specification describes services, requirements, inspection and testing conditions that the product to be developed has to fulfil). The foreword must not contain any technical or functional requirements, images or tables.Rules for handling the VDA component requirement specification structure1. Structure: level 1 and level 2 of the VDA component requirementspecification structure have to be kept and must not be changed.2. Expansion to the structure: if amendments are necessary in theimplementation of the VDA structure, in each case these are to be added to the last chapter with content of Module I or Module II (see Module I, chapter 12 and Module II chapter7).Expansions of the level 2 of the VDA structure are to be placed at the end of a respective sub-chapter structure (see e.g. Module I,chapter 2.6).3. Headlines that are not used may not be deleted on levels 1 and 2 ofthe Modules I and II, in order to guarantee the transparency and clarity of the component requirement specification contents. Instead, thesechapters are to be marked with the reference “not relevant for thiscomponent”.When referencing an external document it has to be entered here.4. Contents on level 3 are to be preferentially used and have the natureof a recommendation. If chapters from level 3 are not used, these may be deleted or renamed.This document is based on the VDA CRS structure. It consists of universal requirements for the component requirement specification (Module I) and the component requirement specification for mechanical and E/E components (Module II). For more information please go to www.vda-qmc.de.2 General Project Guidelines2.1 ObjectiveEditor comments (delete in the final version)The superordinate objectives are to be defined in thischapter (development, production, etc). The component-specificobjectives that go beyond this are to be defined in Module II.2.2 OrganisationEditor comments (delete in the final version)The fundamental, project-wide organisational general conditions are to be defined in this chapter (e.g. committee, control processes, project management plan).These especially include measures for project controlling and theestablishing of development-accompanying reviews and information about risk management.Furthermore, standards (minimum content, interface characteristics or tools to be used, formal layout, etc.) for the documentation of recurrent events along the course of the project (e.g. meeting minutes, status or progress reports and reviews, end of project documentation, etc.) are to be defined in this chapter.2.3 Sub-Supplier ManagementEditor comments (delete in the final version)Stipulations concerning the sub-suppliers that are to be involved by the contractor can be made here (e.g. duty of notification about theinvolvement of sub-suppliers, customer requirements on contractsbetween the contractors, deadline responsibilities, non-disclosureagreements, data formats, documentation).Requirements on the contractor or sub-supplier can correspond to,among other things, the project structure, capacity requirements,communication or auditing duties (proof of qualification)Furthermore, stipulations can be made here that result from the defined duties of the contractor from the chapter “Responsibilities” (e.g. forpartial scopes of a component that are to be developed and produced by the sub-supplier).2.4 Production Process Release and Product ReleaseEditor comments (delete in the final version)The relevant processes for the acceptance of components, systems or patterns are to be described in this chapter. The contractor’s duty to co-operate is to be differentiatedly described. If available, reference should be made to the customer’s existing incoming goods conditions.Furthermore, the relevant rights and obligations of the inspection and release processes for the contractor are to be described here.2.5 Performance SpecificationEditor comments (delete in the final version)In this chapter it is to be agreed how and with what contents thecontractor is to generate a performance specification. For the fulfilment of all requirements, especially with regard to durability, properties and condition, the contractor has to comment in writing in the performance specification.2.6 Variant ManagementEditor comments (delete in the final version)General requirements on the variant management are to be defined in this chapter. Furthermore, it is to be recorded here how additionalvariants are to be handled or how and in which systems variants are to be documented.2.7 Test ManagementEditor comments (delete in the final version)General requirements and stipulations on tests are to be defined in this chapter (e.g. test planning and documentation, etc).2.8 Change ManagementEditor comments (delete in the final version)In this chapter criteria and workflows are to be established for how to, for example, coordinate, approve and document cost, weight and deadline-relevant changes during the development time.2.9 General Development and Supply ScopeEditor comments (delete in the final version)All general requirements on the development and delivery scopes are to be defined in this chapter. This includes all services necessary for the fulfilment of the requirements.2.10 Content AmendmentsEditor comments (delete in the final version)If the specified content structure is not sufficient to assign all require-ments on level 2 to the superordinate subject on level 1, the require-ments can be assigned to this chapter.If this chapter is not necessary, you should delete it!3 Scheduling in the ProjectEditor comments (delete in the final version)Project-specific deadlines that are important for the contractor andcustomer in the development and, if necessary, in the series production of the component are to be defined and communicated in this chapter (to some extent the deadlines themselves are derived from thesuperordinated plans [model politics]).Furthermore, a definition of project-specific milestones or productmaturity level grades that are to be observed by the contractor during the course of the project is to be made. Reference to existing standards is to be made in the definition of the product maturity level grades, if possible.Additionally, metrics for project tracking with which the customer checks the project progress can be listed. Typical metrics are for examplemilestone trend analysis, expense or error tracking. The data for themetrics to be transferred by the contractor and the intervals of the data transfer are established here.4 Reporting and Documentation4.1 Information ExchangeEditor comments (delete in the final version)The mutual information obligations and the project-wide standarddocumentations (e.g. meeting minutes, testing documentation, technical [interim] and status reports, work reports, to-do lists, FMEA reports, FTA reports) are to be defined in this chapter.In addition to formal guidelines, reference is to be made in particular to the principal responsibilities or the obligations to co-operate of thecontractor and customer in the reporting along the development process.4.2 Documentation and Archiving ObligationsEditor comments (delete in the final version)The determination of project-wide retention and archiving periods is to be made taking existing cross-manufacturer standards (e.g. VDA volume 1) into consideration. In addition to the definition of criteria and processes for archiving, the data processing systems required by the contractor are also to be established.4.3 Priority and Up-to-Dateness of DocumentsEditor comments (delete in the final version)Suitable rules are to be defined as to how the contractor and customer are to react in the case of contradictions (e.g. in CRS Module II).Additionally, priority and up-to-dateness rules for different documents are to be defined in this chapter.4.4 Change Documentation and Parts History DocumentationEditor comments (delete in the final version)In this chapter the customer defines the data and its form of recording that are to be made available by the contractor in the framework of a change documentation in the course of the development and, ifapplicable, production processes (e.g. entries in a project manual).4.5 Vehicle DocumentationEditor comments (delete in the final version)In this chapter all parts for which there are special documentationrequirements due to safety or certification relevance are to be listed (see also VDA volume 1 – determination of documents with special archiving).The contractor’s duty to co-operate and the data processing system to be used are also to be established.4.6 TraceabilityEditor comments (delete in the final version)A component-specific determination of processes, procedures and dataprocessing system that ensure the traceability (e.g. part batch) is to be safeguarded here.1.7 Labelling of PartsEditor comments (delete in the final version)The customer requirements on various types of labelling (e.g. for series and original parts, test and prototype parts) is to be established in this chapter.4.8 Content AmendmentsEditor comments (delete in the final version)If the given content structure does not suffice to assign all requirements on level 2 to the superordinated subject on level 1, the requirements can be assigned to this chapter.If this chapter is not needed, you should delete it!5 Quality Requirements on the Product Design5.1 Quality ContributionEditor comments (delete in the final version)In this chapter, general requirements on the contractor concerning its quality assurance (factory, project) are to be defined (e.g. quality testing of prototype, pre-series and series production parts).The OEM-specific Q-guidelines also have to be stated here.5.2 Quality Management SystemEditor comments (delete in the final version)The requirements on the contractor’s QM system (including interfaces to the customer and sub-suppliers) are to be defined here; reference to existing standards if possible (e.g. ISO/TS 16949).5.3 Preventive QM Methods and Safeguarding against RiskEditor comments (delete in the final version)Here the fundamental measures for the concept, product and process safeguarding (e.g. quality functional deployment, FMEA, system, design or process FMEAs, reviews) that are valid for all awardings within aproject are to be requested by the customer.5.4 Maturity Level Assurance in the Supply ChainEditor comments (delete in the final version)Which quality-relevant processes for the maturity level assurance in the supply chain are to be documented and assured at the contractor’s are to be defined in this chapter.5.5 RequalificationEditor comments (delete in the final version)The contractor is to be strictly committed to the requalification test (RQT) in series production. The customer is to bindingly define the objectives, content, processes and cycles of the RQT here.5.6 Complaint ProcessingEditor comments (delete in the final version)In this chapter the requirements of how the contractor is to deal with remedial actions and downstream efficiency examinations within the framework of complaint processing are to be defined.5.7 Error ManagementEditor comments (delete in the final version)Requirements on the contractor’s and the customer’s error management can be defined here (error documentation, error analysis, error remedial actions, efficiency test, etc).5.8 Content AmendmentsEditor comments (delete in the final version)If the given content structure does not suffice to assign all requirements on level 2 to the superordinated subject on level 1, the requirements can be assigned to this chapter.If this chapter is not needed, you should delete it!6 Non-DisclosureEditor comments (delete in the final version)In this chapter the general rights and obligations of the contractor and customer to non-disclosure, reuse, evaluation, etc. of the information contained in the component requirement specification can be defined by the customer.7 Product Data Management7.1 CAx and EDM Supplier Integration7.1.1 Qualification of the SuppliersEditor comments (delete in the final version)In this sub-chapter, the qualification requirements on the contractor or sub-supplier and/or their employees with regard to CAx and EDM are to be listed. If available, a reference should be made to the trainingopportunities offered by the customer.7.1.2 Data Exchange AgreementEditor comments (delete in the final version)In this chapter, the demands for digital safeguarding of the development as well as concerning minimum standards in regard to data exchange formats (e.g. CATIA V.x, PRO ENGINEER V.x, 3D CAD data) are to be defined.The minimum requirements concerning the electronic data exchange between contractor and customer should define not only the reference to all necessary forms but also the differentiated layout of geometricaldescriptions, CAD datasets and data transfers (e.g. RDT standards, online access to engineering portals).If available, reference should be made to any existing cross-manufacturer standards (e.g. VDA volume 4.2).7.2 CAD RequirementsEditor comments (delete in the final version)Describe the component-specific 3D CAD data that is made available by the contractor and the customer (e.g. cross sections, views).The contractor’s obligations in data cleaning or checking, geometricdescription, the CAD data quality and DMU requirements are also to be documented here.7.3 DMU RequirementsEditor comments (delete in the final version)In this chapter the customer’s general requirements on the Digital Mock-Up (DMU) are to be formulated (if necessary with reference to existing regulations, rules, etc.)7.4 Parts List and Documentation MethodEditor comments (delete in the final version)Define the requirements on the contents and the form of the parts list to be kept by the contractor (if the contractor is responsible for keeping the parts list).7.5 Reference Point System and Functional DimensionEditor comments (delete in the final version)Determine the necessary nomenclature and the most importantrequirements on the reference point system to be kept by the contractor.7.6 Requirements on the Creation of DrawingsEditor comments (delete in the final version)Define the requirements on the content and form of the drawings.Especially the references to the customer’s respectively valid rules with regard to the creation of drawings are to be entered here.7.7 Content AmendmentsEditor comments (delete in the final version)If the given content structure does not suffice to assign all requirements on level 2 to the superordinated subject on level 1, the requirements can be assigned to this chapter.If this chapter is not needed, you should delete it!8 Environmental Compatibility8.1 Recycling SchemeEditor comments (delete in the final version)This chapter establishes the general project-wide requirements on the recycling and repair scheme in the development of a component. Ifpossible, this chapter is also to make reference to existing laws and standards (cross-manufacturer), (e.g. VDA volume 31, VDA 260[labelling of materials], directive 2000/53 EC [End of Life Vehicles] and 761/2001 EC [EMAS]).8.2 Environmental Characteristics of the MaterialsEditor comments (delete in the final version)In this chapter the cross-component requirements in regard to permitted and forbidden (e.g. harmful to health) materials (e.g. lead-free solder).8.3 Dismantling SchemeEditor comments (delete in the final version)The dismantling scheme describes the requirements on the contractor in terms of a simple, unmixed dismantling of the component as well as its accessibility when assembled.8.4 Content AmendmentsEditor comments (delete in the final version)If the given content structure does not suffice to assign all requirements on level 2 to the superordinated subject on level 1, the requirements can be assigned to this chapter.If this chapter is not needed, you should delete it!9 Material Specification and Surfaces9.1 Material Directives and ProhibitionsEditor comments (delete in the final version)In this chapter the cross-component requirements on the materials to be used or the materials not to be used are to be defined. These areproject-wide regulations in regard to mandatory materials or theircombinations.9.2 Universal Material RequirementsEditor comments (delete in the final version)In this chapter the universal requirements on the materials themselves, the determination of materials, scope of the material determination, as well as the determinations for material specifications etc. are to bespecified.The general material requirements include requirements on theinflammability of materials, their compatibility, emissions behaviour, etc.9.3 Requirements on the Weather ResistanceEditor comments (delete in the final version)In this chapter the general requirements on the weather resistance of materials and the proof of this are to be determined.9.4 Requirements on Electric ComponentsEditor comments (delete in the final version)In addition to the general requirements on the materials, in this chapter especially the material requirements for electric and electronic parts and components are to be defined.9.5 Surface Protection, Surfaces, EdgesEditor comments (delete in the final version)In this chapter the general requirements and regulations for surface pro-tection and the properties and condition of the surfaces and edges is to be determined.9.6 Corrosion ProtectionEditor comments (delete in the final version)In this chapter the customer’s universal requirements for corrosionprotection are to be described.These include perforation corrosion requirements and/or guarantees, especially in the chassis area and the body, as well as requirements in regard to contact, surface, crevice, cavity, stress and filiform corrosions, etc.10 Logistics RequirementsEditor comments (delete in the final version)In this chapter the customer can make determinations to the logistic scheme that are valid for all components of a project. These include e.g.universal requirements on the supply of individual production sites or standards regarding packaging, carriers, etc. If available, reference is to be made to the additional standards of the customer.11 Customer Service and other Service RequirementsEditor comments (delete in the final version)In this chapter the requirements on the replacement part documentation, such as replacement part catalogue, replacement wear out lists,drawings, isometric replacement part depictions in electronic form, etc., that the customer needs from the contractor are to be determined. The time of provision before the start of series production is to be stated.12 Requirements on Test and Prototype ToolsEditor comments (delete in the final version)In this chapter the general requirements on the handling of test and prototype tools is to be defined (commissioning, development,manufacturing of test parts from prototype tools, costs, disposal, etc).13 Standard and Repeat PartsEditor comments (delete in the final version)The customer-specific requirements regarding installation quota and use of standard, repeat and same parts are to be defined here. It should be observed that all relevant information in terms of standard, repeat and same parts is to be made available to the contractor.14 Content Amendments to Module IEditor comments (delete in the final version)If the given content structure does not suffice to assign all requirements on level 1, the requirements can be assigned to this chapter.If this chapter is not needed, you should delete it!15 Definitions, Terms, AcronymsEditor comments (delete in the final version)The table of acronyms is to be supplemented by a standardised glossary in which the most important terms that are used within the requirement specification are uniformly defined. For this, the same terms from other VDA volumes are to be used for the same facts.CAx Computer Aided (x = variable)CPM Critical Parts ManagementCRS Module I Component Requirement Specification Module I CRS Module II Component Requirement Specification Module II DMU Digital Mock-UpDP Data ProcessingEDM Engineering Data ManagementE/E Electrical/ElectronicEMAS Environmental Management and Auditing Scheme FMEA Failure Mode and Effects AnalysisFTA Fault Tree AnalysisIP Ingress ProtectionISO International Standards OrganisationMMI Multimedia InterfaceOEM Original Equipment ManufacturerQM Quality ManagementRDT Remote Data TransmissionRQT Requalification TestSW SoftwareTS Technical Specification16 Further Applicable DocumentsEditor comments (delete in the final version)In this connection, only the documents quoted from in the requirement specification are to be considered further applicable documents.The further applicable documents (laws, standards, customer-specific rules, etc.) that are referred to in the requirement specification textshould be differentiatedly listed according to type of document.Furthermore, a source (alternative: contact person) of the information for the contractor is to be named.The further applicable documents that were valid at the CRS issue date are applicable.If reference is made to regulations (laws, ordinances and such), thereference has to be in such a manner that the procurement is possible.The access address and modalities for the supplier are also to be named here.。
EP 2.6.14 Bacterial Endotoxins
EUROPEAN PHARMACOPOEIA 5.0 2.6.14.BacterialendotoxinsMaize starch 1.0g Sodium chloride5.0gAgar,according to gelling power 10.0g to 15.0gPurified water1000mlHydrate the agar,dissolve by heating to boiling with continuous stirring.If necessary,adjust the pH so that after sterilisation it is 7.3±0.2.Sterilise by heating in an autoclave at 121°C for 15min.Allow to cool to 45-50°C;add,where necessary,gentamicin sulphate corresponding to 20mg of gentamicin base and pour into Petri dishes.Medium R (Lactose monohydrate sulphite medium)Pancreatic digest of casein 5.0g Yeast extract 2.5g Sodium chloride 2.5g Lactose monohydrate 10.0g Cysteine hydrochloride 0.3g Purified water1000mlDissolve,adjust to pH 7.1±0.1and fill to 8ml in16mm ×160mm tubes containing a small Durham tube.Sterilise by heating in an autoclave at 121°C for 15min and store at 4°C.Before use,heat the medium for 5min in a water-bath and cool.Add to each tube 0.5ml of a 12g/l solution of sodium metabisulphite R and 0.5ml of a 10g/l solution of ferric ammonium citrate,both solutions being freshly preparedand filtered through membranes (pore size:0.45µm).Agar medium S (R2A)Yeast extract 0.5g Proteose peptone 0.5gCasein hydrolysate0.5g Glucose0.5g Starch0.5g Dipotassium hydrogen phosphate0.3g Magnesium sulphate,anhydrous0.024g Sodium pyruvate 0.3g Agar 15.0g Purified water1000mlAdjust the pH so that after sterilisation it is 7.2±0.2.Sterilise by heating in an autoclave at 121°C for 15min.NEUTRALISING AGENTSNeutralising agents may be used to neutralise the activity of antimicrobial agents.They may be added to buffered sodium chloride-peptone solution pH 7.0,preferably before sterilisation.If utilised their efficacy and non-toxicity towards micro-organisms are demonstrated.A typical neutralising fluid has the following composition:Polysorbate 8030g Lecithin (egg)3g Histidine hydrochloride 1g Peptone (meat or casein)1g Sodium chloride4.3g Potassium dihydrogen phosphate 3.6g Disodium hydrogen phosphate dihydrate 7.2g Purified water1000mlSterilise by heating in an autoclave at 121°C for 15min.If the solution has insufficient neutralising capacity the concentration of polysorbate 80or lecithin may be increased.Alternatively,the neutralisers mentioned in Table 2.6.13.-3may be added.Table 2.6.13.-3.–Inactivators for antimicrobial agents to be added to buffered sodium chloride-peptone solution pH 7.0Type of an-timicrobial agentInactivator Concentration Comment Sodium laurilsulfate 4g/l Polysorbate 80and lecithin 30g/l and 3g/l Phenolics Egg yolk 5ml/l -50ml/l Add after sterilisation of buffered sodium chloride-peptone solution pH 7.0Organo-mercurals Sodium thioglycolate 0.5g/l -5g/lHalogens Sodium thiosulphate 5g/l Quaternaryammonium compounds Egg yolk5ml/l -50ml/lAdd after sterilisation of buffered sodium chloride-peptonesolution pH 7.001/2005:206142.6.14.BACTERIAL ENDOTOXINS The test for bacterial endotoxins is used to detect or quantify endotoxins of gram-negative bacterial originusing amoebocyte lysate from horseshoe crab (Limuluspolyphemus or Tachypleus tridentatus ).There are 3techniques for this test:the gel-clot technique,which is based on gel formation;the turbidimetric technique,based on the development of turbidity after cleavage of an endogenous substrate;and the chromogenic technique,based on the development of colour after cleavage of a synthetic peptide-chromogen complex.The following 6methods are described in the present chapter:Method A.Gel-clot method:limit testMethod B.Gel-clot method:semi-quantitative test Method C.Turbidimetric kinetic method Method D.Chromogenic kinetic method Method E.Chromogenic end-point method Method F.Turbidimetric end-point methodProceed by any of the 6methods for the test.In the eventof doubt or dispute,the final decision is made based upon method A unless otherwise indicated in the monograph.The test is carried out in a manner that avoids endotoxin contamination.ApparatusDepyrogenate all glassware and other heat-stable apparatus in a hot-air oven using a validated process.A commonly used minimum time and temperature is 30minutes at 250°C.If employing plastic apparatus,such as microtitre plates and pipette tips for automatic pipetters,use apparatus shown to be free of detectable endotoxin and of interfering effects for the test.NOTE:In this chapter,the term ‘tube’includes all types of receptacles,for example microtitre plate wells .2.6.14.Bacterial endotoxins EUROPEAN PHARMACOPOEIA5.0Preparation of the standard endotoxin stock solutionThe standard endotoxin stock solution is prepared froman endotoxin reference standard that has been calibrated against the International Standard,for example endotoxin standard BRP.Endotoxin is expressed in International Units(IU).The equivalence in IU of the International Standard is stated by the World Health Organisation.NOTE:One International Unit(IU)of endotoxin is equal to one Endotoxin Unit(E.U.).Follow the specifications in the package leaflet and on the label for preparation and storage of the standard endotoxin stock solution.Preparation of the standard endotoxin solutionsAfter vigorously mixing the standard endotoxin stock solution,prepare appropriate serial dilutions of this solution using water for bacterial endotoxins test(water for BET). Use the solutions as soon as possible to avoid loss of activity by adsorption.Preparation of the test solutionsPrepare the test solutions by dissolving or diluting active substances or medicinal products using water for BET. Some substances or preparations may be more appropriately dissolved or diluted in other aqueous solutions.If necessary, adjust the pH of the test solution(or dilution thereof)so that the pH of the mixture of the lysate and test solution falls within the pH range specified by the lysate manufacturer. This usually applies to a product with a pH in the range of6.0 to8.0.The pH may be adjusted by the use of acid,base or a suitable buffer,as recommended by the lysate manufacturer. Acids and bases may be prepared from concentrates or solids with water for BET in containers free of detectable endotoxin.Buffers must be validated to be free of detectable endotoxin and interfering factors.Determination of the Maximum Valid DilutionThe Maximum Valid Dilution(MVD)is the maximum allowable dilution of a sample at which the endotoxin limit can be determined.Determine the MVD using the following formulae:Endotoxin limit:the endotoxin limit for active substances administered parenterally,defined on the basis of dose,is equal to:K=threshold pyrogenic dose of endotoxin perkilogram of body mass in a single hour period,M=maximum recommended dose of product perkilogram of body mass in a single hour period. The endotoxin limit for active substancesadministered parenterally is specified in units suchas IU/ml,IU/mg,IU/Unit of biological activity,etc.,in monographs.Concentration of test solution:—in mg/ml if the endotoxin limit is specified by mass (IU/mg),—in Units/ml if the endotoxin limit is specified by unit of biological activity(IU/Unit),—in ml/ml if the endotoxin limit is specified by volume (IU/ml).λ=the labelled lysate sensitivity in the gel-clottechnique(IU/ml)or the lowest point usedin the standard curve of the turbidimetric orchromogenic techniques.GEL-CLOT TECHNIQUE(METHODS A AND B)The gel-clot technique allows detection or quantificationof endotoxins and is based on clotting of the lysate in the presence of endotoxins.The concentration of endotoxins required to cause the lysate to clot under standard conditions is the labelled lysate sensitivity.To ensure both the precision and validity of the test,confirm the labelled lysate sensitivity and perform the test for interfering factors as described under1.Preparatory testing.1.PREPARATORY TESTING(i)Confirmation of the labelled lysate sensitivity Confirm in4replicates the labelled sensitivityλ,expressed in IU/ml,of the lysate solution prior to use in the test. Confirmation of the lysate sensitivity is carried out when a new batch of lysate is used or when there is any change in the experimental conditions which may affect the outcome of the test.Prepare standard solutions of at least4concentrations equivalent to2λ,λ,0.5λand0.25λby diluting the standard endotoxin stock solution with water for BET.Mix a volume of the lysate solution with an equal volumeof1of the standard solutions(such as0.1ml aliquots)in each tube.When single test vials or ampoules containing lyophilised lysate are employed,add solutions directly to the vial or ampoule.Incubate the reaction mixture for a constant period according to the recommendations of the lysate manufacturer(usually at37±1°C for60±2min), avoiding vibration.Test the integrity of the gel:for tubes, take each tube in turn directly from the incubator and invert it through approximately180°in one smooth motion.If a firm gel has formed that remains in place upon inversion, record the result as positive.A result is negative if an intact gel is not formed.The test is not valid unless the lowest concentration of the standard solutions shows a negative result in all replicate tests.The end-point is the last positive result in the series of decreasing concentrations of endotoxin.Calculate the mean value of the logarithms of the end-point concentrations and then the antilogarithm of the mean value using the following expression:Geometric mean end-point concentration==sum of the log end-point concentrations of the dilution series used,f=number of replicates.The geometric mean end-point concentration is the measured sensitivity of the lysate solution(IU/ml).If this is not less than0.5λand not more than2λ,the labelled sensitivity is confirmed and is used in the tests performed with this lysate. (ii)Test for interfering factorsPrepare solutions A,B,C and D as shown in Table2.6.14.-1, and use the test solutions at a dilution less than the MVD, not containing any detectable endotoxins,operating as described under1.Preparatory testing,(i)Confirmation of the labelled lysate sensitivity.EUROPEAN PHARMACOPOEIA 5.0 2.6.14.BacterialendotoxinsTable 2.6.14.–1Solution Endotoxin concentration/Solution towhich endotoxin is addedDiluent Dilution factorInitial endotoxin concentrationNumber of replicatesA None/Test solution ---4B2λ/Test solutionTest solution12482λ1λ0.5λ0.25λ4444C 2λ/Water for BET Water for BET12482λ1λ0.5λ0.25λ2222D None/Water for BET---2Solution A =solution of the preparation being examined that is free of detectable endotoxins.Solution B =test for interference.Solution C =control of the labelled lysate sensitivity.Solution D =negative control (water for BET).The geometric mean end-point concentrations of solutions B and C are determined using the expression described in 1.Preparatory testing,(i)Confirmation of the labelled lysate sensitivity.The test for interfering factors is repeated when any changes are made to the experimental conditions that are likely to influence the result of the test.The test is not valid unless all replicates of solutions A and D show no reaction and the result of solution C confirms the labelled lysate sensitivity.If the sensitivity of the lysate determined with solution B is not less than 0.5λand not greater than 2λ,the test solution does not contain interfering factors under the experimental conditions used.Otherwise,the solution interferes with the test.If the preparation being examined interferes with the test at a dilution less than the MVD,repeat the test for interfering factors using a greater dilution,not exceeding the MVD.The use of a more sensitive lysate permits a greater dilution of the preparation being examined and this may contribute to the elimination of interference.Interference may be overcome by suitable treatment,such as filtration,neutralisation,dialysis or heat treatment.To establish that the treatment chosen effectively eliminates interference without loss of endotoxins,repeat the test for interfering factors using the preparation being examined to which the standard endotoxin has been added and which has then been submitted to the chosen treatment.2.LIMIT TEST (METHOD A)(i)ProcedurePrepare solutions A,B,C and D as shown in Table 2.6.14.-2,and perform the test on these solutions following the procedure described under 1.Preparatory testing,(i)Confirmation of the labelled lysate sensitivity.Table 2.6.14.-2Solution Endotoxin concentration/Solution to which endotoxin is addedNumber of replicates A None/Diluted test solution2B 2λ/Diluted test solution 2C 2λ/Water for BET2D None/Water for BET2Prepare solution A and solution B (positive product control)using a dilution not greater than the MVD and treatments as described in 1.Preparatory testing,(ii)Test for interferingfactors.Solutions B and C (positive controls)contain the standard endotoxin at a concentration corresponding to twice the labelled lysate sensitivity.Solution D (negative control)consists of water for BET.(ii)InterpretationThe test is not valid unless both replicates of the 2positive control solutions B and C are positive and those of the negative control solution D are negative.The preparation being examined complies with the test when a negative result is found for both replicates of solution A.When a positive result is found for both replicates of solution A:—if the preparation being examined is diluted to the MVD,it does not comply with the test,—if the preparation being examined is diluted to a dilution less than the MVD,the test is repeated at a dilution not greater than the MVD.Repeat the test if a positive result is found for one replicate of solution A and a negative result is found for the other.The preparation being examined complies with the test if a negative result is found for both replicates of solution A in the repeat test.3.SEMI-QUANTITATIVE TEST (METHOD B)(i)ProcedureThe test quantifies bacterial endotoxins in the test solution by titration to an end-point.Prepare solutions A,B,C and D as shown in Table 2.6.14.-3,and test these solutions according to the procedure described under 1.Preparatory testing,(i)Confirmation of the labelled lysate sensitivity.(ii)Calculation and interpretationThe test is not valid unless the following 3conditions are met:(a)both replicates of solution D (negative control)are negative,(b)both replicates of solution B (positive product control)are positive,(c)the geometric mean end-point concentration of solution Cis in the range of 0.5λto 2λ.To determine the endotoxin concentration of solution A,calculate the end-point concentration for each replicate series of dilutions by multiplying each end-point dilutionfactor by λ.The endotoxin concentration in the test solution is the geometric mean end-point concentration of the replicates(see the expression given under 1.Preparatory testing,(i)Confirmation of the labelled lysate sensitivity).If the2.6.14.Bacterial endotoxins EUROPEAN PHARMACOPOEIA5.0test is conducted with a diluted test solution,calculatethe concentration of endotoxin in the original solution by multiplying the result by the dilution factor.If none of the dilutions of the test solution is positive in a valid test,record the endotoxin concentration as less thanλ(or,if a diluted sample was tested,as less thanλ×the lowest dilution factor of the sample).If all dilutions are positive,the endotoxin concentration is recorded as equal to or greater than the greatest dilution factor multiplied byλ(e.g.in Table2.6.14.-3,the initial dilution factor×8×λ).The preparation meets the requirements of the test if the endotoxin concentration is less than that specified in the individual monograph.PHOTOMETRIC TECHNIQUES(METHODS C,D,E AND F) 1.TURBIDIMETRIC TECHNIQUE(METHODS C AND F) This technique is a photometric test to measure the increase in turbidity.Based on the test principle employed,this technique is classified as being the end-point-turbidimetric test or the kinetic-turbidimetric test.The end-point-turbidimetric test(Method F)is basedon the quantitative relationship between the endotoxin concentration and the turbidity(absorbance or transmission) of the reaction mixture at the end of an incubation period. The kinetic-turbidimetric test(Method C)is a method to measure either the time(onset time)needed for the reaction mixture to reach a predetermined absorbance,or the rate of turbidity development.The test is carried out at the incubation temperature recommended by the lysate manufacturer(usually37±1°C).2.CHROMOGENIC TECHNIQUE(METHODS D AND E) This technique is used to measure the chromophore released from a suitable chromogenic peptide by the reactionof endotoxins with the lysate.Depending on the test principle employed,this technique is classified as being the end-point-chromogenic test or the kinetic-chromogenic test.The end-point-chromogenic test(Method E)is basedon the quantitative relationship between the endotoxin concentration and the quantity of chromophore released at the end of an incubation period.The kinetic-chromogenic test(Method D)measures either the time(onset time)needed for the reaction mixture to reach a predetermined absorbance,or the rate of colour development.The test is carried out at the incubation temperature recommended by the lysate manufacturer(usually37±1°C).3.PREPARATORY TESTINGTo assure the precision or validity of the turbidimetric and chromogenic tests,preparatory tests are conducted to assure that the criteria for the standard curve are satisfied and that the test solution does not interfere with the test. Validation of the test method is required when any changes are made to the experimental conditions that are likely to influence the result of the test.(i)Assurance of criteria for the standard curveUsing the standard endotoxin solution,prepare at least3endotoxin concentrations to generate the standard curve.Perform the test using at least3replicates of each standard endotoxin solution as recommended by the lysate manufacturer(volume ratios,incubation time,temperature, pH,etc.).If the desired range is greater than2log in the kinetic methods,additional standards must be included to bracket each log increase in the range of the standard curve.The absolute value of the correlation coefficient,|r|,must be greater than or equal to0.980,for the range of endotoxin concentrations indicated by the lysate manufacturer.(ii)Test for interfering factorsSelect an endotoxin concentration at or near the middle of the endotoxin standard curve.Prepare solutions A,B,C and D as shown in Table2.6.14.-4. Perform the test on at least2replicates of these solutions as recommended by the lysate manufacturer(volume of test solution and lysate solution,volume ratio of test solution to lysate solution,incubation time,etc.).Table2.6.14.-3Solution Endotoxin concentration/Solution towhich endotoxin is added Diluent Dilution factor Initial endotoxinconcentrationNumber of replicatesA None/Test solution Water for BET1248----2222B2λ/Test solution12λ2C2λ/Water for BET Water for BET12482λ1λ0.5λ0.25λ2222D None/Water for BET---2 Solution A=test solution at the dilution,not exceeding the MVD,with which the test for interfering factors was carried out.Subsequent dilution of the test solution must not exceed the e water for BET to make two dilution series of1,1/2,1/4and1/8,relative to the dilution with which the test for interfering factors was carried out.Other dilutions may be used as appropriate.Solution B=solution A containing standard endotoxin at a concentration of2λ(positive product control).Solution C=2series of water for BET containing the standard endotoxin at concentrations of2λ,λ,0.5λand0.25λ.Solution D=water for BET(negative control).EUROPEAN PHARMACOPOEIA 5.0 2.6.14.BacterialendotoxinsTable 2.6.14.-4.Solution Endotoxin concentrationSolution to which endotoxin is added Number of replicates A NoneTest solution Not less than 2B Middle concentration of the standard curve Test solution Not less than 2CAt least 3concentra-tions (lowest concen-tration is designated λ)Water for BETEach concentra-tion not less than 2D NoneWater for BETNot less than 2Solution A =test solution,that may be diluted not to exceed the MVD.Solution B =preparation to be examined at the same dilution assolution A,containing added endotoxin at a concentration equal to or near the middle of the standard curve.Solution C =standard endotoxin solution at the concentrations used in the validation of the method as described under 3.Preparatory testing,(i)Assurance of criteria for the standard curve (positive controls.Solution D =water for BET (negative control).Calculate the mean recovery of the added endotoxin by subtracting the mean endotoxin concentration in the solution (if any)from that in the solution containing the added endotoxin.The test solution is considered free of interferingfactors if under the conditions of the test,the measured concentration of the endotoxin added to the test solution is within 50-200per cent of the known added endotoxin concentration,after subtraction of any endotoxin detected in the solution without added endotoxin.When the endotoxin recovery is out of the specified ranges,the interfering factors must be removed as described in the section Gel-clot technique,under 1.Preparatory testing,(ii)Test for interfering factors.The efficiency of the treatment is verified by repeating the test for interfering factors.4.TEST(i)ProcedureFollow the procedure described in 3.Preparatory testing,(ii)Test for interfering factors.(ii)CalculationCalculate the endotoxin concentration of each replicate of solution A using the standard curve generated by the series of positive controls,solution C.The test is not valid unless the following 3requirements are met:(a)the result obtained with solution D (negative control)does not exceed the limit of the blank value required in the description of the lysate employed,(b)the results obtained with the series of positive controls,solution C,comply with the requirements for validationdefined under 3.Preparatory testing,(i)Assurance of criteria for the standard curve,(c)the endotoxin recovery,calculated from the endotoxin concentration found in solution B after subtracting the endotoxin concentration found in solution A,is within the range of 50-200per cent.(iii)InterpretationThe preparation being examined complies with the test if the mean endotoxin concentration of the replicates of solution A,after correction for dilution and concentration,is less than the endotoxin limit for the product.5.REAGENTS (i)Lysate solutionDissolve amoebocyte lysate in water for BET or in a buffer,as recommended by the lysate manufacturer,by gentle stirring.Store the reconstituted lysate,refrigerated or frozen,as indicated by the manufacturer.(ii)Amoebocyte lysateAmoebocyte lysate is a lyophilised product obtained from amoebocyte lysate from Horseshoe Crab (Limulus polyphemus or Tachypleus tridentatus ).This reagent refers only to a product manufactured in accordance with the regulations of the competent authority.Amoebocyte lysate reacts with some β-glucans in addition to endotoxins.Amoebocyte lysate preparations which do not react with glucans are available;they are prepared by removing from amoebocyte lysate the G factor,which reacts with glucans,or by inhibiting the G factor reacting system of amoebocyte lysate.These preparations may be used for endotoxin testing in the presence of glucans.(iii)Water for BET (water for bacterial endotoxins test)Water for BET is water for injections R or water produced by other procedures that shows no reaction with the lysate employed at the detection limit of the reagent.The following section is published for information.Test for bacterial endotoxins:guidelines1.INTRODUCTIONEndotoxins from gram-negative bacteria are themost common cause of toxic reactions resulting from contamination of pharmaceutical products with pyrogens;their pyrogenic activity is much higher than that of most other pyrogenic substances.These endotoxins are lipo-polysaccharides.Although there are a small number of pyrogens which possess a different structure,theconclusion is generally justified that the absence of bacterial endotoxins in a product implies the absence of pyrogenic components,provided the presence of non-endotoxin pyrogenic substances can be ruled out.The presence of endotoxins in a product may be masked by factors interfering with the reaction between the endotoxins and the amoebocyte lysate.Hence,the analyst who wishes to replace the rabbit pyrogen test required in a pharmacopoeial monograph by a test for bacterial endotoxins has to demonstrate that a valid test can be carried out on theproduct concerned;this may entail a procedure for removing interfering factors.As indicated in the test for bacterial endotoxins,information must be available on the 2following aspects before a test on a sample can be regarded as valid.1.1.The suitability of the material to be used for the test has to be established.The absence of endotoxins in the water for BET and in the other reagents must be assured and the sensitivity of the amoebocyte lysate must be checked to confirm the sensitivity declared by the manufacturer.1.2.As the product to be examined may interfere with the test,the sensitivity of the amoebocyte lysate is determined in the presence and in the absence of the product under examination.There must be no significant difference between the 2sensitivity values.The test for bacterial endotoxins (2.6.14)indicates methods for removing interfering factors;in the case of interference,another test must be carried out after such a method has been applied to check whether the interference has indeed been neutralised or removed.This annex explains the reasons for the requirements in the test for bacterial endotoxins,then deals with the reading and interpretation of the results.Substitution of the rabbit pyrogen test required in apharmacopoeial monograph by an amoebocyte lysate test constitutes the use of an alternative method of analysis and hence requires validation;some guidance on how to proceed is given in section 11.2.6.14.Bacterial endotoxins EUROPEAN PHARMACOPOEIA5.0The reference method for bacterial endotoxins is stated in the monograph on a given product;where no method is stated,method A is the reference method.If a method other than the reference method is to be used,the analyst must demonstrate that the method is appropriate for this product and gives a result consistent with that obtained with the reference method(see also Section13).2.METHODThe addition of endotoxins to amoebocyte lysate may result in turbidity,precipitation or gelation(gel-clot);only thegel-clot method was used in the Pharmacopoeia as an evaluation criterion in the first type of test for bacterial endotoxins.The advantage was the simplicity of basing the decision to pass or fail the product under examination on the absence or presence of a gel-clot,visible with the naked eye. The quantitative methods described as methods C,D,E and F were developed later:they require more instrumentation, but they are easier to automate for the regular testing of large numbers of samples of the same product. Endotoxins may be adsorbed onto the surface of tubesor pipettes made from certain plastics or types of glass. Interference may appear due to the release of substances from plastic materials.Hence,the materials used should be checked;subsequent batches of tubes or pipettes may have a slightly different composition,and therefore the analyst is advised to repeat such tests on starting with new batchesof materials.The decision to use the test for bacterial endotoxins as a limit test implies first,that a threshold endotoxin concentration must be defined for the product to be tested and second,that the objective of the test is to know whether the endotoxin concentration in the product under examination is below or above this threshold.The quantitative methods C,D,E and F make it possible to determine the endotoxin concentration in the sample under examination,but for compliance with the Pharmacopoeia and in routine quality control the final question is whether or not this concentration exceeds a defined limit.In setting a threshold concentration of endotoxin for the product to be tested,due attention should be paid to the dose of the product:the threshold should be set so as to ensure that as long as the endotoxin concentration in the product remains below this threshold even the maximal dose administered by the intended route per hour does not contain sufficient endotoxin to cause a toxic reaction. When the endotoxin concentration in the product exactly equals the threshold value,gelation will occur,as is the case when the endotoxin concentration is much higher,and the product will fail the test,because the all-or-none character of the test makes it impossible to differentiate between a concentration exactly equal to the threshold concentration and one that is higher.It is only when no gelation occurs that the analyst may conclude that the endotoxin concentration is below the threshold concentration.For products in the solid state,this threshold concentration of endotoxin per mass unit or per International Unit(IU)of product has to be translated into a concentration of endotoxin per millilitre of solution to be tested,as the test can only be carried out on a solution.The case of products that already exist in the liquid state(such as infusion fluids) is discussed below.Endotoxin limit:the endotoxin limit for active substances administered parenterally,defined on the basis of dose,is equal to,where:K=threshold pyrogenic dose of endotoxin perkilogram of body mass in a single hour period,M=maximum recommended dose of product perkilogram of body mass in a single hour period. The endotoxin limit depends on the product and its route of administration and is stated in monographs.Values for K are suggested in Table2.6.14.-5.For other routes,the acceptance criterion for bacterial endotoxins is generally determined on the basis of results obtained during the development of the preparation.Table2.6.14.-5Route of administration K(IU of endotoxin per kilogram ofbody mass per hour) Intravenous 5.0Intravanous,forradiopharmaceuticals2.5Intrathecal0.2Which dilution of the product is to be used in the test to obtain maximal assurance that a negative result means that the endotoxin concentration of the product is less thanthe endotoxin limit and that a positive result means that the lysate detected an endotoxin concentration equal to or greater than the endotoxin limit?This dilution depends on the endotoxin limit and on the sensitivity of the lysate:it is called the Maximum Valid Dilution(MVD)and its value may be calculated as follows:Concentration of test solution:—in mg/ml if the endotoxin limit is specified by mass (IU/mg),—in Units/ml if the endotoxin limit is specified by unit of biological activity(IU/Unit),—in ml/ml if the endotoxin limit is specified by volume (IU/ml).λ=the labelled lysate sensitivity in the gel-clottechnique(IU/ml)or the lowest point usedin the standard curve of the turbidimetric orchromogenic techniques.When the value of the maximum valid dilution is not a whole number,a convenient whole number smaller than the MVD may be used for routine purposes(which means preparing a solution of the product which is less diluted than the MVD indicates).In this case,a negative result indicates that the endotoxin concentration of the product lies below the limit value.However,when the endotoxin concentration of the product in such a test is less than the endotoxin limit but high enough to make the reaction with the lysate resultin a clot,the test may be positive under these conditions. Hence,when a test with this‘convenient’dilution factor is positive,the product should be diluted to the MVD and the test should be repeated.In any case of doubt or dispute the MVD must be used.This stresses the importance of the confirmation of the sensitivity of the lysate.。
Ph.Eur 2.6.12. 非无菌产品的微生物检查：微生物计数检查
EUROPEAN PHARMACOPOEIA 6.0
monograph and note whether the contractions produced by the preparation with the added histamine correspond to the amount of histamine added. If this is not the case, or if the contractions caused by the substance to be examined are not reproducible or if subsequent responses to “high” and “low” doses of histamine are diminished, the results of the tests are invalid and the test for depressor substances (2.6.11) must be carried out.
Solution A Atropine sulphate Sodium hydrogen carbonate Glucose monohydrate Water for injections R sufficient to produce
50.0 ml 0.5 mg
1.0 g 0.5 g 1000 ml
2.6.12. MICROBIOLOGICAL EXAMINATION OF NON-STERILE PRODUCTS : TOTAL VIABLE AEROBIC COUNT
This general chapter presents 2 sets of tests. The 1st set gives the reference methods for determining compliance with monographs. Reference to this chapter in a monograph therefore implies compliance with the 1st set of tests, unless use of the 2nd set of tests has been authorised. The tests in the 2nd set also constitute official methods of the European Pharmacopoeia and may be referred to as such, notably in applications for marketing authorisation. It is intended to replace the 1st set by the 2nd set once the monographs concerned have been revised. The 2nd set presents tests developed in co-operation with the Japanese Pharmacopoeia and the United States Pharmacopeia to achieve harmonised requirements.
Chapter 2 Instructor Slides
2.1.1 Set of Integers
The set of integers, denoted by Z, contains all integral numbers (with no fraction) from negative infinity to positive infinity (Figure 2.1).
Note
Euclidean Algorithm
Fact 1: gcd (a, 0) = a Fact 2: gcd (a, b) = gcd (b, r), where r is the remainder of dividing a by b
2.19
2.1.4 Continued
Figure 2.7 Euclidean Algorithm
a=q×n+r
2.7
2.1.3 Continued
Example 2.2
Assume that a = 255 and n = 11. We can find q = 23 and R = 2 using the division algorithm. Figure 2.3 Example 2.2, finding the quotient and the remainder
2.27
2.1.4 Continued
Example 2.10
Given a = 17 and b = 0, find gcd (a, b) and the values of s and t. Solution We get gcd (17, 0) = 17, s = 1, and t = 0.
Chapter 2
Mathematics of Cryptography
ISO9000品质管理体系基础知识
CHAPTER 2學習內容l l l l l l l lISO 9000品質管理系統ISO 9000的沿革 品質管理系統 管理責任 資源管理 產品實現 量測、分析及改善 八項品質管理原則 ISO 9001與ISO 14001品質與環境管理 系統中華大學 營建管理研究所 營建品質管理2-1CHAPTER 2ISO 9000品質管理系統2.1 ISO 9000的沿革ISO－ International Organization for Standardization IOS? “ISO “ is a word derived from the Greek isos, meaning “equal “. Form “equal” via “uniform” to “standard”, the conceptual path followed in selecting “ISO” as the name of the organization is easy to follow.中華大學 營建管理研究所 營建品質管理2-2CHAPTER 2ISO 9000品質管理系統◆1908年，倫敦召開國家電工會議，成立國際電工 委員會（IEC） ◆1926年，國際標準協會世界聯盟（ISA） ◆1947年，2/23成立ISO，總部設於瑞士日內瓦 ◆1987年，公佈「品質管理與品質保證」系列 ◆1994年，公佈修正ISO 9000系列標準修訂版 ◆2000年，公佈2000年版ISO 9000中華大學 營建管理研究所 營建品質管理2-3CHAPTER 2ISO國際標準制定程序階段 ０ １ ２ ３ ４ ５ ６ 階段名稱 Stage 預備階段 Preliminary Stage 提案階段 Proposal Stage 準備階段 Preparatory Stage 委員會階段 Committee Stage 諮詢階段 Inquiry Stage 准許階段 Approval Stage 發行階段 Publication StageISO 9000品質管理系統需要時間 Duration(Months) 依工作進度而定 依工作進度而定 依工作進度而定 依工作進度而定 3~6 個月(1 個月準 備，2~5 個月投票) 6 個月內(4 個月內準 備完成，2 個月投票 )，提交理事會核准 2 個月內準備完成 2-4相關文件 Associated Document 預備工作項目(PWI) Preliminary Work Item 新工作項目提案(NP) New Work Item Proposal 工作小組草案(WD) Working Draft 委員會草案(CD) Committee Draft 國際標準草案(DIS) Draft International Standard 最終國際標準草案(FDIS) Final Draft International Standard 國際標準(IS) International Standard中華大學 營建管理研究所 營建品質管理CHAPTER 22000年版標準改訂作業時程表時 1998.7.30 1999.2.22 1999.3.1~8.1 1999 年 9 月 1999 年第四季 2000 年 6 月 2000 年第三季 2000 年 12 月 ISO/TC 176/SC2(日本) ISO/TC 176/SC2(美國) 間 會 議ISO 9000品質管理系統修訂狀況 CD1 發行，並進行討論 CD2 發行 CD2 進行投票 DIS 完成 DIS 進行投票 FDIS 完成 FDIS 進行投票表決 公告 2000 年版 ISO 9000中華大學 營建管理研究所 營建品質管理2-5CHAPTER 22000年版標準一覽表2000 年版 ISO 9000 品質管理系統－概念與詞彙 ISO 9001 品質管理系統－系統要求 ISO 9004 品質管理系統－績效改善指導綱要 ISO 19011 品質及環境稽核指導綱要 TR 1000X 選擇與使用指南 TR 1000Y 品質原則及其在管理實務之應用 轉換計畫指導 說ISO 9000品質管理系統明將 ISO 8402：1994 與部份 9000-1：1994 合併成為 新標準；而標準的選用與指導將改以技術手冊來取 代 將 ISO 9001/2/3：1994 合併成為單一標準 依 ISO 9004-1：1994 改訂完成 將與 ISO 14010、14011、14012、10011 合併成為 新品質與環境管理系統稽核標準(2001 年第三季) 技術報告手冊，取代 ISO 9000-1：1994 技術報告手冊，說明八項品質管理原則及其應用 指導文件，協助各種使用者順利地轉換，並符合新 版標準的要求中華大學 營建管理研究所 營建品質管理2-6CHAPTER 2轉換時期規劃指導綱要與驗證/登錄機構討論有關新舊版之共存期間事宜，考慮時機 /ISO9001：2000不同草案版發行及其對組織實施計畫的潛在衝擊ISO 9000品質管理系統鑑別ISO9001：2000之變更內容(「比較對照表」或可協助，「轉換 期規劃指導綱要」文件亦可提供對照說明) 評估現有QMS架構以決定應待加強之程度，以符合ISO9001：2000 之管理過程 是否QMS有過程管理焦點 否 否 是否使用者承諾建立一項 過管理焦點系統 是 重新設計現有系統以採行 過管理焦點 建立＆展開過程管理焦點 訓練計畫 重新檢查組織目標 是 開始自我稽核/評估 是 是否符合標準要求 否 修訂程序書與新版要求相一致執行程序以提供符合性之證據申請驗證/登錄升級中華大學 營建管理研究所 營建品質管理2-7CHAPTER 294年版至2000年版轉換模型1999 年底 ISO 9001 1994 及 2000 年版共存期 國家標準機構 認證機構 驗證機構 訓練機構 稽核員升級 登錄廠商 產業計畫 驗證修訂轉換 認證修訂轉換 2000 年底 CD2 DIS FDIS 新標準轉換期ISO 9000品質管理系統2001 年底 2002 年底 IS（國際標準） 翻譯 採用 國家標準發行ISO 9001：2000 驗證中華大學 營建管理研究所 營建品質管理2-8CHAPTER 22000年版與94年版詞彙比較 ISO 9000品質管理系統1994 年版 品質系統 (quality system) 供應者 (supplier) 分包商 (subcontractor) 產品 (product) 供應者管理階層擔負實責者 (supplier’s management with executive responsibility) 利益相關者 (stakeholder） 2000 年版 品質管理系統 (quality management system) 組織 (organization) 供應者 (supplier) 產品和(或)服務 (product and/or service) 高階管理者 (top management) 利害相關團體 (interested party） 說明 強化品質管制與品質改進之構 面，不再侷限於品質保證 供應鏈： 1994:分包商→供應者→顧客 2000:供應者→組 織→顧客 適合各行業別及各類型產品 管理位階之提高 利害相關團體包括： 顧客、企業主、員工、供應者及 社會中華大學 營建管理研究所 營建品質管理2-9CHAPTER 2ISO 9000品質管理系統ISO 9000新版標準特色－建立以顧客導向為主的管理體系 －充份強調PDCA之流程管理模式 －著重持續改善及預防在先的精神 －強化各個系統，流程，作業的有效性中華大學 營建管理研究所 營建品質管理2-10。
2.6.12. Microbiological examination of non-sterile products- microbial enum~~~
EUROPEAN PHARMACOPOEIA 7.0 2.6.12.Microbial enumerationteststhe animal from loss of body heat and maintain it so that the rectal temperature remains within physiological limits.Introduce a cannula into the trachea.Insert a cannula filled with a heparinised 9g/L solution of sodium chloride into the common carotid artery and connect it to a device capable of giving a continuous record of the blood pressure.Insert into the femoral vein another cannula,filled with a heparinised 9g/L solution of sodium chloride,through which can be injected the solutions of histamine and of the substance to be examined.Determine the sensitivity of the animal to histamine by injecting intravenously at regular intervals,doses of histamine solution R corresponding to 0.1μg and 0.15μg of histamine base per kilogram of body mass.Repeat the lower dose at least 3times.Administer the second and subsequent injections not less than 1min after the blood pressure has returned to the level it was at immediately before the previous injection.The animal is used for the test only if a readily discernible decrease in blood pressure that is constant for the lower dose is obtained and if the higher dose causes greater responses.Dissolve the substance to be examined in sufficient of a 9g/L solution of sodium chloride or other prescribed solvent,to give the prescribed concentration.Inject intravenously per kilogram of body mass 1.0mL of histamine solution R ,followed by2successive injections of the prescribed amount of the solution to be examined and,finally,1.0mL of histamine solution R .The second,third and fourth injections are given not less than 1min after the blood pressure has returned to the level it was at immediately before the preceding injection.Repeat this series of injections twice and conclude the test by giving 1.5mL of histamine solution R per kilogram of body mass.If the response to 1.5mL of histamine solution R per kilogram of body mass is not greater than that to 1.0mL the test isinvalid.The substance to be examined fails the test if the mean of the series of responses to the substance is greater than the mean of the responses to 1.0mL of histamine solution R per kilogram of body mass or if any one dose of the substance causes a greater depressor response than the concluding dose of the histamine solution.The test animal must not be used in another test for depressor substances if the second criterion applies or if the response to the high dose of histamine given after the administration of the substance to be examined is less than the mean response to the low doses of histamine previously injected.07/2010:206122.6.12.MICROBIOLOGICALEXAMINATION OF NON-STERILE PRODUCTS:MICROBIAL ENUMERATION TESTS (1)1.INTRODUCTION The tests described hereafter will allow quantitative enumeration of mesophilic bacteria and fungi that may grow under aerobic conditions.The tests are designed primarily to determine whethera substance or preparation complies with an establishedspecification for microbiological quality.When used for such purposes follow the instructions given below,including the number of samples to be taken,and interpret the results as stated below.The methods are not applicable to products containing viable micro-organisms as active ingredients.Alternative microbiological procedures,including automated methods,may be used,provided that their equivalence to the Pharmacopoeia method has been demonstrated. 2.GENERAL PROCEDURESCarry out the determination under conditions designed to avoid extrinsic microbial contamination of the product to be examined.The precautions taken to avoid contamination must be such that they do not affect any micro-organisms that are to be revealed in the test.If the product to be examined has antimicrobial activity,this is insofar as possible removed or neutralised.If inactivators are used for this purpose,their efficacy and their absence of toxicity for micro-organisms must be demonstrated.If surface-active substances are used for sample preparation,their absence of toxicity for micro-organisms and their compatibility with inactivators used must be demonstrated.3.ENUMERATION METHODSUse the membrane filtration method or the plate-count methods,as prescribed.The most-probable-number (MPN)method is generally the least accurate method for microbial counts,however,for certain product groups with a very low bioburden,it may be the most appropriate method.The choice of method is based on factors such as the nature of the product and the required limit of micro-organisms.The chosen method must allow testing of a sufficient sample size to judge compliance with the specification.The suitability of the method chosen must be established.4.GROWTH PROMOTION TEST,SUITABILITY OF THE COUNTING METHOD AND NEGATIVE CONTROLS 4-1.GENERAL CONSIDERATIONSThe ability of the test to detect micro-organisms in the presence of product to be tested must be established.Suitability must be confirmed if a change in testing performance,or the product,which may affect the outcome of the test is introduced.4-2.PREPARATION OF TEST STRAINSUse standardised stable suspensions of test strains or prepare them as stated below.Seed lot culture maintenance techniques (seed-lot systems)are used so that the viable micro-organisms used for inoculation are not more than 5passages removed from the original master seed-lot.Grow each of the bacterial and fungal test strains separately as described in Table e buffered sodium chloride-peptone solution pH 7.0orphosphate buffer solution pH 7.2to make test suspensions;to suspend A.brasiliensis spores,0.05per cent of polysorbate 80may be added to the e the suspensions within 2h or within 24h if stored at 2-8°C.As an alternative to preparing and then diluting a fresh suspension of vegetative cells of A.brasiliensis or B.subtilis ,a stable spore suspension is prepared and then an appropriate volume of the sporesuspension is used for test inoculation.The stable sporesuspension may be maintained at 2-8°C for a validated period of time.4-3.NEGATIVE CONTROLTo verify testing conditions,a negative control is performed using the chosen diluent in place of the test preparation.There must be no growth of micro-organisms.A negative controlis also performed when testing the products as described in section 5.A failed negative control requires an investigation.4-4.GROWTH PROMOTION OF THE MEDIA Test each batch of ready-prepared medium and each batch of medium,prepared either from dehydrated medium or from the ingredients described.Inoculate portions/plates of casein soya bean digest broth and casein soya bean digest agar with a small number (not more than 100CFU)of the micro-organisms indicated in Table 2.6.12.-1,using a separate portion/plate of medium for each.Inoculate plates of Sabouraud-dextrose agar with a small number (not(1)This chapter has undergone pharmacopoeial harmonisation.See chapter 5.8.Pharmacopoeial harmonisation .2.6.12.Microbial enumeration tests EUROPEAN PHARMACOPOEIA7.0Table 2.6.12.-1.–Preparation and use of test micro-organismsGrowth promotionSuitability of counting method in thepresence of the productMicro-organismPreparation of teststrainTotal aerobic microbialcountTotal yeasts and moulds countTotal aerobic microbial count Total yeasts andmoulds countStaphylococcus aureussuch as:ATCC 6538NCIMB 9518CIP 4.83NBRC 13276Casein soya bean digest agar or casein soya bean digest broth30-35°C 18-24h Casein soya bean digest agar and casein soya bean digest broth ≤100CFU 30-35°C ≤3days -Casein soya bean digest agar/MPN casein soya bean digest broth≤100CFU30-35°C ≤3days -Pseudomonas aeruginosa such as:ATCC 9027NCIMB 8626CIP 82.118NBRC 13275Casein soya bean digest agar or casein soya bean digest broth30-35°C 18-24hCasein soya bean digest agar and casein soya bean digest broth ≤100CFU 30-35°C ≤3days -Casein soya bean digest agar/MPN casein soya bean digest broth ≤100CFU 30-35°C ≤3days -Bacillus subtilissuch as:ATCC 6633NCIMB 8054CIP 52.62NBRC 3134Casein soya bean digest agar or casein soya bean digest broth30-35°C 18-24h Casein soya bean digest agar and casein soya bean digest broth ≤100CFU 30-35°C ≤3days -Casein soya bean digest agar/MPN casein soya bean digest broth ≤100CFU 30-35°C ≤3days -Candida albicanssuch as:ATCC 10231NCPF 3179IP 48.72NBRC 1594Sabouraud-dextrose agar or Sabouraud-dextrose broth 20-25°C2-3daysCasein soya bean digest agar ≤100CFU 30-35°C ≤5days Sabouraud-dextroseagar ≤100CFU 20-25°C ≤5days Casein soya bean digest agar ≤100CFU 30-35°C ≤5daysMPN:not applicable Sabouraud-dextroseagar ≤100CFU 20-25°C ≤5days Aspergillus brasiliensissuch as:ATCC 16404IMI 149007IP 1431.83NBRC 9455Sabouraud-dextrose agar or potato-dextroseagar 20-25°C5-7days,or until good sporulation is achievedCasein soya bean digest agar ≤100CFU 30-35°C ≤5daysSabouraud-dextroseagar ≤100CFU 20-25°C ≤5daysCasein soya bean digest agar ≤100CFU 30-35°C ≤5daysMPN:not applicableSabouraud-dextroseagar ≤100CFU 20-25°C ≤5daysmore than 100CFU)of the micro-organisms indicated in Table 2.6.12.-1,using a separate plate of medium for each.Incubate in the conditions described in Table 2.6.12.-1.For solid media,growth obtained must not differ by a factor greater than 2from the calculated value for a standardised inoculum.For a freshly prepared inoculum,growth of the micro-organisms comparable to that previously obtained with a previously tested and approved batch of medium occurs.Liquid media are suitable if clearly visible growth of themicro-organisms comparable to that previously obtained with a previously tested and approved batch of medium occurs.4-5.SUITABILITY OF THE COUNTING METHOD IN THE PRESENCE OF PRODUCT4-5-1.Preparation of the sample .The method for sample preparation depends upon the physical characteristics of the product to be tested.If none of the procedures described below can be demonstrated to be satisfactory,an alternative procedure must be developed.Water-soluble products .Dissolve or dilute (usually a 1in 10dilution is prepared)the product to be examined in buffered sodium chloride-peptone solution pH 7.0,phosphate buffer solution pH 7.2or casein soya bean digest broth.If necessary,adjust to pH 6-8.Further dilutions,where necessary,are prepared with the same diluent.Non-fatty products insoluble in water .Suspend the product to be examined (usually a 1in 10dilution is prepared)in buffered sodium chloride-peptone solution pH 7.0,phosphate buffer solution pH 7.2or casein soya bean digest broth.A surface-active agent such as 1g/L of polysorbate 80may be added to assist the suspension of poorly wettable substances.If necessary,adjust to pH 6-8.Further dilutions,where necessary,are prepared with the same diluent.Fatty products .Dissolve in isopropyl myristate,sterilised by filtration or mix the product to be examined with the minimum necessary quantity of sterile polysorbate 80or another non-inhibitory sterile surface-active agent,heated if necessary to not more than 40°C,or in exceptional cases to not more than 45°C.Mix carefully and if necessary maintain the temperature in a water-bath.Add sufficient of the pre-warmed chosen diluent to make a 1in 10dilution of the original product.Mix carefully whilst maintaining the temperature for the shortest time necessary for the formation of an emulsion.Further serial tenfold dilutions may be prepared using the chosen diluent containing a suitable concentration of sterile polysorbate 80or another non-inhibitory sterile surface-active agent.Fluids or solids in aerosol form .Aseptically transfer theproduct into a membrane filter apparatus or a sterile container for further e either the total contents or a defined number of metered doses from each of the containers tested.Transdermal patches .Remove the protective cover sheets (‘release liners’)of the transdermal patches and place them,adhesive side upwards,on sterile glass or plastic trays.Cover the adhesive surface with a sterile porous material,for example sterile gauze,to prevent the patches from sticking together,and transfer the patches to a suitable volume of the chosen diluent containing inactivators such as polysorbate 80and/or lecithin.Shake the preparation vigorously for at least 30min.4-5-2.Inoculation and dilution .Add to the sample prepared as described above (4-5-1)and to a control (with no test material included)a sufficient volume of the microbial suspension to obtain an inoculum of not more than 100CFU.The volume of the suspension of the inoculum should not exceed 1per cent of the volume of diluted product.To demonstrate acceptable microbial recovery from the product,the lowest possible dilution factor of the prepared sample must be used for the test.Where this is not possible due to antimicrobial activity or poor solubility,further appropriate protocols must be developed.If inhibition of growth by the sample cannot otherwise be avoided,the aliquot of the microbialEUROPEAN PHARMACOPOEIA 7.0 2.6.12.Microbial enumerationtestssuspension may be added after neutralisation,dilution orfiltration.4-5-3.Neutralisation/removal of antimicrobial activity .Thenumber of micro-organisms recovered from the preparedsample diluted as described in 4-5-2and incubated followingthe procedure described in 4-5-4,is compared to the number of micro-organisms recovered from the control preparation.If growth is inhibited (reduction by a factor greater than 2),then modify the procedure for the particular enumeration test toensure the validity of the results.Modification of the procedure may include,for example,(1)an increase in the volume ofthe diluent or culture medium,(2)incorporation of specificor general neutralising agents into the diluent,(3)membranefiltration,or (4)a combination of the above measures.Neutralising agents .Neutralising agents may be used to neutralise the activity of antimicrobial agents (Table 2.6.12.-2).They may be added to the chosen diluent or the medium preferably before sterilisation.If used,their efficacy and theirabsence of toxicity for micro-organisms must be demonstratedby carrying out a blank with neutraliser and without product.Table 2.6.12.-2.–Common neutralising agents for interfering substancesInterfering substance Potential neutralisingmethod Glutaraldehyde,mercurials Sodium hydrogensulfite(sodium bisulfite)Phenolics,alcohol,aldehydes,sorbate Dilution Aldehydes GlycineQuaternary Ammonium Compounds (QACs),parahydroxybenzoates (parabens),bis-biguanidesLecithin QACs,iodine,parabens PolysorbateMercurials ThioglycollateMercurials,halogens,aldehydes ThiosulfateEDTA (edetate)Mg 2+or Ca 2+ions If no suitable neutralising method can be found,it can be assumed that the failure to isolate the inoculated organism is attributable to the microbicidal activity of the product.This information serves to indicate that the product is not likely to be contaminated with the given species of the micro-organism.However,it is possible that the product only inhibits some of the micro-organisms specified herein,but does not inhibit others not included amongst the test strains or for which the latter are not representative.Then,perform the test with the highest dilution factor compatible with microbial growth and the specific acceptance criterion.4-5-4.Recovery of micro-organism in the presence of product .For each of the micro-organisms listed,separate tests are performed.Only micro-organisms of the added test strain are counted.4-5-4-1.Membrane filtration .Use membrane filters having anominal pore size not greater than 0.45μm.The type of filtermaterial is chosen such that the bacteria-retaining efficiency is not affected by the components of the sample to be investigated.For each of the micro-organisms listed,one membrane filter is used.Transfer a suitable amount of the sample prepared as described under 4-5-1to 4-5-3(preferably representing 1g of the product,or less if large numbers of CFU are expected)to the membrane filter,filter immediately and rinse the membrane filter with anappropriate volume of diluent.For the determination of total aerobic microbial count (TAMC),transfer the membrane filter to the surface of casein soyabean digest agar.For the determination of total combined yeasts/moulds count (TYMC),transfer the membrane to the surface of Sabouraud-dextrose agar.Incubate the plates as indicated in Table 2.6.12.-1.Perform the counting.4-5-4-2.Plate-count methods .Perform plate-count methods at least in duplicate for each medium and use the mean count of the result.4-5-4-2-1.Pour-plate methodFor Petri dishes 9cm in diameter,add to the dish 1mL of thesample prepared as described under 4-5-1to 4-5-3and 15-20mL of casein soya bean digest agar or Sabouraud-dextrose agar,both media being at not more than 45°C.If larger Petri dishes are used,the amount of agar medium is increased accordingly.For each of the micro-organisms listed in Table 2.6.12.-1,at least 2Petri dishes are used.Incubate the plates as indicated in Table 2.6.12.-1.Take the arithmetic mean of the countsper medium and calculate the number of CFU in the original inoculum.4-5-4-2-2.Surface-spread method For Petri dishes 9cm in diameter,add 15-20mL of casein soya bean digest agar or Sabouraud-dextrose agar at about 45°C to each Petri dish and allow to solidify.If larger Petri dishes areused,the volume of the agar is increased accordingly.Dry theplates,for example in a laminar-air-flow cabinet or an incubator.For each of the micro-organisms listed in Table 2.6.12.-1,at least 2Petri dishes are used.Spread a measured volume of not less than 0.1mL of the sample prepared as described under 4-5-1to 4-5-3over the surface of the medium.Incubate and count as prescribed under 4-5-4-2-1.4-5-4-3.Most-probable-number (MPN)method .The precisionand accuracy of the MPN method is less than that of the membrane filtration method or the plate-count method.Unreliable results are obtained particularly for the enumerationof moulds.For these reasons the MPN method is reserved for the enumeration of TAMC in situations where no other methodis available.If the use of the method is justified,proceed as follows.Prepare a series of at least 3serial tenfold dilutions of the product as described under 4-5-1to 4-5-3.From each level ofdilution,3aliquots of 1g or 1mL are used to inoculate 3tubeswith 9-10mL of casein soya bean digest broth.If necessary,asurface-active agent such as polysorbate 80or an inactivator of antimicrobial agents may be added to the medium.Thus,if 3levels of dilution are prepared,9tubes are inoculated.Incubate all tubes at 30-35°C for not more than 3days.If reading of the results is difficult or uncertain owing to the nature of the product to be examined,subculture in the same broth,or in casein soya bean digest agar,for 1-2days at the same temperature and use these results.Determine the most probable number of micro-organisms per gram or millilitre of the product to be examined from Table 2.6.12.-3.4-6.RESULTS AND INTERPRETATIONWhen verifying the suitability of the membrane filtration method or the plate-count method,a mean count of any of the test organisms not differing by a factor greater than 2from the value of the control defined in 4-5-2in the absence of theproduct must be obtained.When verifying the suitability of the MPN method the calculated value from the inoculum must be within 95per cent confidence limits of the results obtained with the control.If the above criteria cannot be met for one or more of the organisms tested with any of the described methods,the methodand test conditions that come closest to the criteria are used totest the product.5.TESTING OF PRODUCTS 5-1.AMOUNT USED FOR THE TESTUnless otherwise prescribed,use 10g or 10mL of the productto be examined taken with the precautions referred to above.For fluids or solids in aerosol form,sample 10containers.For transdermal patches,sample 10patches.2.6.12.Microbial enumeration tests EUROPEAN PHARMACOPOEIA7.0Table2.6.12.-3.–Most-probable-number values ofmicro-organismsObserved combinations of numbers oftubes showing growth in each set Number of grams or millilitres ofproduct per tube0.10.010.001MPN pergram or permillilitre ofproduct95per centconfidencelimits000<30-9.400130.1-9.501030.1-10011 6.1 1.2-17020 6.2 1.2-170309.4 3.5-35100 3.60.2-171017.2 1.2-17102114-351107.4 1.3-20111114-35120114-35121155-38130165-382009.2 1.5-35201144-35202205-38210154-38211205-38212279-94220215-40221289-94222359-94230299-94231369-94300235-94301389-1043026416-181310439-1813117517-19931212030-36031316030-3803209318-36032115030-38032221030-40032329090-99033024040-99033146090-19803321100200-4000333>1100The amount to be tested may be reduced for active substances that will be formulated in the following conditions:the amount per dosage unit(e.g.tablet,capsule,injection)is less thanor equal to1mg or the amount per gram or millilitre(for preparations not presented in dose units)is less than1mg.In these cases,the amount to be tested is not less than the amount present in10dosage units or10g or10mL of the product. For materials used as active substances where sample quantity is limited or batch size is extremely small(i.e.less than1000mL or1000g),the amount tested shall be1per cent of the batch unless a lesser amount is prescribed or justified and authorised. For products where the total number of entities in a batch is less than200(e.g.samples used in clinical trials),the sample size may be reduced to2units,or1unit if the size is less than100. Select the sample(s)at random from the bulk material or from the available containers of the preparation.To obtain the required quantity,mix the contents of a sufficient number of containers to provide the sample.5-2.EXAMINATION OF THE PRODUCT5-2-1.Membrane filtrationUse a filtration apparatus designed to allow the transfer of the filter to the medium.Prepare the sample using a method that has been shown suitable as described in section4and transfer the appropriate amount to each of2membrane filters and filter immediately.Wash each filter following the procedure shown to be suitable.For the determination of TAMC,transfer one of the membrane filters to the surface of casein soya bean digest agar.For the determination of TYMC,transfer the other membrane to the surface of Sabouraud-dextrose agar.Incubate the plate of casein soya bean digest agar at30-35°C for3-5days and the plate of Sabouraud-dextrose agar at20-25°C for5-7days.Calculate the number of CFU per gram or per millilitre of product.When examining transdermal patches,filter10per cent of the volume of the preparation described under4-5-1separately through each of2sterile filter membranes.Transfer one membrane to casein soya bean digest agar for TAMC and the other membrane to Sabouraud-dextrose agar for TYMC.5-2-2.Plate-count methods5-2-2-1.Pour-plate methodPrepare the sample using a method that has been shown to be suitable as described in section4.Prepare for each medium at least2Petri dishes for each level of dilution.Incubate the plates of casein soya bean digest agar at30-35°C for3-5days and the plates of Sabouraud-dextrose agar at20-25°C for5-7days. Select the plates corresponding to a given dilution and showing the highest number of colonies less than250for TAMC and50 for TYMC.Take the arithmetic mean per culture medium of the counts and calculate the number of CFU per gram or per millilitre of product.5-2-2-2.Surface-spread methodPrepare the sample using a method that has been shown to be suitable as described in section4.Prepare at least2Petri dishes for each medium and each level of dilution.For incubation and calculation of the number of CFU proceed as described for the pour-plate method.5-2-3.Most-probable-number methodPrepare and dilute the sample using a method that has been shown to be suitable as described in section4.Incubate all tubes at30-35°C for3-5days.Subculture if necessary,using the procedure shown to be suitable.Record for each levelof dilution the number of tubes showing microbial growth. Determine the most probable number of micro-organisms per gram or millilitre of the product to be examined from Table 2.6.12.-3.5-3.INTERPRETATION OF THE RESULTSThe total aerobic microbial count(TAMC)is considered to be equal to the number of CFU found using casein soya bean digest agar;if colonies of fungi are detected on this medium,they are counted as part of the TAMC.The total combined yeasts/mould count(TYMC)is considered to be equal to the number of CFU found using Sabouraud-dextrose agar;if colonies of bacteria are detected on this medium,they are counted as part of theEUROPEAN PHARMACOPOEIA 7.0 2.6.13.Test for specifiedmicro-organismsTYMC.When the TYMC is expected to exceed the acceptance criterion due to the bacterial growth,Sabouraud-dextrose agar containing antibiotics may be used.If the count is carried out by the MPN method the calculated value is the TAMC.When an acceptance criterion for microbiological quality is prescribed it is interpreted as follows:—101CFU:maximum acceptable count =20;—102CFU:maximum acceptable count =200;—103CFU:maximum acceptable count =2000,and so forth.The recommended solutions and media are described in general chapter 2.6.13.04/2010:206132.6.13.MICROBIOLOGICALEXAMINATION OF NON-STERILE PRODUCTS:TEST FOR SPECIFIED MICRO-ORGANISMS (2)1.INTRODUCTIONThe tests described hereafter will allow determination of the absence or limited occurrence of specified micro-organisms that may be detected under the conditions described.The tests are designed primarily to determine whether a substance or preparation complies with an established specification for microbiological quality.When used for such purposes,follow the instructions given below,including the number of samples to be taken,and interpret the results as stated below.Alternative microbiological procedures,including automated methods,may be used,provided that their equivalence to the Pharmacopoeia method has been demonstrated.2.GENERAL PROCEDURESThe preparation of samples is carried out as described in general chapter 2.6.12.If the product to be examined has antimicrobial activity,this is insofar as possible removed or neutralised as described in general chapter 2.6.12.If surface-active substances are used for sample preparation,their absence of toxicity for micro-organisms and theircompatibility with inactivators used must be demonstrated as described in general chapter 2.6.12.3.GROWTH-PROMOTING AND INHIBITORY PROPERTIES OF THE MEDIA,SUITABILITY OF THE TEST AND NEGATIVE CONTROLSThe ability of the test to detect micro-organisms in the presence of the product to be tested must be established.Suitability must be confirmed if a change in testing performance,or the product,which may affect the outcome of the test is introduced.3-1.PREPARATION OF TEST STRAINSUse standardised stable suspensions of test strains or prepare them as stated below.Seed lot culture maintenance techniques (seed-lot systems)are used so that the viable micro-organisms used for inoculation are not more than 5passages removed from the original master seed-lot.3-1-1.Aerobic micro-organisms .Grow each of the bacterial test strains separately in casein soya bean digest broth or on casein soya bean digest agar at 30-35°C for 18-24h.Grow the test strain for Candida albicans separately on Sabouraud-dextrose agar or in Sabouraud-dextrose broth at 20-25°C for 2-3days.—Staphylococcus aureus such as ATCC 6538,NCIMB 9518,CIP 4.83or NBRC 13276;—Pseudomonas aeruginosa such as ATCC 9027,NCIMB 8626,CIP 82.118or NBRC 13275;—Escherichia coli such as ATCC 8739,NCIMB 8545,CIP 53.126or NBRC 3972;—Salmonella enterica subsp.enterica serovar Typhimurium,such as ATCC 14028or,as an alternative,Salmonella enterica subsp.enterica serovar Abony such as NBRC 100797,NCTC 6017or CIP 80.39;—Candida albicans such as ATCC 10231,NCPF 3179,IP 48.72or NBRC 1594.Use buffered sodium chloride-peptone solution pH 7.0orphosphate buffer solution pH 7.2to make test e the suspensions within 2h or within 24h if stored at 2-8°C.3-1-2.Clostridia .Use Clostridium sporogenes such as ATCC 11437(NBRC 14293,NCIMB 12343,CIP 100651)or ATCC 19404(NCTC 532or CIP 79.03)or NBRC 14293.Grow the clostridial test strain under anaerobic conditions in reinforced medium for clostridia at 30-35°C for 24-48h.As an alternative to preparing and then diluting down a fresh suspension of vegetative cells of Cl.sporogenes ,a stable spore suspension is used for test inoculation.The stable spore suspension may be maintained at 2-8°C for a validated period.3-2.NEGATIVE CONTROLTo verify testing conditions,a negative control is performed using the chosen diluent in place of the test preparation.There must be no growth of micro-organisms.A negative control is also performed when testing the products as described in section 4.A failed negative control requires an investigation.3-3.GROWTH PROMOTION AND INHIBITORY PROPERTIES OF THE MEDIATest each batch of ready-prepared medium and each batch of medium prepared either from dehydrated medium or from ingredients.Verify suitable properties of relevant media as described in Table 2.6.13.-1.Test for growth promoting properties,liquid media :inoculate a portion of the appropriate medium with a small number (not more than 100CFU)of the appropriate micro-organism.Incubate at the specified temperature for not more than the shortest period of time specified in the test.Clearly visible growth of the micro-organism comparable to that previously obtained with a previously tested and approved batch of medium occurs.Test for growth promoting properties,solid media :perform the surface-spread method,inoculating each plate with a small number (not more than 100CFU)of the appropriate micro-organism.Incubate at the specified temperature for not more than the shortest period of time specified in the test.Growth of the micro-organism comparable to that previously obtained with a previously tested and approved batch of medium occurs.Test for inhibitory properties,liquid or solid media :inoculate the appropriate medium with at least 100CFU of the appropriate micro-organism.Incubate at the specified temperature for not less than the longest period of time specified in the test.No growth of the test micro-organism occurs.Test for indicative properties :perform the surface-spread method,inoculating each plate with a small number (not more than 100CFU)of the appropriate micro-organism.Incubate at the specified temperature for a period of time within the range specified in the test.Colonies are comparable in appearance and indication reactions to those previously obtained with a previously tested and approved batch of medium.3-4.SUITABILITY OF THE TEST METHODFor each product to be tested,perform the sample preparation as described in the relevant paragraph in section 4.Add each test strain at the time of mixing,in the prescribed growth medium.Inoculate the test strains e a number of micro-organisms equivalent to not more than 100CFU in the inoculated test preparation.(2)This chapter has undergone pharmacopoeial harmonisation.See chapter 5.8.Pharmacopoeial harmonisation .。
数据库系统概念(英文精编版.第六版)
Attributes
Attribute Domain
The set of allowed values for each attribute is called the domain of the attribute
The special value null is a member of every domain
Instructor_schema = (ID, name, dept_name, salary)
r(R) is a relation on the relation schema R
We use lowercase names for relations.
Example: instructor (Instructor _schema)
2.5 Relational Query Languages
2.6 Relational Operations
Chapter 2: Relational Model
教学目的：
熟悉关系数据模型
教学重点：
简单属性、多值属性、复合属性
关系、关系模式、码等概念 关系模式图 关系代数的操作
?简单属性多值属性复合属性?关系关系模式码等概念?关系模式图?关系代数的操作?教学难点
Chapter 2: Relational Model
2.1 Structure of Relational Databases 2.2 Database Schema 2.3 Keys 2.4 Schema Diagrams
referenced relation
Exercise: 找出左图里面
存在的其他外码、参照关 系和被参照关系
Chapter 2(简化)
2 Supply and Demand 2.1 Supply curve--Relationship between the quantity of a good that producers are willing to sell and the price of the good. QS= QS(P) S S’
Substitutes--Two goods for which an increase in the price of one leads to an increase in the quantity demanded of the other. Complements--Two goods for which an increase in the price of one leads to a decrease in the quantity demanded of the other.
Infinitely elastic demand--Consumers will buy as much of a good as they can get at a single price, but for any higher price the quantity demanded drops to zero, while for any lower price the quantity demanded increases without limit. Completely inelastic demand--Consumers will buy a fixed quantity of a good regardless of its price.
Price
S
P1 P3 D’ D Q1 Q3 Quantity New Equilibrium Following Shift in Demand
汽车英语 Engine(2.6)
Chapter 2
internal combustion engine
Basic words(３):
needle valve 针阀
float 浮子 float chamber 浮子室 discharge tube 喷管 jet 量孔
venturi
throttle
喉管
节气门
SEA—Special English for Automobile
Chapter 2
internal combustion engine
1)Gasoline :
Gasoline must vaporize easily. This characteristic, called volatility, is important. However, it must not vaporize too easily, or it will turn to vapor inside the fuel tank or fuel lines. Inside the fuel line, fuel vapor may block the flow of liquid gasoline. This is called vapor lock. Vapor lock is common in fuel lines where the inlet side of the pump is exposed to high temperatures. 汽油应易于蒸发，这个重要的特性称为挥发性。但是汽油也不 能挥发得过快，不然它会在油箱或油管里转变为蒸气。在油管 中汽油蒸气会阻碍液态汽油的流动，这称为气阻。汽油泵的入 口处承受着高温，就经常出现气阻。
Distribution－uniform mixture delivered to manifold
波函数与薛定谔方程
定态Schr dinger方程的解 Schrödinger 2．定态Schr dinger方程的解 ψ ( x) = 0 x > a （3） 有限， 因 ψ(x) 及 E 有限，由（2） 令 （1）
α
2
2 µE = h2
d 2ψ + α 2ψ ( x) = 0 dx 2
从物理考虑， 从物理考虑，粒 （4） 子不能透过无穷 高的势壁。 高的势壁。 （4） 4
◆ 波函数的标准条件
Chapter 2 The wave function and Schrödinger Equation
r r 2 根据Born统计解释， Born统计解释 ω （1）根据Born统计解释， (r , t ) = ψ (r , t ) 是粒子在 t
r 点的几率，这是一个确定的数， 时刻出现在 r 点的几率，这是一个确定的数，所以 r r 的单值函数且有限。 要求 ψ (r , t ) 应是 (r , t ) 的单值函数且有限。
(6)
nπ αn = 2a
（n为奇数） 为奇数）
(7)
(6)和(7)两式统一写成 (6)和(7)两式统一写成
nπ αn = , 2a
2µ E α = 2 h
2
n = 1,2,3, L
（8）
n2π 2 h2 本征能量： 本征能量： En = 8µ a 2
（9）
11
一维无限深势阱（ §2.6 一维无限深势阱（续4）
（3）写出定态波函数 即得到对应第 n 个 本征值 En 的定态波 函数
∞
4.求解定态问题的步骤 4.求解定态问题的步骤
r r Ψ n ( r , t ) = Cnψ n (r ) e
−
i En t h
胡壮麟语言学教程Chapter 2
Chapter 2 Speech Sounds
2.2 Speech organs voiceless sound: when the vocal folds are apart and the air can pass through easily. voiced sound: when the vocal folds are close together and the air stream causes them to vibrate.
vocal cords pharynx back of tongue soft palate hard palate tongue tip tongue blade tongue front teeth lips
8
Chapter 2
Chapter 2 Speech Sounds
2.2 Speech organs What kinds of sounds can we make when the vocal cords are (a) tightly closed; (b) wide open; (c) loosely together and vibrating? (a) no sound or inaudible sound symbolized as /?/; (b) voiceless sound such as /h/; (c) voiced sounds such as /d/.
14 Chapter 2
Chapter 2 Speech Sounds
Voicing (有声化): pronouncing a sound (usually a vowel or a voiced consonant) by vibrating the vocal cords. Manners of articulation: stop (plosive)（爆破音）, fricative（摩擦音）, median approximant（中通音）, lateral approximant（边通 音）, affricate（塞擦音）, nasal Places of articulation: bilabial, labio-dental, dental, alveolar（齿槽音）, postalveolar, palate, velar（软腭音）, glottal（声门音）
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2.6.1在组装前，完成易熔塞的密封测试do the sealing test of the fusible plug before assembly1.将润滑脂涂在封圈上。
Let the grease painted on the seal ring 。
2.将安装封圈的易熔塞安装到测试夹具上，按手册要求力矩拧紧。
Let the fusible plug of sealing ring install to Fixture ,screw it in accordance with the provided torque of the manual.3.供氮气压力17 bar（250 psi），待压力稳定后，调解压力至17 bar（250 psi）。
Supply of the nitrogen, the pressure of nitrogen is 17 bar（250 psi）,adjust the pressure to 17 bar（250 psi）after the pressure is stable.4.保持测试压力3分钟后，检查无压力降，将肥皂液涂抹于易熔塞上，检查应无渗漏。
Keep the testing pressure constant after 3 minutes , check it and no pressure down; smear the fusible plug with the soap water, and find it no leakage.5.完成测试后，释放测试压力，并用水冲洗干净After the testing is done, release the testing pressure, and wash it clear with water.6. 从测试夹具上拆下测试件Remove the testware from the testing fixture.2.6.2轮毂组装：Assembly of the hub以A320飞机主轮毂件号C20195162为例介绍轮毂组装程序：Introduce the assembly program of the hub case of the A320 main hub(Part NO.C20195162)：1.轮毂轴承的使用和安装过程中的注意事项The use of hub bearing and the attentions of installing.1).为了确保安全性和可靠性，每次更换轮胎时要认真检查轮毂轴承，注意轴承是否有磨损和卡阻，安装轴承时要完全注油For safety and reliability, heck the hub bearing Carefully when replace the wheel everytime. Note bearing for abrasion and jamming. Filled oil entirely when install the bearings.2).因为轮毂的两个轴承协同工作的，如果一个轴承损坏，应该成对替换The two bearings of hub is Collaborative work ,so replace them in pairs when one bearing is damage3).在拆卸和安装轮毂轴承外环的过程中，应采用正确的方法和合适的专用工具。
以防止轮毂和相关零部件损坏。
when remove and install out-cup of bearing ,The right approach and tools should be adopted to prevent damage to hub and related parts.4).安装轴承时应该在干净整洁的环境中，细小的颗粒和水进入轴承会缩短轴承的使用寿命，注意轴承不要掉在地上，安装前应对轴承座的状况进行检查，即使是微小的磨损也会导致配合不良，从而引起轴承的损坏。
Bearings should be installed in a clean and tidy environment,Small particles and water into the bearing will shorten the bearing life. Note that bearings do not fall to the ground。
Before bearing installed status of bearing supports should be checked.5). 对轮毂轴承单元，注意检查轮毂轴承的的密封件，及时更换损坏的轴承密封件，否则会使密封性能降低导致水或灰尘的进入，使轴承和外环受到损坏。
For the hub bearing unit, pay attention to check the bearing seals, replace thedamaged seals timely, or seals will result in performance degradation and water ordust enter , the bearing and the out-cup damage.6). 注意轮毂轴承在安装之前要在轴承的滚棒部分和轴承表面涂足够的润滑脂，要保证轴承中有润滑脂，如果润滑脂太少，轴承内部容易进水和污染物造成轴承干磨损坏和腐蚀。
Before installing bearings note that roller and bearing surface to coated the greaseenough ，if the grease is little, water and pollutants enter easy ,and Bearing willdamage caused by dry grinding and corrosion.2.组装内半轮毂组件：assembly of half hub1）.参考轮毂修理部分程序，安装轴承外环。
Reference part of the hub repair program, install bearing out-cup.2）按照手册要求润滑零件，参见图2.6-1：Lubricate parts in accordance with the manual requires（1）在组装时，机轮的固定螺栓要涂防咬剂MIL-T-5544或MIL-T-83483，这两种防咬剂的使用，其扭矩值是不同的。
其中MIL-T-5544防咬剂是含人工石墨的。
In the assembly, wheel bolts should be coated with anti- bite agent MIL-T-5544 or MIL-T-83483, the two anti- bite agents are used, and the torque valuesare different.And MIL-T-5544 anti-bite agent is artificial graphite.（2）在安装封圈时，在封圈上要涂硅润滑剂，如：DOW CORNING DC-4或MS-4.When installing the seal ring ，seal ring should be coated silicon lubricant,such as: DOW CORNING DC-4 or MS-4.(3) 挡油圈和轴承上使用的油脂可用AEROSHELL NO.22 MOBIL NO.28或SHC100,也可使用润滑剂AERO SHELL NO.5。
Retaining rings and bearings can be smeard on grease AEROSHELL NO.22 MOBIL NO.28 or SHC100, also can use lubricants AERO SHELL NO.5.（4）不同种类的油脂不允许混用。
Not allowed to mix different types of grease（5）润滑轴承建议使用压力方法润滑，因为其简单、快捷，可以减小污染的可能性，而且还能确保关键区域的油脂量均匀分布。
Pressure method is recommended for bearing lubrication, because of its simple,fast, can reduce the possibility of contamination, but also ensure that keyareas of grease to be distributed uniformity。
（6）用手润滑轴承时，在一只手的手掌中放置大量干净、无水的油脂，将轴承抓在另一只手中，将油脂推入轴承滚棒间润滑轴承。
当使用手涂油脂时，应当涂在轴承的大端，然后推到小端。
确保滚棒轨道被充分覆盖。
在滚棒上擦一层油脂。
完成之后，不要将轴承放在油脂可能被潮气或其他外界物质污染的地方，参见图2.6-2When lubricate bearings by hand, in the palm of one hand placed in a largenumber of clean grease, the other hand grasps the bearing, push the grease between the rod roller and bearings to lubricated bearings. When using a handpainted grease, should be applied to the big end bearing, and then pushed to the small end. Ensure that the roll bar track is fully covered. Rub a layer of grease on the roll bar. When completed, bearing cannot on the outside, grease may be contaminated by moisture or other external, see Figure 2.6-2 3)安装封圈和易熔塞，并拧紧易熔塞到规定力矩。
Install the seal ring and fusible plug, and tighten the fusible to the specified torque4）选择合适尺寸的驱动块，安装驱动块前必须在轮毂的驱动键上涂防腐剂，然后安装驱动块。