Directed Probabilistic Reachability Analysis
USP-1092-溶出度试验的开发和验证(中英文对照版)
（1092）溶出度试验的开发和验证【中英文对照版】INTRODUCTION前言Purpose目的The Dissolution Procedure: Developmentand Validation <1092> provides a comprehensive approach covering items to considerfor developing and validating dissolution procedures and the accompanyinganalytical procedures. It addresses the use of automation throughout the testand provides guidance and criteria for validation. It also addresses thetreatment of the data generated and the interpretation of acceptance criteriafor immediate- and modified-release solid oral dosage forms.溶出实验:开发和验证（1092）指导原则提供了在溶出度方法开发和验证过程中以及采用相应分析方法时需要考虑的因素。
本指导原则贯穿溶出度实验的全部过程，并对方法提供了指导和验证标准。
同时它还涉及对普通制剂和缓释制剂所生成的数据和接受标准进行说明。
Scope范围Chapter <1092> addresses the development andvalidation of dissolution procedures, with a focus on solid oral dosage forms.Many of the concepts presented, however, may be applicable to other dosageforms and routes of administration. Generalrecommendations are given with theunderstanding that modifications of the apparatus and procedures as given inUSP general chapters need to be justified.<1092>章节讨论了溶出度实验的开发和验证，重点是口服固体制剂。
REACH法规 第二卷译稿-2
1. 对人体健康危害的评估1.0. 引言1.0.1.对人体健康危害的评估目标是：-根据指令67/548，确定一种化学物质的分类和标签；并且-得出某种物质可与人类暴露接触的允许程度，这一暴露程度被称为“衍生无影响程度”（DNEL）。
1.0.2.人体健康危害评估应当考虑以下各组潜在的影响：（1）毒性动力学，新陈代谢和生物分布状态；（2）急性影响（急性中毒、刺激和腐蚀性）；（3）致敏性；（4）累计剂量中毒；及（5）CMR影响（致癌、诱变和生殖障碍）。
根据所有可利用的信息，必要时其他影响也应被考虑。
1.0.3.危害评估由以下四个步骤组成；第1步非人体数据的评估；第2步人体数据的评估：第3步分类和标签：第4步得出“衍生无影响程度”（DNELs）。
1.0.4.当存在可利用的信息时，对每一种影响都应执行前三个步骤，并且还应在化学安全性报告的相关部分记录结果并根据第29条规定，摘录在标题2和11下的安全性数据表中。
1.0.5.对于任一无法得到信息的影响，应在相关章节内填写以下句子“根据该法规无需此项信息，判断理由见…”。
1.0.6.人体健康危害评估中的第4步也应该综合前三个步骤的结果执行，同时应将其填至化学安全性报告相关标题下并摘录在标题8.1.下的安全性数据表中。
1.1. 第1步：非人体数据的评估1.1.1.非人体数据的评估应包含：- 以所有可利用的非人体数据为基础，对某种影响进行危害鉴定；- 确定定量剂量（浓度）与反应（影响）之间的关系。
1.1.2.当不可能确定定量剂量（浓度）与反应（影响）之间的关系时，就应通过半定量的或者定性的分析对这种关系进行证明。
对于急性影响，以附件X所进行的某项实验的结论为基础，通常不可能确定定量的剂量（浓度）与反应（影响）之间的关系。
在这种情况下，是有充分理由断定是否这种具有固有能力的物质引发了某种影响，及所引发的影响到了何种程度的。
1.1.3.用来评定对人类的某种特定影响及确定剂量（浓度）和反应（影响）之间关系的全部非人体数据，通常应以简要的方式提交。
上海证券交易所主板投资风险揭示书必备条款 英文版
上海证券交易所主板投资风险揭示书必备条款英文版Paragraph 1:Pursuant to the relevant regulations of the Shanghai Stock Exchange, investors are required to sign a risk disclosure statement before purchasing securities on the main board.This document serves as a crucial safeguard for investors, outlining the potential risks associated with investing in the stock market.根据上海证券交易所的相关规定，投资者在购买主板证券前必须签署一份投资风险揭示书。
该文件对投资者具有重要的保护作用，明确了股票市场投资可能带来的潜在风险。
Paragraph 2:The risk disclosure statement must clearly state the risks inherent in investing on the Shanghai Stock Exchange main board, including but not limited to market risk, liquidity risk, credit risk, and regulatory risk.Investors should carefully review and understand these risks before making any investment decisions.投资风险揭示书必须明确指出在上海证券交易所主板投资所固有的风险，包括但不限于市场风险、流动性风险、信用风险和监管风险。
投资者在做出任何投资决策前应仔细阅读并理解这些风险。
FDA给印度生产商Polydrug的警告信(内容很不可思议)
FDA给印度生产商Polydrug的警告信(内容很不可思议)April 14, 2016 Mr. Punit Thakrar, Managing DirectorPolydrug Laboratories Pvt. Ltd. Corporate OfficeA201-202, Navbharat Estates, Zakaria Bonder RoadSewri(W)Mumbai – 400015Maharashtra, India Dear Mr. Thakrar: From March 16-23, 2015, an investigator from the U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Polydrug Laboratories Pvt. Ltd., PlotN-37, Addl. Ambarnath Industrial Area, MIDC, Anand Nagar, Ambarnath (East), Maharashtra, Mumbai.2015年3月16-23日，我们FDA的调查员检查了你们位于上述地址的生产工厂。
We identified significant deviations from current good manufacturing practice (CGMP) for the manufacture of active pharmaceutical ingredients (API).我们发现了严重违反原料药生产CGMP的问题。
These deviations cause your drugs to be adulterated within the meaning of Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B), in that the methods used in, or the facilities or controls used for, their manufacture, processing, packing, or holding do not conform to, or are not operated or administered in conformity with, CGMP.这些问题导致你们生产的药品根据联邦食品药品化妆品法案501(a)(2)(B) 部分21 U.S.C. 351(a)(2)(B)被认定为掺假药。
REACH法规 第二卷译稿-10
附件VI对于生产或者进口数量大于或等于10吨的物质的附加标准信息要求本附件表的第1列根据第11 (1) (b)条确定的标准信息，适用于生产或者进口数量为大于或等于10吨的所有物质。
因而，本附件第1列中要求的信息是对附件V第1列所要求信息的补充。
本附件第2列依据下列内容列出了具体的规则，可能被其他信息忽略、代替的所要求的标准信息，假如在另一不同的阶段或者以另外一种方式被改变。
如果条件符合本附件第2列中允许改动的情况，那么注册者在注册档案的适当的标题下，应清楚地说明每一处改动的事实并给出正当理由。
除了这些具体的规则，注册者可以根据包含在附件IX中的通用规则，改写本附件第1列所描述的标准信息要求。
同时，这一种情况下，他应在注册档案的适当标题下清楚地说明每一处改动标准信息的决定理由。
参见附件IX或X8的第2列中有关的适当特殊标准。
在进行新的实验以测定附件中列出的特性之前，应首先评估所有可利用的试管和活体数据、历史数据、有效的定性定量结构活性分析数据以及由在结构上相关的物质得出的数据（可参照方法）。
最终只为本附件中第2列或附件IX中提到的原因提供了信息，而没有为其他原因提供信息，应清楚地说明此事实和原因。
8注：第二栏中没有重复的不要求进行附件十中适当的试验方法里规定的特殊试验的条件也被适用。
6. 毒理学信息在使用具有腐蚀性物质的活体实验中，应避免使该物质达到产生腐蚀性的浓度/剂量水平。
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欧盟指令-关于使用低硫油
EU Sulphur Directive 2005/33/ECFrequently Asked Questions on the ‘At berth’ requirements⁖Ⰾ Г2005/33/ECνĆ 䲏ć㺰ⅱ⮳ 㻰䬝䷇EU Directive 2005/33/EC⁖Ⰾ Г2005/33/ECEU Directive 2005/33/EC amends an earlier Directive, 1999/32/EC, relating to a reduction in the sulphur content of certain liquid fuels which itself amended Directive 93/12/EEC.⁖Ⰾ Г2005/33/EC䦷 㝨⩗⛲⇨䰯㺰䭼ѽ 䛾ҋ ε 㻳 ȡOne aspect of the 2005/33/EC amendments is Article 4b which requires that, from 1 January 2010, the fuel oil used by ships while ‘at berth’ in EU ports is to be limited to 0.1% m/m maximum sulphur content.Г2005/33/EC⮳』㞱4b͜㺰ⅱ喌Ͻ2010 1 1 䊦喌 ⇹ν⁖Ⰾ⍞ ⮳㝨㝥喌 Ү⩗⮳⛲⇨ͺ 䛾̼ 倇ν0.1% m/mȡArticle 4b requires:』㞱4b͜㺰ⅱ䖂喚The change-over to this sulphur limited fuel oil is to be undertaken as soon as possible after arrival and from it as late as possible prior to departure.㝨㝥 ⍞ Ү⩗ѽ⇨喌 㝙 Ү⩗ 䛾䪮⮳ 䬣ȡThe times of these change-overs are to be recorded in the ship’s logbook.⛲⇨ ⮳ 䬣 䄔䃟 㝨㝥 ȡThese ‘at berth’ requirements to not apply to:䄔Ć 䲏ć㺰ⅱ̼䔱⩗ν喚(a)ships which are, according to published timetables, due to be at berthfor less than 2 hours;䬣㶗喌㝨㝥䲏⍞ 䬣̼䊴䓶2(b)certain named vessels as given in the Directive; andГ͜ ⮳͙ 㝨㝥喌(c)ships which switch off all engines and use shore-side electricity whileat berth in ports.㝨㝥䲏⍞ 喌 䬜 喌Ү⩗ ⩤䔊㵻 ҋȡFrequently Asked Questions Regarding the ‘At Berth’ RequirementsνĆ 䲏ć㺰ⅱ⮳ 㻰䬝䷇As is standard practice with all Directives the given requirements are being implemented directly by the individual Member States in respect of their respectiveterritories with any definitive interpretations to be given by the European Court of Justice.䕉 喌 Г͜⮳㻳 䘬⩠ 䦷 㜙䶵 㼒䛹 㵻ȡNevertheless the FOBAS service receives many questions on this topic. Consequently, in order to assist shipowners and others we have collated these questions and our responses into this publication.♥㔻喌 ℾ㝨㏖⮳⛲⇨ ≺ 䘗䬗(FOBAS)ϼ♥ ε䲍 ν䄔㻳 ⮳䄑䬝ȡͩ 㝨͋ ЅⰧ 喌 Л➨ₓ ⤵ε̯ϊ 㻰䬝䷇ ₓ 㶗ȡIn providing these responses it must however be understood that FOBAS is operating only as an ‘informed observer’ and that actual implementation will be by the appropriate department of the Administration of the Member State(s) within whose waters the ship(s) affected operate and which may itself be guided or directed by advice from the European Maritime Safety Agency, the European Commission or other relevant authorities.䄦∗ FOBASϴҋͩĆ㻱 㔴ć ₓゃ⫀㼒 喌∄㻳⮳ 䭴 㵻ϼ⩠Ⱗ 䘗䬗䔊㵻ȡFurther questions䬝䷇FOBAS hopes that we have addressed most of the possible questions however if there are further questions please contact on fobas@Л ⮳ ⫀䬝㘬 䔈Ь Х͜ 㼒ゃȡ ⫀䬝喌䄦㖃㈪fobas@Frequently Asked Questions㻰䬝䷇1.Do these requirements apply to all ships?㻳 䔱⩗ν 㝨㝥 喟Yes, the requirements apply to all ships irrespective of flag (EU or non-EU), ship type, date of construction or tonnage.⮳喌䔈ϊ㻳 䔱⩗ν 㝨㝥喌̼䃩 喈⁖Ⰾ 䲍⁖Ⰾ 喉喌㝨喌 䕏 㔴 Ѽȡ2.‘At berth’ – what is meant by this term?Ć 䲏ć̯䃼 ϯͷ 喟This covers ships in EU ports which are secured at anchor, on moorings (including single buoy moorings) or alongside irrespective of whether they are working cargo or not.Ć 䲏ć̯䃼 㝨㝥 ⁖Ⰾ⍞ ͜ ν 䩉Ƞ㈪⇹喈 ⊝め㈪⇹喉䓨䲏⇹喌 䃩 䔊㵻䉖➘㷴 ȡ3.Does this requirement apply to all ports in EU countries?㻳 䔱⩗ν⁖Ⰾ ⮳ ⍞ 喟The requirement does not apply to ports in the ‘outermost regions’. The ‘outermost regions’ are the French overseas departments, the Azores, Madeira, and the Canary Islands provided, in each case, local air quality standards are maintained.㻳 ̼䔱⩗ν νĆվ䔋 ć⮳⍞ ȡĆվ䔋 ć ∄ ⊦ ⰰȠω䕎 㓓 Ƞ供 㓓 ̽ 䗒 㓓 喈 ⾩⅃䉗䛾Ⅳ ̼䭼ѽ喉ȡ4.Does this requirement apply whenever a ship is anchored in EU waters?䃩҄ 㝨㝥 ⁖ⰎⅣ ͜ 䩉 喌䄔㻳 䘬䔱⩗ 喟Since the requirement is given as ‘…ships at berth in EU ports…’ it would be considered that if a ship anchors within EU waters but outside a zone controlled by a particular port or navigation authority (i.e. to effect repairs or awaiting orders) then the requirement does not apply.㻳 ͜⮳ 䔟ͩĆ….. 㝨㝥 ⁖Ⰾ⍞ 䲏 .....ć喌䗒ͷ Д䃓ͩ喌㝨㝥 ⁖ⰎⅣ ͜ 䩉㔻䲍 ⍞ 㝙⊦ バ䓅 ⮳ 喈 喌ԝ⤵へ Г喉喌䗒ͷ㻳 ̼䔱⩗ȡ5.Are shipyards or ship repair facilities considered to be ‘ports’?㝨 㔴㝨㝥ԝ⤵䃭 㷚㻵ҋͩĆ⍞ ć 喟The Directive does not define the term ‘port’ however since the overall objective is to restrict the sulphur emissions from stationary ships then such facilities should be considered as included as ‘ports’.Г͜ ⇐ Ć⍞ ć䔊㵻 ȡ♥㔻喌 ♥䄔 Г⮳Ⱍ⮳ ͩε䭿 䲈ₑ㝨㝥⮳ 喌䗒ͷ㝨 㝨㝥ԝ⤵䃭 䄔㷚㻵ҋĆ⍞ ćȡ6.Why is it that ‘at berth’ is the part of a ship’s operations which is beingcontrolled by these requirements?ͩ҄Ć 䲏ć㷚ҋͩ㝨㝥㥔䓿⮳̯䘗 㔻 䄔㻳 ⮳バ⤵喟Studies, including Lloyd’s Register’s Marine Exhaust Emission ResearchProgramme, have identified stationary ships as being particular point sources of air pollution and hence, by controlling the maximum sulphur content of the fuels used ‘at berth’, this will directly reduce the sulphur oxides (SO x) and related particulate matter emissions.ℾ㝨㏖⊦κ ⅃ ⵃ⾥䶨Ⱍ ⮳ⵃ⾥㶗 喌䲈ₑ㝨㝥⮳ ⾩⅃← 䕏 ⮳ ℃䒲 ȡ ₓ喌 䭿 Ć 䲏ć㝨㝥 Ү⩗⛲⇨⮳ 䛾㘬 Ⱓ 䭼ѽ⅖ ➘(SOx)Д Ⱗ ䷆㇁➘䉗 ȡ7.Could a residual fuel oil be used ‘at berth’?Ć䲏 ć ДҮ⩗₺҈⛲ ⇨ 喟In theory yes since it is only the maximum sulphur content which is stipulated, not the fuel type. However, in practice it must be expected that generally only distillate grade fuels will be produced which meet the 0.1% m/m maximum sulphur limit. Consequently, throughout this review wherever the term ‘residual fuel oil’ is used it implies a fuel with sulphur content above0.1% m/m.⤵䃩̹ ДҮ⩗喌 ͩ㻳 ͜ 倇 䛾 ε㺰ⅱ喌㔻䲍⛲⇨ㆪ ȡѵκ ̹ 亾 ⛲⇨ 㘬䓭 0.1% m/m⮳ 倇 䛾䭿 ȡ ₓ喌 Х͜喌 Ć₺҈⛲ ⇨ć ⮳ 䛾䊴䓶0.1% m/m⮳⛲⇨ȡ8.Is it required that only gas oil is used ‘at berth’?Ć 䲏ć 㘬Ү⩗㝨⩗↬⇨ 喟No, it is only the maximum sulphur content which is stipulated. However, in practice it must be expected that generally only distillate grade fuels will be produced which meet the 0.1% m/m maximum sulphur limit.̼ 喌㻳 ͜ 倇 䛾 ε㺰ⅱȡ♥㔻喌κ ̹ 亾 ⛲⇨ 㘬䓭 0.1% m/m⮳ 倇 䛾䭿 ȡ9.What ISO 8217 DM grade fuels would be acceptable for use while ‘atberth’?Ć 䲏ć 㘬 Ү⩗҄ISO 8217 DM㏖ ⛲⇨喟In the ISO 8217:2005 specification the DMA grade is limited to 1.50% m/m maximum sulphur content and the DMB and DMC grades to 2.00% m/m.Hence, to be compliant any of these fuel grades must be ordered with a tighter sulphur specification, 0.1% m/m maximum, than that given in the 2005 version of the specification.ISO 8217:2005͜喌DMA⮳ 倇 䛾ͩ1.50% m/m喌DMB DMC⮳ 倇 䛾 ͩ2.00% m/mȡ ₓ喌㠔㺰さ ⁖Ⰾ⮳㻳 喌 䉜⇨ 䶪∗ 喌 䔈ϊ㏖ ⮳⛲⇨䘬䰯 ͔ ⮳ 䛾 喌 倇 䛾ͩ0.1% m/mȡ10.What is meant by ‘m/m’ after the figure of 0.1%?0.1% 䲑⮳Ćm/mć ϯͷ 喟The ‘m/m’ term indicates the percentage on a mass basis - % mass. This is the standard means of stating the sulphur test result. Previously this may alternatively have been given in terms of % weight.Ćm/mć ⮳ 䉗䛾 ̹⮳⮭ ℃ - 䉗䛾⮭Ь℃喌 䛾⮳ 喌㔻ͺ ⩗ 㶗 䛾⮳ Ѽ 䛼䛾⮭ ℃ȡ11.What sulphur test method is applicable?ДҮ⩗ 䛾≺䄄 ∄喟For marine fuels – ISO 8754:1992 is the given method however this method has been subsequently revised to ISO 8754:2003. The differences between the two methods are not expected to be significant in terms of the resultobtained.㝨⩗⛲⇨ 䄣喌ISO 8754:1992 㻳 ⮳≺䄄 ∄喌䔈 ∄⣟ 㷚ԝ ͩISO 8754:2003ȡϽ≺䄄㐂 ⮳㼁 ⰺ喌͓ ∄⮳ ̼ ȡ12.What margin would be expected between the sulphur content of fuel oils asdelivered and the limit of 0.1% m/m maximum?⛲⇨ 䭴⮳ 䛾̽0.1% m/m⮳ 倇䭿 㘬щ 䄞 ҈ 喟In many instances this 0.1% m/m sulphur limit will be the production driver of these fuels limiting what source streams can be used and the respective proportions. The possible exception to this will be where gas oil grade fuels originally intended for automotive applications (EU limit 10 mg/kg – 0.001%) are supplied to ships. This may be as a result of supplier convenience –particularly ships (such as yachts) which bunker by road tanker remote from the main bunker ports.䕉 ̺喌0.1% m/m⮳ 䛾䭿 щҮ⩎ϖ䄔ㆪ⛲⇨ 㘬Ү⩗⮳ Д ℃Һ 䭿 ȡ 㘬⮳Һ ↬䒕⩗⇨㏖ ⮳⛲⇨㷚ӊ 㝨̹喈⁖Ⰾ䭿 ͩ10 mg/kg – 0.001%喉喌䔈Ύ 㘬 ν Ӯ㔻 㜣⮳㐂 – ➨ ㆪѫ 㝶ͺㆪ⮳㝨㝥喌⩠ν⻪ͪ㺰 ⇨⍞ ℃䒲䔋䕉 䘬⩠⇨Ἤ↬䒕 ⇨ȡ13.What issues are there in view of the expected narrow margin between asloaded and limit sulphur values?⩠ν 䭴 㷴⮳⛲⇨ 䛾 倇䭿 䶳 ⮳䄞 ҈ 喌щ ϊϯͷ䬝䷇喟Ideally any fuel oil stem, including gas oils, would be stored onboardseparate from other deliveries so that if problems are encountered with aparticular fuel the issue can be contained and other, known performancefuel oils, are not degraded as a result of mixing. However with the gas oil grades this is often not possible with current ship designs and in any case there are not the same potential incompatibility problems as there are with the residual fuel oils. Nevertheless, with the 0.1% m/m maximum sulphur fuel oils as the actual value will normally only be marginally below that limit there will be very little, or no, tolerance to mixing with other higher sulphur content fuel oils and still remaining compliant. Consequently, particular care will be required during the loading, storage, transfer or treatment of these0.1% m/m maximum fuel oils to ensure that they are not mixed with other,higher sulphur content, fuel oils – either by intent or due to remainingquantities in tanks or pipes.⤵ ⟥ ̺喌 㝨⩗↬⇨ ⮳⛲⇨ 䘬 䄔̽ ̯⛲⇨ 喌䔈 喌 ̯⛲⇨ ⣟䬝䷇ Д⌴ẉ䓗 喌 ̓ ⛲⇨⮳䉗䛾̼щ ͩ̽ ⌦ 㔻䭼ѽȡ♥㔻喌⩠νⰝ 㝨㝥⮳䃭䃐 喌䔈 ҋ ̼ 㵻喌㔻̓喌㝨⩗↬⇨ 㘬 ⣟⮳⒋ ̼Ⱗ 䬝䷇̽₺҈⛲ ⇨ 㘬 ⣟⮳䬝䷇ ̼Ⱗ ȡѵ 倇 䛾0.1% m/m⮳⛲⇨ 䄣喌 䭴 䛾䕉 щ ͽ⇐ ҈ 䌎 倇⇨⌦ 㔻ϼ♥ Дさ ȡ ₓ喌 㷴Ƞ Ƞ䒛⼪ ⤵ 倇 䛾 0.1% m/m⮳⛲⇨ 䰯㺰➨ ∗ 喌Ԍ ̼щ ν ⇨㝠 バ䌞͜⮳₺⇨㔻̽ Ѕ倇⇨⌦ ȡ14.What if a ship which also operates outside the EU does not have thecapability to handle two different grades of gas oil?̯㞇 㝙㵻ν䲍⁖Ⰾ ⮳㝨㝥⇐ 㘬 Ү⩗͓㏖ ⮳⛲⇨喌䄔 ҄ ⤵喟Under this circumstance it would probably be necessary that the ship only uses gas oil with a maximum sulphur content of 0.1% m/m even at sea and at ports outside the EU.䔈 ̺喌㝨㝥 㘬 䲍⁖Ⰾ⮳Ⅳ ⍞ ͜Ύ 䶪Ү⩗ 倇 䛾 0.1% m/mД̺⮳㝨⩗↬⇨ȡ15.What onboard inspection of a ship may be undertaken to verify that 0.1%maximum sulphur fuel oil is being used?㝨̹㘬Ү⩗ϯͷ 䞣 Ү⩗⮳⛲⇨ 倇 䛾 0.1%喟In the first instance the relevant Bunker Delivery Notes (BDN), which under MARPOL Annex VI reg. 18 are required to be retained onboard for a minimum of 3 years from the date of delivery, would be inspected together with the Oil Record Book detailing into which tanks that fuel was loaded.However the BDN only shows the sulphur content of the fuel as received. It is necessary that during loading, storage, transfer, treatment and use that the fuel has not been mixed with other, higher sulphur content, fuel oils.Consequently the inspector may require a sample of the fuel oil being used to be drawn which would then be analysed to verify that the fuel was compliant.仅 喌 MARPOL䭳 せ18 㻳 喌 ⇨ 䶪Ͻ ⇨䗒 䊦 㝨̹Ԍ⪈㜢 3 喌 ⇨ㆪ䃟 ㅮ͜䰯㺰 䃟 䄔⛲⇨㷚㷴ν ͙⇨ム喌 ⇨ ⇨ㆪ䃟 ㅮ䘬 䰯㺰 Ⱗ ⮳ 侻ȡ♥㔻喌 ⇨ ̹ ⮳ϴϴ ⛲⇨ ⮳ 䛾ȡ㝨 䶪∗ ⛲⇨⮳㷴⇨Ƞ Ƞ䒛⼪Ƞ ⤵ Ү⩗䓶⼺͜喌ѽ⇨̼㘬̽ Ѕ倇⇨⌦ ȡ 㘬щ㺰ⅱ ̯͙⇨ 喌䮾 䔊㵻 侻Д䃰 ⛲⇨ さ Ⱗ 㻳 ȡ16.Article 6 of the Directive gives that ‘…sampling shall commence within sixmonths of the date on which the relevant limit for maximum sulphur content in the fuel comes into force.’ Does this mean that there will be a six month period until July 2010 over which the ‘at berth’ requirements will not be enforced?Г͜』㞱6͜ Ć 䄔⩠ 倇 䛾ͺ㻳 ⩎ 䊦 ͙ ć喌䔈 ⱯĆ 䲏ć㻳 䭴̹Ͻ2010 7 ⩎ 喟This clause relates to Articles 3 and 4 of the Directive and in any case gives ‘…within..’ not a full six month exclusion. The ‘at berth’ requirements are given under Article 4b and hence the inspection regime given under Article 6(1a) would apply which gives no such period of grace before the requirements will be enforced.䄔 ̽ Г⮳』㞱3 4 喌 ͜ ⇐ 㐈 ͙ ⮳Һ 䬣ȡĆ 䲏ć㻳 䭴̹ 』㞱4b͜ ⮳喌 ₓ 』㞱6(1a)͜⮳ 侻㠲 ̼㶗 䔈⃤䕉㲼 䬣ȡ17.Is it possible to detect the level of sulphur content in the fuel being usedwithout boarding a ship?⇐ 㘬 ⇐ ⮪㝨⮳ ̺ 侻 ⛲⇨ 䛾喟There are certain air quality measurement techniques which can be applied which, by focusing a beam across the gas plume issuing from the funnel, would detect the sulphur oxide concentration levels. This data may then be used to target onboard inspections of ships where it was suspected that fuel oil with higher sulphur content than that required was being used.ДҮ⩗ ϊ⾩⅃䉗䛾≺䄄 䔊㵻 ≺喌䕉䓶㖉♕ ☎ ⮳⅃☎喌 Д ≺ ➘⮳⊂ ȡ䄔 Д ⫀⛲⇨ 䒲倇 䛾⮳ Ո㷚⩗ ϊ㝨㝥䰯㺰⮪㝨 侻ȡ18.What technical concerns are there in respect of the use of 0.1% m/mmaximum sulphur distillates?倇 䛾 0.1%Д̺⮳⛲⇨ 㘬щ ϊ ̹⮳䬝䷇喟There are a number of possible technical issues to be aware of:a)low viscosity叾 䒲ѽb)poor lubricity⋕␀ 䒲c)unacceptable or undesirable blend components̼㘬 ̼ ⮳⌦d)potential power shortfall⒋ ⮳ ̼䋢e)engine starting problemsͪ 䬝䷇f)cleaning action⌴≆ҋ⩗g)attention to pre-heating control䶳☜h)correct settings for boiler safety and combustion control systems䨴▸ ⛲☖ ㈪㐎⮳ₒ䃭i)These are covered in greater detail in FOBAS Bulletin 05/2009FOBAS 05/2009͜ 䄕㏵19.What specific concerns are there with regard to the supply of automotivetype fuels to ships?㝨̹Ү⩗↬䒕⩗⇨喌щ ϯͷ䬝䷇喟The concerns identified relating to the use of 0.1% m/m maximum sulphur fuel oils will tend to be intensified in those instances where automotive fuels have been supplied. Furthermore, automotive gas oils are often found tohave flash point values below the statutory minimum of 60o C for marine fuel oils used in machinery spaces and hence are unfit for such service. Anadditional concern would be in those instances where such fuels are supplied as a result of not having met one or other of the quality specification forautomotive use and the implications of that on their usability in marineengines or other combustion machinery.㠔㝨㝥 Ү⩗䒕䒵⩗⇨喌䗒ͷҮ⩗ 倇 䛾ͩ0.1% m/m⮳⛲⇨㔻 ⮳ 䬝䷇ щ ȡ ̓喌䒕⩗↬⇨⮳䬙◨䕉 䘬ѽν㝨⩗⛲⇨⮳∄ ѽ䬙◨60o C喌 ₓ ̼䔱 ⩗ν㝨㝥 ͜ȡ ̯͙ 㘬 ⣟⮳䬝䷇ 喌 䒕⩗⛲⇨ӊ 㝨̹喌 㘬 ⩠ν 䉗䛾䬝䷇ ̼䔱 ⩗ 䒕䒵̹喌䔈 ⮳䄌喌䔈⛲⇨ 㝨⩗ͪ Ѕ⛲☖ ͜⮳ Ү⩗ ի ⫀εȡ20.The change-over requirement does not apply to ships which are ‘at berth’ forless than two hours?⛲⇨䒛 ⮳㺰ⅱ̼䔱⩗νĆ 䲏ć͓ Д̺⮳㝨㝥 喟No, the ‘two hours’ given in the Directive only applies where there is a published timetable (i.e. in the case of ferries on scheduled services) which gives that the time ‘at berth’ is less than two hours. There is not a general exemption for ships which will be ‘at berth’ for less than two hours.Г͜⮳Ć͓ ćϴ䔱⩗ν㝨㝥 ⮳ 䬣㶗 䲏 䬣 ͓ Д̺⮳ ̺喈 喌 ⮳⍐䒝喉ȡ䦷 Ć 䲏ć 䬣 ν͓ ⮳㝨㝥 ⇐ 䕉⩗⮳ 䮓㻳 ȡ21.What engines or other combustion devices need to be changed-over to a0.1% m/m maximum sulphur fuel oil?ϊ ⛲☖㷴㒝䰯㺰䒛 倇 䛾ͩ0.1%⮳⛲⇨喟Only those engines, boilers, incinerators or other combustion devices which are to be used while the ship is ‘at berth’ need to be changed-over to a0.1% maximum sulphur fuel oil. Attention is necessary to intermittentlyoperated combustion machinery with separate, stand-alone, ready use tanks, such as incinerators, to ensure that the fuel in those tanks is compliant.䗒ϊ 㝨㝥Ć 䲏ć ϼ♥䰯㺰Ү⩗⮳ Ƞ䨴▸Ƞ♉☖▸ Ѕ⛲☖㷴㒝 䰯㺰䒛 倇 䛾ͩ0.1%⮳⛲⇨ȡ䰯㺰∗ 䗒ϊ ⠛⿺⛲⇨㝠⮳䬣⁶ ҋ⮳⛲☖䃭 喌 ♉☖▸喌Ԍ 䗒ϊ⇨㝠͜⮳⛲⇨Ύさ 㻳 ȡ22.Do the ‘at berth’ requirements apply to main engines?䄔㻳 䔱⩗νͪ 喟Only in machinery arrangements where the engines used for propulsion are also used to supply power for other purposes while the ship is ‘at berth’. This would include:㝨㝥 Ć 䲏ć 喌 ̼ѵ⩗ν 䔊㔻̓⩗ν ӊ⩤ ⮳ ̺喌䄔㻳 䔱⩗ȡ䔈 喚a)diesel-electric systems where the engines also provide power for ship, engine room or cargo services; or⇨ ⩤ ㈪㐎喌ͪ ⩗νͩ㝨㝥Ƞ 䉖➘㷴㒝 ӊ⩤ 喌b)where a propulsion engine is declutched from the propeller and either idles or provides power to a generator, pump or other devices.ͪ 㳩 ⻪喌 ν⾩䒛⟥ 㔴 ӊ⩤ 㐈 ⩤ Ƞ∤ Ѕ㷴㒝ȡ23.Is the circulation of heated residual fuel oil through an engine allowed while ‘at berth’?㝨㝥Ć 䲏ć 喌 䃧 ☜⮳₺҈⛲ ⇨ ͜≰䕉 喟The circulation of heated residual fuel oil through an engine (main or auxiliary) in order to maintain readiness would be permitted as that does not constitute ‘use’ within the meaning of the Directive as the fuel oil is not being combusted.䃧 ☜⮳₺҈⛲ ⇨ ͪ 䒴 ͜≰䕉Д㐣 ⟥ 喌 ͩ⛲⇨ ⇐ 㷚⛲☖喌 Д ̼ Г͜⮳ĆҮ⩗ćͺ ȡ24.If an engine, which is normally operated on residual fuel oil, is subject to repair is it allowed to test that engine on that grade of fuel oil while ‘at berth’ for the purpose of verifying engine is ready for service?̯ 䕉 ☖₺҈⛲ ⇨⮳ 䰯㺰ԝ⤵喌䗒ͷ 㝨㝥Ć 䲏ć⮳ Ո Ү⩗₺҈⛲ ⇨ ⮳≺䄄Д 侻 㘬さ ₒ ҋ⟥ 喟While Article 1 (2)(a) gives that the requirements would not apply to fuels used for ‘…purposes of research and testing’ it would be understood that ‘ ..testing’ as given would not cover the subject scenario.㮬♥ 』㞱1(2)(a)͜ 䄔㻳 ̼䔱⩗νĆ⩗νⵃ⾥ ≺䄄ć⮳⛲⇨喌ѵ Ć≺䄄ć̯䃼 ̼ ̹䔟 ȡ25.Do the ‘at berth’ requirements apply to main boilers as installed, for example, on LNG tankers?䄔㻳 䔱⩗ν 㷴 ㆪѫνLNG ⇨䒝㝨㝥̹⮳ͪ䨴▸ 喟The requirements apply to any fuel oil used by such boilers. Since there can be significant issues associated with the ‘on load’ use of gas oil type fuel oils in such boilers reference should be made to manufacturers recommendations, relevant statutory and classification society rule requirements together with various other publications which have been produced on this topic, for example those from L loyd’s Register: Classification News 35/2009 and ‘Guidance Notes for Design Appraisal of Main and Auxiliary Boilers Operating on Low Sulphur Distillate Oil, October 2009’.㻳 䔱⩗ν䄔ㆪ䨴▸ Ү⩗⮳ ⛲⇨ȡ⩠ν 㝨̹䄔ㆪ䨴▸͜Ү⩗㝨⩗↬⇨ ⛲⇨ 㘬 䄧 䬝䷇喌 Д㝨̹ Ү⩗ 䰯㺰 㔲䨴▸⩎ϖ ⮳ 㻰喌Ύ䰯 䬴Ⱗ ∄ 㝨㏖㻳㠲 Ѕ⮳ ❷➘喌Һ ℾ㝨㏖2009 10 ❷⮳せ35 㝨㏖ 䬪Ԑ ĆҮ⩗ѽ⇨⮳ͪ䨴▸ 䒴䨴▸⮳ ćȡ26.Do the ‘at berth’ requirements apply to auxiliary boilers?䄔㻳 䔱⩗ν䒴䨴▸ 喟The requirements apply to any fuel oil used by all sizes of auxiliary boiler from the relatively large water tube boilers installed on some motor tankers through to those which are essentially simply hot water heaters. As with main boilers, there can be significant issues associated with the ‘on load’ use of gas oil type fuel oils in such boilers consequently reference should be made to manufacturers recommendations, relevant statutory and classification society rule requirements together with various other publications which have been produced on this topic, for example those from Lloyd’s Register: Classification News 35/2009 and ‘Guidance Notes for Design Appraisal of Main and Auxiliary Boilers Operating on L ow Sulphur Distillate Oil, October 2009’.䄔㻳 䔱⩗ν 䒴䨴▸ Ү⩗⮳⛲⇨喌 㷴ν ϊ ⛲ ⇨䒝⮳ Ⅳバ䨴▸喌 ク ⮳☜Ⅳ ☜ ȡ⩠ν 㝨̹ͪ䨴▸͜Ү⩗㝨⩗↬⇨ ⛲⇨ 㘬 䄧 䬝䷇喌 Д㝨̹ Ү⩗ 䰯㺰 㔲䨴▸⩎ϖ ⮳ 㻰喌Ύ䰯 䬴Ⱗ ∄ 㝨㏖㻳㠲 Ѕ⮳ ❷➘喌Һ ℾ㝨㏖2009 10 ❷⮳せ35 㝨㏖ 䬪Ԑ ĆҮ⩗ѽ⇨⮳ͪ䨴▸ 䒴䨴▸⮳ ćȡ27.The Directive mentions that the ‘at berth’ requirements to not apply to shipswhich ‘…switch off all engines and use shore-side electricity while at berth …’ hence would it be possible in such circumstances to still use a fuel oil with a sulphur content above 0.1% m/m in boilers which provide steam to, for example, cargo pump turbines?Г͜ 䄔㻳 ̼䔱⩗νĆ 䲏 䬜 Ү⩗ ⩤ć⮳㝨㝥喌䗒ͷ 䨴▸͜Ү⩗ 䛾倇ν0.1%⮳⛲⇨⩗ ͩㆪѫ䉖∤⋐䒝 ⮳ ӊ㧧↬喟It is probable that this would not be accepted by the authorities as being in compliance with the Directive since the key requirement is that ‘…ships shall not use….’ rather than only some types of combustion devices being controlled.䄔 ҋ 㘬̼щ㷚バ⤵ ȡ ͩ Г͜⮳ 䩝㺰ⅱ Ć…..㝨㝥̼㘬Ү⩗…..ć喌㔻䲍ϴϴ䦷 ⛲☖㷴㒝⮳バ ȡ28.If a ship, which uses shore-side electricity when alongside, is required toanchor in an EU port is it allowed to use a fuel with a sulphur content above0.1% m/m while at anchor?䲏 Ү⩗ ⩤⮳㝨㝥喌 䰯㺰 ⁖Ⰾ⍞ 䩉喌䗒ͷ 䩉 ДҮ⩗ 䛾倇ν0.1%⮳⛲⇨ 喟No since to be covered by this exemption it would be necessary that there is the necessary infrastructure for shore-side electricity to be supplied also to ships which are anchored.̼ Дȡ ͩ 㺰さ 䄔 䉒 Х喌 䩉㝨㝥 Ү⩗⮳ ⩤Ύ䰯㺰 㺰⮳ ⵯ䃭 ȡ29.Do the requirements apply to fuel oil fired inert gas generators?䄔㺰ⅱ䔱⩗ν⩗ ⅃҂ ⩎ ̹⮳⛲⇨ 喟Although such units typically incorporate a water wash stage and do not directly vent the gases produced to the atmosphere, except when in purge mode, there is no specific exemption for this type of combustion device given within the Directive. Consequently it should be concluded that the requirements do apply to these devices.バ䔈 ⮳㷴㒝㷴 Ⅳ≆䃭 ̼̓щⰣ ϖ⩎⮳⅃҂ ⅃喌䮓䲍 ⌴≆ὐ ̺喌ѵ Г͜ ⇐ 䦷 䔈⛲☖䃭 ⮳➨ 䉒 Һȡ Д喌䄔㻳 䄔 䔱⩗ν䔈ϊ䃭 ȡ30.When is a ship considered to have ‘arrived’?҄⩻ 㝨㝥Ć 䓭ć喟Since the requirement applies to ships which are secured, the point at whicha ship is considered to have ‘arrived’ would be when Finished With Engines isgiven. Alternatively, for a ship at anchor, it could be when the anchoring crew are stood down.♥㻳 䔱⩗ν ⽢⮳㝨㝥喌䗒ͷ㝨㝥⮳Ć 䓭ć 䬜ȡ 㔴喌 䩉⮳㝨㝥Ć 䓭ć 䩉㝨 ̯㝛 ҋ⟥ ȡ31.How long is allowed for the change-over to 0.1% m/m maximum sulphurfuel oil?䃧Ү⩗ 䪮 䬣 ⛲⇨䒛 倇 䛾ͩ0.1%⮳⛲⇨喟No time is stipulated in the Directive since this will differ for different fuel mixes, the particular machinery arrangements and change-over procedures.Whatever procedures are to be followed these should commence as soon as is reasonably possible after arrival. The ship-owner has the option to either:a)change-over the grade of fuel oil in the system; orb)change-over the machinery in use (where there is duplicatedprovision)Scenario (a) in this case the rate of change-over from a heated residual fuel oil to a compliant gas oil will need to be managed in accordance with engine builders guidance. Typically this will give that the rate of change of temperature should not exceed 2o C per minute to avoid undue thermal loading and differential expansion of heated components. However if change-over was to be from a non-compliant gas oil to a compliant gas oil then the change-over time would only be that required for the latter to be the only fuel in the supply system. The FOBAS fuel oil change-over calculator may be of assistance in estimating the time required for the fuels in the system to change from one to other.Scenario (b) could, for example, apply to generator engines. The ship manoeuvres with two generators running on residual fuel oil. On Finished With Engines being given the third (or additional) generator(s), which haspreviously be set up to operate on a compliant fuel oil, is started and loadtransferred thereby enabling the previously running engines to be shut down.Г͜ ⇐ 㻳 ⛲⇨䒛 䬣喌 ͩ䒛 䬣щ⩠ν̼ ⛲⇨ㆪ Ƞ Д 䒛 ⼺ 㔻 ̼ ȡѵ 喌 䃩 Ү⩗⮳ ⼺ 喌䘬 䶪 㝨㝥 䓭Д 䒛 ⼺ ȡ㝨͋ Д䔸 喚a)䒛 ㈪㐎͜⮳⛲⇨b)䒛 Ү⩗⮳a)͜喌҄ ☜⮳₺҈⛲ ⇨䒛 さ 㻳 ⮳㝨⩗↬⇨䰯㺰㻵䕏 ⮳ 㔻 ȡ➨ 䰯㺰∗ ⮳ 喌⛲⇨䒛 ⮳⍘ 䕎 ̼㘬䊴䓶 䧎2o C喌Д䖮 䓶 ⮳☜䉎㢦Д ☜䘗Х⮳̼ 㛗㗯ȡѵ 喌 䒛 Ͻ̼さ 㻳 ⮳㝨⩗↬⇨ さ 㻳 ⮳㝨⩗↬⇨喌䗒ͷ喌䒛 ⮳ 䬣 Ү㈪㐎͜ さ 㻳 ⮳⛲⇨ 䰯㺰⮳ 䬣ȡFOBAS⮳⛲⇨䒛 䃐テ Д џテϽ̯⛲⇨ ̯⛲⇨ 䰯㺰⮳ 䬣ȡb)͜喌 Л ₓД ⩤ ͭҺȡ㝨㝥Д͓ ⛲☖₺҈⛲ ⇨⮳ ⩤䔊㵻Ѽ⼪ȡ ͓ 䬜 喌䃭 Ү⩗ 䛾0.1% m/m⛲⇨䓿ҋ⮳せ̸ ⩤ ҋ喌 䉎㢦䒛 䔈 ̹ȡ32.Is it required to have approved change-over procedures?䰯㺰 ㏾䃓 ⮳䒛 ⼺ 喟There should be established change-over procedures in order to meet ISM requirements. These would ensure that the correct sequence of operations is undertaken and would provide guidance as to the time required for the procedure to be undertaken, the latter would prove of assistance if the local authorities questioned the length of time taken. These procedures however do not need to be specifically approved.䄔 ⮳䒛 ⼺ Дさ ISM⮳ ȡ䄔⼺ Ԍ ҋ≰⼺⮳ 喌 䦷 ҋ 䰯 䬣 ӊ 喌 㔴 Д 䉗⫀䒛 ҋ 䬣⮳ Ո ӊ 䃰 ȡ♥㔻喌䄔⼺ ̼䰯㺰㏾䓶➨ ⮳䃓 ȡ33.With regard to arrival, what times should be recorded in the ship’s logbook?ν 䓭喌 ϊ 䬣䰯㺰㷚䃟 㝨㝥 ͜喟It would be recommended that three specific entries are made as part of a block of data:a)the time at which the when the ship is considered to be ‘secured atberth’ – this may be when Finished With Engines or equivalent (i.e.anchor crew stood down) is given.b)the time at which the first action (as given in the relevant procedures)is taken to commence the change-over of a particular combustionsystem or machinery group (i.e. auxiliary engines). Where there ismore than one system or group there will be a corresponding numberof start times.c)the time at which it is considered that a particular combustion systemor machinery group is operating only on 0.1% m/m maximum fuel oil.Where there is more than one system or group there will be acorresponding number of end times.䃝䃟 Д̸̺͙ 䬣喚a)㝨㝥 䓨 ⽢⮳ 䬣 – ➨ 䬜喌喈 㝨㝥 䩉 䩉㝨䩉 ҋ Ѕ̯㝛 ҋ⟥ 喉ȡb) ⛲☖㈪㐎 ㏳喈 䒴 喉⮳䒛 ҋ⮳せ̯͙ͭ 喈 㔲Ⱗ ⮳⼺ 喉⮳ 䬣ȡ 㝨̹ 䊴䓶̯͙㈪㐎 ㏳喌䗒ͷ 䄔䃟̯㈪ ⮳ 䬣ȡc) ⛲☖㈪㐎 ㏳ ϴД 倇 䛾 0.1% m/m⛲⇨䔊㵻䓿ҋ⮳ 䬣ȡ 㝨̹ 䊴䓶̯͙㈪㐎 ㏳喌䗒ͷ 䄔䃟 ̯㈪ ⮳㐂䬣ȡ34.In which ship’s logbook should the entries be made?䄔 䬣 䄔䃟 㝨㝥 ͜喟The Directive is not specific hence whichever logbook is specified in the relevant procedures. This should however be one of the logbooks which is countersigned by either the master or chief engineer.Г͜⇐ ₓ➨ 㻳 喌ͩₓ喌 䰯 Ⱗ ≰⼺͜ ⮳㝨㝥 ͜ 䃟 ȡѵ ∗ 喌䄔 䶪⩠㝨䪮 㔴䒝 䪮キ㒡ȡ35.What change-over arrangements apply to engines or other combustiondevices which are not operating when the ship arrives but are subsequently used while the ship is ‘at berth’?ν䗒ϊ㝨㝥 䓭 ̼䓿ҋѵ Ć 䲏ć щҮ⩗⮳ ̽ Ѕ⛲☖㷴㒝喌 䄔䛶⩗҄䒛 喟The temporary allowance for non-compliance during the change-over from a non-compliant fuel oil to a 0.1% m/m maximum sulphur fuel oil is only for those engines or other devices which are running on arrival. Any other machinery should have been duly prepared before arrival to operate on a0.1% m/m maximum sulphur fuel oil and hence, when started while ‘atberth’, is compliant from the outset.䦷 䗒ϊ 㝨㝥 䓭 䓿ҋ⮳ 䃭 喌㘬 䃧 Ͻ倇⇨䒛 ѽ⇨⮳䓶⍐ 䬣ȡЪ҄ Ѕ 䃭 䘬䰯㺰 ⍞ ⛲☖ 倇 䛾 0.1%⛲⇨⮳ 喌 ₓ喌㝨㝥̯ Ć 䲏ć喌 㺰 喌 䶪さ 㻳 ȡ36.On arrival at an EU port if a ship first goes to anchor and then later moves toa berth alongside is it required to use a 0.1% m/m maximum sulphur fuel oilduring that passage from anchorage to berth?䓭⁖Ⰾ⍞ ⮳㝨㝥喌 䩉喌䮾 ⼪ 䓨喌䗒ͷₓ㝨㝥 䩉 ⇹Ѽ⮳䔈⃤䌌⻪͜喌 䰯㺰Ү⩗ 倇 䛾 0.1%⮳⛲⇨喟It is not required to use a 0.1% m/m maximum sulphur fuel oil during that passage. As a matter of convenience however the ship may decide to continue the usage of that fuel oil in the auxiliary engines and boilers (in order to avoid additional change-overs) while using a residual fuel oil for the main (propulsion) engine(s).䔈⃤䌌⻪͜ ̼㺰ⅱҮ⩗ 倇 䛾 0.1%⮳⛲⇨ȡ♥㔻 ν Ӯ㔲㮀喌㝨㝥 㘬щ㔲㮀 ͪ ͜Ү⩗₺҈⛲ ⇨⮳ 喌 䒴 䒴䨴▸͜Ү⩗Ү⩗ 倇 䛾 0.1%⮳⛲⇨喈ͩ䖮 ䷌ ⮳䒛 ⼺ 喉ȡ37.Does being secured in a lock during passage into or out of a port count asbeing ‘at berth’?㝨㝥 䔊⍞ ⻪⍞⮳Ⅳ䬧͜ ⪈喌テҋ Ć 䲏ć 喟No since this is only an interim stage in the overall manoeuvring process.̼ 喌 ͩ䔈 ͙䓶⼺͜⮳ͣ ⟥ ȡ38.What defines ‘departure’ time?ϯͷ Ć ć 䬣Departure time should be set on the basis of the when engines are required for. In this it is recognised that the actual departure from ‘at berth’ may be later due any one of any number of factors which impact on a ship’s schedule.㝨㝥 䬣 ⤵㼒ͩ ⮳䃭 䬣ȡ ₓ喌㝨㝥⻪ ⮳ 䭴 䬣 㘬⩠ν ⮳ 㔻℃䶳 ⮳ ȡ39.When should the change-over from a 0.1% m/m maximum sulphur fuel oilto another fuel oil (i.e. residual fuel oil) commence?ϯͷ 䬣 䔱 Ͻ 倇 䛾ͩ0.1%⮳⛲⇨ ̯⛲⇨喈 ₺҈⛲ ⇨喉⮳䒛 喟In order to comply with the ‘…as late as possible before departure …’ requirement this should be in advance of the given ‘departure’ time by the expected duration of the change-over as given in the ship’s change-over procedures (which itself should include some reasonable margin to cover usual eventualities). This should be such that the engines (and other combustion devices) are fully established on the fuel oil to be used during departure passage prior to the first actions being taken to ‘unsecure’ the ship.ͩεさ Ć….. ⻪⍞ 㘬 …..ć⮳㺰ⅱ喌 䄔 䃐 ⻪⍞ 䬣 ⮳⛲⇨䒛 䶳䃐 䰯 䬣 䒛 ⛲⇨喈 䰯㺰㔲㮀 㘬 ⩎⮳ ♥κХ 㜣⮳䷌ 䬣喉ȡ䔈 䄔 㝨⮳せ̯͙ͭ 䃘 喈 Ѕ⛲☖㷴㒝喉䘬 Д⩗䔱 ⮳⛲⇨䓿ҋ ȡ40.With regard to departure, what times should be recorded in the ship’slogbook?ν 喌 ϊ 䬣䰯㺰㷚䃟 㝨㝥 ͜喟It would be recommended that three specific entries are made as part of a block of data:a)the time given for ‘engines required for’.b)the time at which the first action (as given in the relevant procedures)is taken to commence the change-over of a particular combustionsystem or machinery group (i.e. auxiliary engines). Where there ismore than one system or group there will be a corresponding numberof start times.c)the time at which it is considered that a particular combustion systemor machinery group is fully operating on the fuel to be usedsubsequently. Where there is more than one system or group therewill be a corresponding number of end times.䃝䃟 Д̸̺͙ 䬣喚。
EN 1999-45-EC
Avis juridique important31999L0045Directive 1999/45/EC of the European Parliament and of the Council of 31 May 1999 concerning the approximation of the laws, regulations and administrative provisions ofthe Member States relating to the classification, packaging and labelling of dangerous preparationsOfficial Journal L 200 , 30/07/1999 P. 0001 - 0068DIRECTIVE 1999/45/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCILof 31 May 1999concerning the approximation of the laws, regulations and administrative provisions of theMember States relating to the classification, packaging and labelling of dangerouspreparationsTHE EUROPEAN PARLIAMENT AND THE COUNCIL OF THE EUROPEAN UNION,Having regard to the Treaty establishing the European Community, and in particular Article95 thereof,Having regard to the proposal of the Commission(1),Having regard to the opinion of the Economic and Social Committee(2),Acting in accordance with the procedure laid down in Article 251 of the Treaty(3),(1) Whereas Council Directive 88/379/EEC of 7 June 1988 on the approximation of the laws,regulations and administrative provisions of the Member States relating to the classification,packaging and labelling of dangerous preparations(4) has been amended on severaloccasions; whereas on the occasion of further amendments, the said Directive should, forreasons of clarity, be recast;(2) Whereas, in spite of Community provisions, the rules applying to certain dangerouspreparations in the Member States exhibit considerable differences as regards classification,packaging and labelling; whereas these differences constitute a barrier to trade, createunequal competition conditions and directly affect the functioning of the internal market;whereas it is therefore necessary to remove this barrier to trade by approximating therelevant legislation existing in the Member States;(3) Whereas measures for the approximation of the provisions of the Member States affectingthe establishment and functioning of the internal market must, in so far as they concernhealth, safety and protection of man and the environment, adopt a high level of protection asa basis; whereas this Directive must, at the same time, ensure protection for the generalpublic, and, in particular, persons who come into contact with dangerous preparations in thecourse of their work or in the pursuit of a hobby, protection for consumers and for theenvironment;(4) Whereas containers containing certain categories of dangerous preparations offered orsold to the general public must be fitted with child-resistant fastenings and/or carry a tactilewarning of danger; whereas certain preparations not falling within these categories of dangermay nevertheless, owing to their composition, present a danger for children; whereas thepackaging of such preparations should therefore be equipped with child-resistant fastenings;(5) Whereas it is necessary to provide concentration limits expressed as a volume/volumepercentage in the case of preparations marketed in gaseous form;(6) Whereas this Directive contains special labelling provisions applicable to certainpreparations; whereas, to ensure an adequate level of protection for man and theenvironment, special labelling provisions must also be introduced for certain preparationswhich, although not dangerous within the meaning of this Directive, may neverthelesspresent a danger to the user;(7) Whereas on 30 April 1992 the Council adopted Directive 92/32/EEC amending for the seventh time Directive 67/548/EEC on the approximation of the laws, regulations and administrative provisions relating to the classification, packaging and labelling of dangerous substances(5); whereas on 27 April 1993 the Commission adopted Directive 93/21/EEC(6) adapting to technical progress for the 18th time Council Directive 67/548/EEC; whereas new criteria developed for classifying and labelling substances dangerous for the environment were introduced by those Directives, together with the appropriate symbols, indications of danger, risk phrases and safety advice required to appear on labelling; whereas provisions should be adopted at Community level on the classification and labelling of preparations to take account of their effects on the environment and whereas it is therefore necessary to introduce a method for assessing the hazards of a given preparation for the environment either by a calculation method, or by determining the ecotoxicological properties by test methods under certain conditions;(8) Whereas the number of animals used for experiments should be reduced to a minimum, in accordance with the provisions of Council Directive 86/609/EEC of 24 November 1986 on the approximation of laws, regulations and administrative provisions of the Member States regarding the protection of animals used for experimental and other scientific purposes(7); whereas Article 7(2) of that Directive stipulates that an experiment shall not be performed if another scientifically satisfactory method of obtaining the results sought, not entailing the use of an animal, is reasonably and practically available; whereas, therefore, this Directive makes use of the results of assessments of toxicological and ecotoxicological properties only when these are already known and entails no obligation to conduct further experiments on animals;(9) Whereas it is necessary to define what human experience might be considered for the evaluation of the health hazards of a preparation; whereas, if clinical studies may be accepted, it is taken as given that such studies comply with the Helsinki Declaration and OECD Guidelines for Good Clinical Practice;(10) Whereas the characteristics of alloys are such that it may not be possible accurately to determine their properties using currently available conventional methods; whereas it is therefore necessary to develop a specific method of classification which takes into account their particular chemical properties; whereas the Commission, in consultation with Member States, will examine this need and submit a proposal, if appropriate, before the implementation date of this Directive;(11) Whereas classification, packaging and labelling of plant protection products covered by Council Directive 78/631/EEC of 26 June 1978 on the approximation of the laws of the Member States relating to the classification, packaging and labelling of dangerous preparations (pesticides)(8) need to be revised taking into account technical and scientific developments as well as regulatory developments following implementation of Council Directive 91/414/EEC of 15 July 1991 concerning the placing of plant protection products on the market(9);(12) Whereas Directive 91/414/EEC and Directive 98/8/EC of the European Parliament and of the Council of 16 February 1998 concerning the placing of biocidal products on the market (10), in contrast to the provisions applicable to chemical preparations covered by this Directive, provide for an authorisation procedure for each product on the basis of a dossier presented by the applicant and an assessment carried out by the competent authority in each Member State; whereas furthermore that authorisation procedure includes a control relating specifically to the classification, packaging and labelling of each product before it is placed on the market; whereas it is appropriate, as part of a clear and transparent information process, to classify and label plant protection products according to the provisions of this Directive, and also to provide instructions for use in accordance with the results of the evaluation carried out in the framework of Directive 91/414/EEC and to ensure that the labelling satisfies the high level of protection sought by both this Directive and Directive 91/414/EEC; whereas, in addition, a safety data sheet has to be established for plant protectioon products in accordance with this Directive;(13) Whereas it is appropriate to provide, in relation to environmental labelling, that specific exemptions or specific provisions may be decided upon in specific cases where it can be demonstrated that the overall environmental impact of the product types in question is lower than that of corresponding product types;(14) Whereas, although munitions are not covered by this Directive, explosives marketed to produce an explosive or pyrotechnic effect may, through their chemical composition, present dangers to health; whereas it is therefore necessary as part of a transparent informationprocess to classify them and assign to them a safety data sheet in accordance with the provisions of this Directive and also to label them in accordance with the international rules used for the transport of dangerous goods;(15) Whereas, in order to take account of certain preparations which, although they are not considered dangerous under this Directive, may nevertheless present a danger for users, it is necessary to extend certain provisions of this Directive to cover such preparations;(16) Whereas the label constitutes a basic tool for users of the dangerous preparations in so far as it provides them with the initial essential concise information; whereas it nevertheless needs to be supplemented by a two-fold system of more detailed information, consisting firstly of the safety data sheet, intended for professional users as defined by Commission Directive 91/155/EEC of 5 March 1991 defining and laying down the detailed arrangements for the system of specific information relating to dangerous preparations in implementation of Article 10 of Directive 88/379/EEC(11) and secondly of the bodies appointed by the Member States which are responsible for the provision of information solely for medical purposes, both preventive and curative;(17) Whereas, on the basis of information to be supplied by the Member States and the various parties concerned, the Commission will submit a report to the European Parliament and the Council within two years of the entry into force of this Directive on experience with the present overall approach to labelling of dangerous preparations and in particular on its understanding and application by users, experience with publicity campaigns and educational and training programmes; whereas, on the basis of this report, the Commission will, if appropriate, submit the necessary proposals;(18) Whereas it is necessary to require safety data sheets providing proportionate information on the dangers to man and the environment arising from preparations not classified as dangerous within the meaning of this Directive but containing substances classified as dangerous or having a Community exposure limit; whereas the Commission, on the basis of information submitted by Member States, will review Directive 91/155/EEC and submit proposals, if appropriate, before the expiry of the date for implementation of this Directive; (19) Whereas, in the case of preparations classified as dangerous within the meaning of this Directive, it is appropriate to permit Member States to allow certain derogations with respect to labelling where the packaging is too small, or otherwise unsuitable for labelling, or where such small packaging or such small quantities are involved that there is no reason to fear any danger to man or the environment; whereas in such cases appropriate consideration should also be given to the approximation of the relevant provisions at Community level; whereas the Commission will therefore examine the needs for harmonisation and, if appropriate, submit proposals;(20) Whereas the confidentiality of certain substances contained in the preparations should be guaranteed and whereas it is therefore necessary to institute a system which allows the person responsible for placing the preparation on the market to request confidentiality for such substances;(21) Whereas the provisions of this Directive will have regard to the commitment entered into by the Community and its Member States, in accordance with the goals for sustainable development set under Agenda 21, Chapter 19, at the UNCED conference held in June 1992 in Rio de Janeiro, to strive for the future harmonisation of systems for the classification of dangerous substances and preparations;(22) Whereas the Commission should be given the powers necessary to adapt all the Annexes to this Directive to technical progress;(23) Whereas the adoption of this Directive should not affect the obligations of the Member States concerning the deadlines for transposition into national law and for application of the Directives indicated in Annex VIII;(24) Whereas the Directives indicated in Annex VIII should be repealed, subject to certain conditions; whereas the conditions for repealing the Directives indicated in Annex VIII should be specified for Austria, Finland and Sweden in order to take account of the present level of their legislation, in particular as regards the protection of health and the protection of the environment,HAVE ADOPTED THIS DIRECTIVE:Article 1Objectives and scope1. This Directive aims at the approximation of the laws, regulations and administrative provisions of the Member States relating to:- the classification, packaging and labelling of dangerous preparations, and to- the approximation of specific provisions for certain preparations which may present hazards, whether or not they are classified as dangerous within the meaning of this Directive,when such preparations are placed on the market of the Member States.2. This Directive shall apply to preparations which:- contain at least one dangerous substance within the meaning of Article 2,and- are considered dangerous within the meaning of Article 5, 6 or 7.3. The specific provisions set out:- in Article 9 and defined in Annex IV,- in Article 10 and defined in Annex V, and- in Article 14shall also apply to preparations which are not considered dangerous within the meaning of Articles 5, 6 or 7 but may nevertheless present a specific hazard.4. Without prejudice to Directive 91/414/EEC, the articles on classification, packaging, labelling and safety data sheets of this Directive shall apply to plant protection products.5. This Directive shall not apply to the following preparations in the finished state, intended for the final user:(a) medicinal products for human or veterinary use, as defined in Directive 65/65/EEC(12);(b) cosmetic products as defined in Directive 76/768/EEC(13);(c) mixtures of substances which, in the form of waste, are covered by Directives 75/442/EEC(14) and 78/319/EEC(15);(d) foodstuffs;(e) animal feedingstuffs;(f) preparations containing radioactive substances as defined by Directive 80/836/Euratom(16);(g) medical devices which are invasive or used in direct physical contact with the human body in so far as Community measures lay down provisions for the classification and labelling of dangerous substances and preparations which ensure the same level of information provision and protection as this Directive.6. This Directive shall not apply to:- the carriage of dangerous preparations by rail, road, inland waterway, sea or air,- preparations in transit which are under customs supervision, provided they do not undergo any treatment or processing.Article 2Definitions1. For the purposes of this Directive:(a) "substances" means chemical elements and their compounds in the natural state or obtained by any production process, including any additive necessary to preserve the stability of the products and any impurity deriving from the process used, but excluding any solvent which may be separated without affecting the stability of the substance or changing its composition;(b) "preparations" means mixtures or solutions composed of two or more substances;(c) "polymer" means a substance consisting of molecules characterised by the sequence of one or more types of monomer units and comprising a simple weight majority of molecules containing at least three monomer units which are covalently bound to at least one other monomer unit or other reactant and consists of less than a simple weight majority of molecules of the same molecular weight. Such molecules must be distributed over a range of molecular weights wherein differences in the molecular weight are primarily attributable to differences in the number of monomer units. In the context of this definition a "monomerunit" means the reacted form of a monomer in a polymer;(d) (...);(e) "placing on the market" means making available to third parties. Importation into the Community customs territory shall be deemed to be placing on the market for the purposes of this Directive;(f) "scientific research and development" means scientific experimentation, analysis or chemical research carried out under controlled conditions; it includes the determination of intrinsic properties, performance and efficacy as well as scientific investigation related to product development;(g) "process-orientated research and development" means the further development of a substance in the course of which pilot plant or production trials are used to test the fields of application of the substance;(h) "Einecs" means the European Inventory of Existing Commercial Chemical Substances. This inventory contains the definitive list of all chemical substances deemed to be on the Community market on 18 September 1981.2. The following are "dangerous" within the meaning of this Directive:(a) explosive substances and preparations: solid, liquid, pasty or gelatinous substances and preparations which may also react exothermically without atmospheric oxygen thereby quickly evolving gases, and which, under defined test conditions, detonate, quickly deflagrate or upon heating explode when partially confined;(b) oxidising substances and preparations: substances and preparations which give rise to a highly exothermic reaction in contact with other substances, particularly flammable substances;(c) extremely flammable substances and preparations: liquid substances and preparations having an extremely low flash-point and a low boiling-point and gaseous substances and preparations which are flammable in contact with air at ambient temperature and pressure; (d) highly flammable substances and preparations:- substances and preparations which may become hot and finally catch fire in contact with air at ambient temperature without any application of energy, or- solid substances and preparations which may readily catch fire after brief contact with a source of ignition and which continue to burn or to be consumed after removal of the source of ignition, or- liquid substances and preparations having a very low flash-point, or- substances and preparations which, in contact with water or damp air, evolve extremely flammable gases in dangerous quantities;(e) flammable substances and preparations: liquid substances and preparations having a low flash-point;(f) very toxic substances and preparations: substances and preparations which in very low quantities cause death or acute or chronic damage to health when inhaled, swallowed or absorbed via the skin;(g) toxic substances and preparations: substances and preparations which in low quantities cause death or acute or chronic damage to health when inhaled, swallowed or absorbed via the skin;(h) harmful substances and preparations: substances and preparations which may cause death or acute or chronic damage to health when inhaled, swallowed or absorbed via the skin;(i) corrosive substances and preparations: substances and preparations which may, on contact with living tissues, destroy them;(j) irritant substances and preparations: non-corrosive substances and preparations which, through immediate, prolonged or repeated contact with the skin or mucous membrane, may cause inflammation;(k) sensitising substances and preparations: substances and preparations which, if they are inhaled or if they penetrate the skin, are capable of eliciting a reaction of hypersensitisation such that on further exposure to the substance of preparation, characteristic adverse effects are produced;(l) carcinogenic substances and preparations: substances or preparations which, if they are inhaled or ingested or if they penetrate the skin, may induce cancer or increase its incidence; (m) mutagenic substances and preparations: substances and preparations which, if they are inhaled or ingested or if they penetrate the skin, may induce heritable genetic defects or increase their incidence;(n) substances and preparations which are toxic for reproduction: substances and preparations which, if they are inhaled or ingested or if they penetrate the skin, may produce, or increase the incidence of, non-heritable adverse effects in the progeny and/or an impairment of male or female reproductive functions or capacity;(o) substances and preparations which are dangerous for the environment: substances and preparations which, were they to enter the environment, would or could present an immediate or delayed danger for one or more components of the environment.Article 3Determination of dangerous properties of preparations1. The evaluation of the hazards of a preparation shall be based on the determination of:- physico-chemical properties,- properties affecting health,- environmental properties.These different properties shall be determined in accordance with the provisions laid down in Articles 5, 6 and 7.Where laboratory tests are conducted, they shall be carried out on the preparation as placed on the market.2. Where the determination of dangerous properties is carried out in accordance with Articles 5, 6 and 7, all dangerous substances within the meaning of Article 2 and in particular those which:- are listed in Annex I to Directive 67/548/EEC,- are listed in Elincs in accordance with Article 21 of Directive 67/548/EEC,- are classified and labelled provisionally by the person responsible for the placing on the market in accordance with Article 6 of Directive 67/548/EEC,- are classified and labelled in accordance with Article 7 of Directive 67/548/EEC and are not yet included in Elincs,- are covered by Article 8 of Directive 67/548/EEC,- are classified and labelled in accordance with Article 13 of Directive 67/548/EEC,shall be taken into consideration in accordance with the provisions laid down in the method used.3. For preparations covered by this Directive, dangerous substances as referred to in paragraph 2 which are classified as dangerous on the basis of their health and/or environmental effects, whether they are present as impurities or additives, shall be taken into consideration when their concentrations are equal to, or greater than, those defined in the following table unless lower values are given in Annex I to Directive 67/548/EEC, or in Part B of Annex II to this Directive or in Part B of Annex III thereto, unless otherwise specified in Annex V to this Directive.>TABLE>Article 4General principles of classification and labelling1. The classification of dangerous preparations according to the degree and specific nature of the hazards involved shall be based on the definitions of categories of danger laid down in Article2.2. The general principles of the classification and labelling of preparations shall be applied in accordance with the criteria laid down in Annex VI to Directive 67/548/EEC, save where alternative criteria referred to in Article 5, 6, 7 or 10 and the relevant Annexes of this Directive are applied.Article 5Evaluation of the hazards deriving from physico-chemical properties1. The hazards of a preparation deriving from its physico-chemical properties shall be assessed by determining, by means of the methods specified in Part A of Annex V to Directive 67/548/EEC, the physico-chemical properties of the preparation necessary for appropriate classification and labelling in accordance with the criteria laid down in Annex VI to that Directive.2. By way of derogation from paragraph 1:the determination of the explosive, oxidising, extremely flammable, highly flammable, or flammable properties is not necessary provided that:- none of the constituents possesses such properties and that, on the basis of the information available to the manufacturer, the preparation is unlikely to present hazards of this kind,- in the event of a change in the composition of a preparation of known composition, scientific evidence indicates that a reassessment of the hazards will not lead to a change in classification,- preparations placed on the market in the form of aerosols satisfy the provisions of Article 9a of Directive 75/324/EEC(17).3. For certain cases for which the methods laid down in Part A of Annex V to Directive67/548/EEC are not appropriate, alternative calculation methods are laid down in Part B of Annex I to this Directive.4. Certain exemptions from the application of the methods laid down in Part A of Annex V to Directive 67/548/EEC are referred to in Part A of Annex I to this Directive.5. The hazards deriving from the physico-chemical properties of a preparation covered by Directive 91/414/EEC shall be assessed by determining the physico-chemical properties of the preparation necessary for appropriate classification in accordance with the criteria set out in Annex VI to Directive 67/548/EEC. These properties shall be determined by means of the methods laid down in Part A of Annex V to Directive 67/548/EEC unless other internationally recognised methods are acceptable in accordance with the provisions of Annexes II and III to Directive 91/414/EEC.Article 6Evaluation of health hazards1. The health hazards of a preparation shall be assessed by one or more of the following procedures:(a) by a conventional method described in Annex II;(b) by determining the toxicological properties of the preparation necessary for appropriate classification in accordance with the criteria in Annex VI to Directive 67/548/EEC. These properties shall be determined by means of the methods laid down in Part B of Annex V to Directive 67/548/EEC, unless, in the case of plant protection products, other internationally recognised methods are acceptable in accordance with the provisions of Annexes II and III to Directive 91/414/EEC.2. Without prejudice to the requirements of Directive 91/414/EEC, only where it can be scientifically demonstrated by the person responsible for placing the preparation on the market that the toxicological properties of the preparation cannot correctly be determined by the method outlined in paragraph 1(a), or on the basis of existing test results on animals, the methods outlined in paragraph 1(b) may be used, provided they are justified or specifically authorised under Article 12 of Directive 86/609/EEC.When a toxicological property is established by the methods outlined in paragraph 1(b) to obtain new data, the test shall be conducted in compliance with the principles of good laboratory practice provided for in Council Directive 87/18/EEC of 18 December 1986 on the harmonisation of laws, regulations and administrative provisions relating to the application of the principles of good laboratory practice and the verification of their applications for tests on chemical substances(18) and the provisions of Directive 86/609/EEC, in particular Articles 7 and 12 thereof.Subject to the provisions of paragraph 3, where a toxicological property has been established on the basis of both the methods outlined in paragraphs 1(a) and (b), the results from the methods outlined in paragraph 1(b) shall be used for classifying the preparation, except in the case of carcinogenic, mutagenic or toxic effects for reproduction for which only the method。
REACH法规 第二卷译稿-5
附件Ib配制品的化学品安全性评估配制品的化学品安全性评估应根据附件一操作，其中有下列修改：1. 信息基础配制品的化学品安全性评估应基于技术档案中包含的配制品中单独化学品的信息和/或安全性数据表中供应商提供的信息。
同时也应以配制品本身的可得信息为基础。
2. 有害评估有害评估（人类健康，涉及物理化学性质和环境的人类健康）应依据1，2，3小节进行，其中有下列变更：（1）在数据评价步骤中，应提出所有有关配制品的数据，配制品中所有物质的分类和特殊浓度限量。
（2）在分类和标签步骤中，要提出依据欧洲议会和理事会指令1999/45/EC的配制品分类和标签并给出理由。
（3）导出衍生无影响程度（DNELs）时，应列出适当依据供应商的安全性数据表的配制品中的各个物质的DNEL以及导出的配制品的DNEL，并说明导出过程正当的理由。
如缺乏相反的任一信息，应假设结果叠加。
然后，配制品在各个暴露途径和暴露说明中的DNELs都可以通过配制品中的各个物质的DNELs加权平均计算出来，权数是配制品中的物质暴露与配制品中所有物质的总暴露之比。
（4）导出预期无影响浓度（PNECs）时，应列出适当依据供应商的安全性数据表的配制品中的各个物质的PNECs以及导出的配制品的PNECs，并说明导出过程正当的理由。
如缺乏相反的任一信息，应采用结果叠加。
然后，配制品在各个环境范围和暴露说明中的PNECs都可以通过配制品中的各个物质的PNECs加权平均计算出来，权数是配制品中的物质暴露与配制品中所有物质的总暴露之比。
3. PBT评估如配制品包含符合附件XII中的标准的物质，那么这种情况应在化学安全报告中加以说明。
4. 暴露评估4.1. 暴露评估的目的是对人或环境暴露可能暴露于其中的配制品的剂量/浓度进行定性或定量的估计。
4.2. 暴露说明需根据附件I的5.1节编写。
应根据附件I的5.2节，编写每一暴露说明都要做暴露估计同时对配制品中的每一物质也要做暴露估计。
detailed banlanced 条件
detailed banlanced 条件"Detailed balanced" is a term commonly used in the field of chemical kinetics to describe a special condition in a reaction system. In a reaction network, a set of reactions is said to be "detailed balanced" if the system has reached a state of equilibrium where there is no net flow of reactants to products.More specifically, a reaction network is considered detailed balanced if the rate at which each reaction proceeds is perfectly balanced by the rate at which its reverse reaction proceeds. This means that for every pair of reactions in the network, the ratio of their forward and reverse rate constants is equal to the ratio of their reactant and product concentrations at equilibrium.Formally, if we consider a reaction network with reactions:A +B ⇌C +D (1)C +D ⇌E +F (2)G + H ⇌ I + J (3)The condition for detailed balanced is met if the following equations hold for all reactions in the network:k_1 * [A] * [B] = k_1' * [C] * [D] (4)k_2 * [C] * [D] = k_2' * [E] * [F] (5)k_3 * [G] * [H] = k_3' * [I] * [J] (6)Where k_1, k_1', k_2, k_2', k_3, and k_3' are the rate constants for the forward and reverse reactions, and [A], [B], [C], [D], [E], [F], [G], [H], [I], and [J] are the concentrations of the species involvedin the reactions.The detailed balanced condition reflects a state of chemical equilibrium where the rates of forward and reverse reactions are equal, allowing for a stable concentration profile of species in the system. It is an important concept in chemical kinetics and is used in various theoretical analyses and modeling of reaction networks.。
概率流程计算
01 简单介绍概率图模型是图论和概率论结合的产物，它的开创者是鼎鼎大名的Judea Pearl,我十分喜欢概率图模型这个工具，它是一个很有力的多变量而且变量关系可视化的建模工具，主要包括两个大方向：无向图模型和有向图模型。
无向图模型又称马氏网络，它的应用很多，有典型的基于马尔科夫随机场的图像处理，图像分割，立体匹配等，也有和机器学习结合求取模型参数的结构化学习方法。
严格的说他们都是在求后验概率:p(y|x)，即给定数据判定每种标签y的概率，最后选取最大的后验概率最大的标签作为预测结果。
这个过程也称概率推理(probabilistic inference）。
而有向图的应用也很广，有向图又称贝叶斯网络(bayes networks),说到贝叶斯就足以可以预见这个模型的应用范围咯，比如医疗诊断，绝大多数的机器学习等。
但是它也有一些争议的地方，说到这就回到贝叶斯派和频率派几百年的争议这个大话题上去了，因为贝叶斯派假设了一些先验概率，而频率派认为这个先验有点主观，频率派认为模型的参数是客观存在的，假设先验分布就有点武断，用贝叶斯模型预测的结果就有点“水分”，不适用于比较严格的领域，比如精密制造，法律行业等。
好吧，如果不遵循贝叶斯观点，前面讲的所有机器学习模型都可以dismiss咯，我们就通过大量数据统计先验来弥补这点“缺陷”吧。
无向图和有向图的例子如（图一）所示：图一(a)无向图（隐马尔科夫）(b)有向图概率图模型吸取了图论和概率二者的长处，图论在许多计算领域中扮演着重要角色，比如组合优化，统计物理，经济等。
图的每个节点都可看成一个变量，每个变量有N个状态（取值范围），节点之间的边表示变量之间的关系，它除了可以作为构建模型的语言外，图还可以评价模型的复杂度和可行性，一个算法的运行时间或者错误界限的数量级可以用图的结构性质来分析，这句话说的范围很广，其实工程领域的很多问题都可以用图来表示，最终转换成一个搜索或者查找问题，目标就是快速的定位到目标，试问还有什么问题不是搜索问题？树是图，旅行商问题是基于图，染色问题更是基于图，他们具有不同的图的结构性质。
FDApart11Discussion（中文）
FDApart11Discussion（中文）三、讨论A、第11条款概述正如以下详述，该指南概括的方法基于以下3个方面：对第11条款的详细解读，FDA明确了记录可以不遵守第11条款；对于遵守第11条款的记录，就该指南中提出的与第11条款有关的验证、审计追踪、记录保留和记录复印及在第11条款的生效之前的系统（通常称为遗留系统），FDA会采取自由裁量权。
FDA会强制执行所有的预定法规，包括预定记录和记录保存要求。
需要注意的是本指南提到的FDA执行自由裁量权仅限于第11条款中的特定要求（遗留系统除外，在特定情况下，遗留系统自由裁量权的范围更广）。
FDA打算执行第11条款中的所有其他条款，包括但不限于条款中§11.10封闭系统的控制。
例如，对以下控制和要求，FDA将执行条款中的规定：进入授权的限制系统使用操作系统检查使用授权检查使用设备检查确定研发、维护或使用电子系统的人员所需的学历、培训和经验发起电子签名，建立并遵守书面规定对系统文件的合理控制开放系统管理同上述封闭系统管理一致（§11.30）电子签名相关要求（例如，§§11.50, 11.70, 11.100, 11.200, and 11.300）FDA期望符合这些规定，并会继续执行这些规定。
此外，必须符合适用的预定法规，按照预定法规，记录必须维护、递交的记录必须可靠且长期保留。
B. 方法描述-第11条款适用范围1.狭义适用范围对第11条款的适用范围会有些费解，有人认为第11条款的适用范围是相当宽泛的。
FDA相信对这些宽泛范围的解释可能会导致不必要的控制和成本，还可能会阻碍创新和技术进步，对公众健康不会带来有利影响。
因此，FDA需要澄清第11条款的狭义适用范围。
在狭义适用范围下，记录需在预定法规要求下保存或递交FDA，第11条款适用于当选择使用电子文件替代纸质文件时。
另一方面，§§ 11.2(a)和11.2(b)指出，当使用计算机打印电子记录，且电子记录符合预定法规的所有要求，并依据纸质记录进行法规操作，FDA不会建议使用电子记录代替纸质记录。
离散数学双语专业词汇表
《离散数学》双语专业词汇表Abelian group：交换（阿贝尔）群absorption property：吸收律acyclic：无（简单）回路的adjacent vertices：邻接结点adjacent vertices：邻接结点adjacent vertices：邻接结点algorithm verification：算法证明algorithm：算法alphabet：字母表alternating group：交替群analogous：类似的analysis of algorithm：算法分析antisymmetric：反对称的approach：方法，方式argument：自变量associative：可结合的associative：可结合的asymmetric：非对称的backtracking：回溯base 2 exponential function：以2为底的指数函数basic step：基础步biconditional, equivalence：双条件式，等价bijection, one-to-one correspondence：双射，一一对应binary operation on a set A：集合A上的二元运算binary operation：二元运算binary relation：二元关系(complete) binary tree：(完全)二元(叉)树bland meats：未加调料的肉block, cell：划分块，单元Boolean algebra：布尔代数Boolean function：布尔函数Boolean matrix：布尔矩阵Boolean polynomial, Boolean expression：布尔多项式（表达式）Boolean product：布尔乘积bounded lattice：有界格brace：花括号bridge：桥，割边by convention：按常规，按惯例cancellation property：消去律capacity：容量cardinality：基数，势category：类别，分类catenation：合并，拼接ceiling function：上取整函数certain event：必然事件characteristic equation：特征方程characteristic function：特征函数chromatic number of G：G的色数chromatic polynomial：着色多项式circuit design：线路设计circuit：回路closed under the operation：运算对…是封闭的closed with respect to：对…是封闭的closure：闭包collision：冲突coloring graphs：图的着色column：列combination：组合common divisor：公因子commutative：可交换的commutative：可交换的commuter：经常往来于两地的人comparable：可比较的compatible with：与…相容compatible：相容的complement of B with respect to A：A与B的差集complement：补元complementary relation：补关系complete graph：完全图complete match：完全匹配complete n-tree：完全n-元树component sentence：分句component：分图composition：复合composition：关系的复合compound statement：复合命题conditional statement, implication：条件式，蕴涵式congruence relation：同余关系congruent to：与…同余conjecture：猜想conjunction：合取connected：连通的connected：连通的connection：连接connectivity relation：连通性关系consecutively：相继地consequent, conclusion：结论，后件constructive proof：构造性证明contain(in)：包含（于）contingency：可满足式contradiction, absurdity：永假(矛盾)式contrapositive：逆否命题conversation of flow：流的守恒converse：逆命题conversely：相反地coordinate：坐标coset：陪集countable(uncountable)：可数（不可数）counterexample；反例counting：计数criteria：标准，准则custom：惯例cut：割cycle：回路cyclic permutation：循环置换，轮换de Morgan’s laws：德摩根律declarative sentence：陈述句degree of a vertex：结点的度depot：货站，仓库descendant：后代diagonal matrix：对角阵die：骰子digraph：有向图dimension：维(数)direct flight：直飞航班discipline：学科disconnected：不连通的discrete graph(null graph)：零图disjoint sets：不相交集disjunction：析取distance：距离distinguish：区分distributive lattice：分配格distributive：可分配的distributive：可分配的division：除法dodecahedron：正十二面体domain：定义域doubly linked list：双向链表dual：对偶edge：边edge：边element, member：成员，元素empty relation：空关系empty sequence(string)：空串empty set：空集end point：端点entry(element)：元素equally likely：等可能的，等概率的equivalence class：等价类equivalent relation：等价关系Euclidian algorithm：欧几里得算法，辗转相除法Euler path(circuit)：欧拉路径(回路)event：事件everywhere defined：处处有定义的excess capacity：增值容量existence proof：存在性证明existential quantification：存在量词化expected value：期望值explicit：显式的extensively：广泛地，全面地extremal element：极值元素factor：因子factorial：阶乘finite (infinite) set：有限（无限）集finite group：有限（阶）群floor function：下取整函数free semigroup generated by A：由A生成的自由半群frequency of occurrence：出现次数(频率) function, mapping, transformation：函数，映射，变换GCD(greatest common divisor)：最大公因子gender：性别generalize：推广generic element：任一元素graduate school：研究生院graph：(无向)图graph：无向图greatest(least) element：最大(小)元greedy algorithm：贪婪算法group：群growth of function：函数增长Hamiltonian path(circuit)：哈密尔顿路径(回路) hashing function：杂凑函数Hasse diagram：哈斯图height：树高homomorphic image：同态像homomorphism：同态hypothesis：假设，前提，前件idempotent：等幂的idempotent：幂等的identity function on A：A上的恒等函数identity(element)：么（单位）元identity：么元，单位元impossible event：不可能事件inclusion-exclusion principle：容斥原理in-degree：入度indirect method：间接证明法induction step：归纳步informal brand：不严格的那种inorder search：中序遍历intersection：交intuitively：直觉地inverse：逆关系inverse：逆元inverse：逆元inverter：反向器invertible function：可逆函数involution property：对合律irreflexive：反自反的isolated vertex：孤立结点isomorphism：同构isomorphism：同构join：，保联，并join：并Karnaugh map：卡诺图Kernel：同态核key：键Klein 4 group：Klein四元群Konisberg Bridge problem：哥尼斯堡七桥问题Kruskal’s algorithm：Kruskal算法labeled digraph：标记有向图lattice：格LCM(least common multiple)：最小公倍数leaf(leave)：叶结点least upper(greatest lower) bound：上(下)确界level：层，lexicographic order：字典序likelihood：可能性linear array(list)：线性表linear graph：线性图linear homogeneous relation of degree k：k阶线性齐次关系linear order(total order)：线序，全序linearly ordered set, chain：线（全）序集，链linked list：链表linked-list representation：链表表示logarithm function to the base n：以n为底的对数logical connective：命题联结词logically equivalent：（逻辑）等价的logically follow：是…的逻辑结论logician：逻辑学家loop：自回路lower order：低阶main diagonal：主对角线map-coloring problem：地图着色问题matching function：匹配函数matching problems：匹配问题mathematical structure(system)：数学结构（系统）matrix：矩阵maximal match：最大匹配maximal(minimal) element：极大(小)元maximum flow：最大流meet：保交，交meet：交minimal spanning tree：最小生成树minterm：极小项modular lattice：模格modulus：模modus ponens：肯定律m odus tollens：否定律monoid：含么半群，独异点multigraph：多重图multiple：倍数multiplication table：运算表multi-valued function：多值函数mutually exclusive：互斥的，不相交的natural homomorphism：自然同态nearest neighbor：最邻近结点negation：否定（式）normal subgroup：正规(不变)子群notation：标记notion：概念n-tree：n-元树n-tuple：n-元组odd(even) permutation：奇（偶）置换offspring：子女结点one to one：单射，一对一函数onto：到上函数，满射operation on sets：集合运算optimal solution：最佳方法or(and, not) gate：或(与，非)门order of a group：群的阶order relation：序关系ordered pair：有序对，序偶ordered tree：有序树ordered triple：有序三元组ordinance：法规out-degree：出度parent：父结点partial order：偏序关系partially ordered set, poset：偏序集partition, quotient set：划分，商集path：路径path：通路，路径permutation：置换，排列pictorially：以图形方式pigeonhole principle：鸽巢原理planar graph：(可)平面图plausible：似乎可能的pointer：指针Polish form：（表达式的）波兰表示polynomial：多项式positional binary tree：位置二元(叉)树positional tree：位置树postorder search：后序遍历power set：幂集predicate：谓词preorder search：前序遍历prerequisite：预备知识prescribe：命令，规定Prim’s algorithm：Prim算法prime：素（数）principle of mathematical induction：（第一）数学归纳法probabilistic：概率性的probability(theory)：概率(论)product partial order：积偏序product set, Caretesian set：叉积，笛product：积proof by contradiction：反证法proper coloring：正规着色propositional function：命题公式propositional variable：命题变元pseudocode：伪码（拟码）pumping station：抽水站quantifier：量词quotient group：商群random access：随机访问random selection(choose an object at random)：随机选择range：值域rational number：有理数reachability relation：可达性关系reasoning：推理recreational area：游乐场所recursive：递归recycle：回收，再循环reflexive closure：自反闭包reflexive：自反的regular expression：正则表达式regular graph：正规图，正则图relation：关系relationship：关系relay station：转送站remainder：余数representation：表示restriction：限制reverse Polish form：（表达式的）逆波兰表示(left) right coset：(左)右陪集root：根，根结点rooted tree：（有）根树row：行R-relative set：R相关集rules of reference：推理规则running time：运行时间same order：同阶sample space：样本空间semigroup：半群sensible：有意义的sensible：有意义的sequence：序列sequential access：顺序访问set corresponding to a sequence：对应于序列的集合set inclusion(containment)：集合包含set：集合siblings：兄弟结点simple cycle：简单回路simple path(circuit)：基本路径(回路)simple path：简单路径（通路）sink：汇sophisticated：复杂的source：源spanning tree：生成树，支撑树square matrix：方阵statement, proposition：命题storage cell：存储单元string：串，字符串strong induction：第二数学归纳法subgraph：子图subgroup：子群sublattice：子格submonoid：子含么半群subscript：下标subsemigroup：子半群subset：子集substitution：替换subtree：子树summarize：总结，概括symmetric closure：对称闭包symmetric difference：对称差symmetric group：对称群symmetric：对称的tacitly：默认tautology：永真(重言)式tedious：冗长乏味的terminology：术语the capacity of a cut：割的容量topological sorting：拓扑排序transitive closure：传递闭包transitive：传递的transport network：运输网络transposition：对换traverse：遍历，周游tree searching：树的搜索（遍历）tree：树truth table：真值表TSP(traveling salesperson problem)：货郎担问题unary operation：一元运算undirected edge：无向边undirected edge：无向边undirected tree：无向树union：并unit element：么(单位)元universal quantification：全称量词化universal set：全集upper(lower) bound：上(下)界value of a flow：流的值value, image：值，像，应变量V enn diagram：文氏图verbally：用言语vertex(vertices)：结点vertex(vertices)：结点，顶点virtually：几乎Warshal’s algorithm：Warshall算法weight：权weight：树weighted graph：（赋）权图well-defined：良定，完全确定word：词zero element：零元。
In-Process and Bulk Drug Product Holding Times说明书
Regulatory Basis:FDA Quality Systems RegulationsReference: FDA CFR - Code of Federal Regulations Title 21General Discussion:This Document sets out guidelines for the determination and validation of in-process and bulk product holding times.Maximum allowable hold times should be established for bulk and in-process drug products (where applicable). Typically one lot can be used for validating hold times. Data to justify the hold time can be collected during development on pilot scale batches, during process validation, via a historical review of batch data, or as part of a deviation with proper testing.Although there are no specific regulations or document documents on bulk product holding times, good manufacturing practice dictates that holding times should be validated to ensure that in-process and bulk product can be held, pending the next processing step, without any adverse effect to the quality of the material. This practice is supported by indirect references made to determining holding times in various FDA document documents, FDA regulations as follows:__ “if a firm plans to hold bulk drug products in storage…..stability data should be provided to demonstrate that extended storage in the described containersdoes not adversely affect the dosage form”.__ “stability data also may be necessary when the finished dosage form is stored in interim containers prior to filling into the marketed package. If the dosageform is stored in bulk containers for over 30 days, real-time stability dataunder specified conditions should be generated to demonstrate comparablestability to the dosage form in the marketed package. Interim storage of thedosage form in bulk containers should generally not exceed six months”.__ “when appropriate, time limits for the completion of each phase of production shall be established to assure the quality of the drug product.” .Thisregulation could be interpreted to include the time for holding bulk product aspart of the production process. “holding times (includes storage times) studiesmay be conducted during development or carried out in conjunction withprocess validation lots and shall be representative of full scale holding conditions”.For purposes of clarification, refer to Appendix A for definitions relating to bulkholding time. Holding time data may be generated in the following situations:•Bulk holding studies may be conducted on product developmental pilot scale batches to demonstrate comparable stability to the dosage form in the marketedpackage.•Holding data may be generated as part of a process validation study. Data can be collected on the bulk product itself after holding or collected after the heldproduct has been packaged.Typically, if these in-process products are used within 24 hours of manufacturing, no bulk holding time studies are deemed necessary. An in-process product that is held for longer than 24 hours should be monitored for physical characteristics and microbialcontamination. A solution/suspension should be held for the defined hold period. Atthe test points, a sample should betaken from the storage container and tested. Results obtained should be compared with the initial baseline data of the solution/suspensioncontrol sample results.Typical tests include the following: Microbial count; Yeast/Mould count; SpecificGravity; and Viscosity.3) Holding time considerations for Tablet Cores, Extended-Release Beads orPellets.Typically, in-process products such as cores, extended-release beads or pellets may be held for up to 30 days from their date of production without being retested prior touse. An in-process product that is held for longer than 30 days should be monitoredfor stability under controlled, long-term storage conditions for the length of theholding period. A representative portion of the core/bead/pellet should be held for the defined hold period. At the test points, a sample should be taken from the storagecontainer and tested. Results obtained should be compared with the initial baselinedata of the core/bead/pellet control sample results.Typical tests include the following: Hardness; Friability; Appearance;Dissolution/Disintegration; Assay; Degradation Products (where applicable); andMoisture Content.4)Holding time considerations for Bulk Tablets and Capsules.Typically, bulk tablets and capsules may be held for up to 30 days from their date ofproduction without being retested prior to use. A bulk product that is held for longerthan 30 days should be monitored for stability under controlled, long-term storageconditions for the length of the holding period. Interim storage of the dosage form inbulk containers should generally not exceed six months. At the test points, a sampleshould be taken from the storage container and tested. Results obtained should becompared with the initial baseline data of the tablet/capsule control sample results.Typical tests include the following: Hardness; Friability; Appearance; Dissolution (in the case of controlled and extended release products, the establishment of adissolution profile is recommended); Disintegration; Assay; Degradation Products(where applicable); Moisture Content, and microcount (where applicable).5) Holding time considerations for Oral Liquids and Semi-Solids (Suspensions,Creams, and Ointments).Typically, liquid and semi-solid dosage form products should be held for no morethan 5 days without a hold time study. Full scale batches should be used for thesestudies. Samples should be taken from the holding vessel after transfer from themanufacturing vessel, and again at the completion of the holding period. Multiplesamples should be taken at each time point if holding can impact product uniformity.Samples would be taken to prove that product uniformity of actives and preservatives。
FDA警告信翻译
W-185Keywords: Software and computer system validation, back-up, limited access, audit trail, data encryption, accurate copies∙Primary deviations: Inadequate storage and back-up, missing ability to discern invalid or altered electronic records, access to computer records without unique user ID and password, no or inadequate validation,inaccurate copies of electronic records.∙Examples:-Failure to store records so as to minimize deterioration, prevent lossand back up of automated data processing systems- The electronic data did not correlate with the paper records; you hadnot established an electronic data back-up procedure; and finally, datawas copied onto the server from one system to the next via floppy:therefore, no limited access or data protection had been established- You failed to encrypt and/ or physically secure your data back-upsystem to comply with the requirements to prevent deterioration ordeletion of the analyzer data- Failure to adequately validate the intended use of this PC and itssoftware- The dedicated PC [redacted] attached to the [redacted] was notsecure in that access to the data on [redacted] was not granted by aunique username and password or equivalent method- there as no documentation associated with the electronic data forwhom was responsible for collection of the analytical results as several quality control personnel have access to the [redacted] no softwarechanges in the study data could be detected as there was no audit trailcapability; and finally, the electronic data did not correlate with thepaper records.- your response and have concluded that it is inadequate because nosystem validation was conducted to ensure accuracy, reliability,consistent intended performance, and the ability to discern invalid oraltered records关键词：软件和计算机系统的验证，备份，权限限制，审核追踪，数据加密，精确复制∙主要偏差：不适当的存储和备份，无法区分有效的或经更改的电子记录，无需唯一的用户ID和密码就可访问计算机记录，没有进行验证或验证不适当，电子记录的复制不准确。
Development and Characterization of a Cell Culture Manufacturing Process Using Quality
Development and Characterizationof a Cell Culture Manufacturing ProcessUsing Quality by Design (QbD)PrinciplesDaniel M.Marasco,Jinxin Gao,Kristi Griffiths,Christopher Froggatt,Tongtong Wang and Gan WeiAbstract The principles of quality by design (QbD)have been applied in cell culture manufacturing process development and characterization in the biotech industry.Here we share our approach and practice in developing and char-acterizing a cell culture manufacturing process using QbD principles for establishing a process control strategy.Process development and character-ization start with critical quality attribute identification,followed by process parameter and incoming raw material risk assessment,design of experiment,and process parameter classification,and conclude with a design space con-struction.Finally,a rational process control strategy is established and documented.Keywords Cell culture process characterization ÁCell culture process develop-ment ÁCell culture process scale-up ÁControl strategy ÁCritical quality attribute ÁDesign space ÁQuality by design ÁRisk assessment AbbreviationsQbDQuality by design QTPPQuality target product profile CQACritical quality attributes DOEDesign of experiment CPMControl point matrix FMEA Failure modes and effects analysisD.M.Marasco (&)ÁJ.Gao ÁK.Griffiths ÁC.Froggatt ÁT.Wang ÁG.WeiBioproduct Research and Development,Lilly Research Laboratories,Eli Lilly and Company,Indianapolis,IN 46285,USAe-mail:marasco_daniel_m@Adv Biochem Eng Biotechnol (2014)139:93–121DOI:10.1007/10_2013_217ÓSpringer-Verlag Berlin Heidelberg 2013Published Online:5July 201394 D.M.Marasco et al. Contents1Introduction (94)2Development and Characterization of Cell Culture Manufacturing Process for Establishing a Process Control Strategy (96)2.1Construct CQA(s)Control Points Matrix (96)2.2Initial Process Parameter Risk Assessment (98)2.3Risk Mitigation/Initial Process Characterization Experiments (101)2.4Final Characterization Experiment (106)2.5FMEA Process Parameter Risk Assessment (106)2.6Classification of Process Parameters (108)2.7Process Excursion Studies (110)2.8Construction of the Design Space/Operating Space (110)2.9Cell Culture Process Control Strategy (110)3Case Study (111)3.1Construct CQA(s)Control Points Matrix (111)3.2Initial Process Parameter Risk Assessment (111)3.3Scale-Down Model (112)3.4Initial Process Characterization Experiments (112)3.5Final Process Characterization Experiment (115)3.6FMEA Process Parameter Risk Assessment (116)3.7Process Excursion Study (116)3.8Classification of Process Parameters (117)3.9Construction of Design Space (117)References (121)1IntroductionThe quality by design(QbD)concepts embodied in the International Conference on Harmonization(ICH)guidelines Q8(R2),Q9,Q10,and Q11have been applied to cell culture manufacturing process development and characterization[1–4].The January2011revised FDA Guidance for Industry,Process Validation:General Principles and Practices,integrates QbD principles into process validation prac-tices[5].These guidance documents outline the application of QbD principles in the lifecycle of a product from process design,process definition,and process characterization to process validation and continued process verification.The expectation from regulatory agencies is that quality is designed or built into the product and its manufacturing process and quality cannot be adequately assured by testing[5].The benefit of QbD is twofold:one is to provide a high level of assurance for product quality through lifecycle management of the product;the other is the potential forflexibility in the reporting responsibilities for movements within a registered design space[1].The implementation of QbD principles means product characteristics are designed and fully understood and their linkage to patient safety and clinical efficacy is established,the interaction between critical product quality attributes and its manufacturing process are fully characterized,and control strategyDevelopment and Characterization of a Cell Culture Manufacturing Process95including design space is established to ensure that the manufacturing process is capable of consistently producing the product with the desired quality attributes [6,7].Figure1presents our approach in applying QbD principles to developing and characterizing a cell culture manufacturing process for establishing a process control strategy.Development of a cell culture manufacturing process control strategy starts from identifying drug substance critical quality attributes based on the quality target product profile(QTTP).Critical quality attributes(CQAs)are identified through risk assessment that evaluates severity based on impact on patient safety and/or clinical efficacy[8].The list of CQA(s)evolves during the development lifecycle.Then,a matrix is created to describe the interaction between critical quality attributes and process unit operations based on previous process development work,platform knowledge,literature information,andfirst principles.This control point matrix (CPM)visually indicates the origin,growth,reduction,or clearance of the quality attributes over the entire drug substance manufacturing process and demonstrates the process control points for each critical quality attribute.96 D.M.Marasco et al.Using the CPM as a guide,initial process parameter risk assessments are per-formed to evaluate the impact of process parameters and incoming raw materials systematically,within common cause variability,on critical product quality attributes.Process parameters are selected based on risk assessment for empirical evaluation using design of experiments(DOE)utilizing a qualified scale-down model.The purpose of the initial characterization study is to link process parameters to critical quality attributes.A resolution III or IV,fractional factional DOE is conducted depending on the number of parameters to be evaluated.Pro-cess parameters having statistically significant impact on CQA(s)are selected for further study using response surface DOE.The functional relationships between these process parameters and CQA(s)are fully characterized.A secondary risk assessment,failure mode and effects analysis(FMEA),is performed during technology transfer to the commercial manufacturing site.Risks identified during the FMEA are further reduced or mitigated through process excursion and/or process challenge studies.Process parameters are classified as critical or noncritical postprocess charac-terization studies.The classification is performed based on risk assessment and experimental results from process characterization studies.Based on risk assess-ments conducted throughout the development lifecycle,those process parameters assessed as not likely to affect CQAs are classified as noncritical.For process parameters evaluated in characterization studies,if a parameter is both statistically significant and practically significant in affecting CQA(s),it is classified as critical. Otherwise,it is classified as noncritical.A design space/operating space is constructed post parameter classification.Per ICH Q8,design space is the multidimensional combination and interaction of input variables(e.g.,material attributes)and process parameters that have been dem-onstrated to provide assurance of quality.A cell culture process control strategy is established and documented based on information generated through risk assessments and process characterization studies during the development lifecycle.The establishment of analytical control strategy and microbiological control strategy is beyond the scope of this chapter.In the next sections,we describe our practices for process parameter risk assessments,CQA-driven process characterization by design of experiment,pro-cess parameter classification,design space/operating space construction,and process control strategy establishment.2Development and Characterization of Cell Culture Manufacturing Process for Establishing a ProcessControl StrategyThe process development lifecycle consists of process design,process definition, process characterization,process validation,and continued process verification.Development and Characterization of a Cell Culture Manufacturing Process97Table1Control points matrix describing the probable quality attribute control pointsCritical quality attribute Analytical method Unit operation influencing CQA(s)12345…N CQA#1OCQA#2OCQA#3O:XCQA#4O l X; CQA#5O X;O Origin of attribute at this unit operation:Growth of attribute at this unit operation;Reduction of attribute at this unit operationl Potential for growth or reduction of attribute at this unit operationX Significant reduction/clearance of attribute at this unit operationAfter definition of an initial baseline process,characterization studies are initiated to understand fully the impact of process parameters and incoming raw material attributes,within common cause variability,on critical quality attributes.Process characterization starts with risk assessment.The intention of the initial risk assessment is systematically to evaluate the potential risk of process parameters and incoming raw material attributes from each unit operation,within common cause variability,on critical quality attributes.A cause and effect methodology is utilized in the initial risk assessment.2.1Construct CQA(s)Control Points MatrixPrior to initializing process characterization,sufficient information should be available to describe,or reasonably estimate,the relationship between the unit operations and critical quality attributes.In order to facilitate the initial cause-and-effect risk assessment,a unit operation-based,control points matrix(CPM),is created to describe the probable control points(one or many)for each critical quality attribute.The matrix should include the most likely origin,growth, reduction,or clearance of the critical quality attributes across the entire drug substance manufacturing process.An example of a unit operation-based control point matrix is displayed in Table1.The control points matrix is used to guide the process parameter risk assessment by allowing unit operation characterization studies to focus only on the relevant critical quality attributes that are significantly influenced by the purpose or design intent of the unit operation.The control points matrix is updated as additional information becomes available.2.2Initial Process Parameter Risk AssessmentInitial process parameter risk assessments are based on process knowledge,that is, a combination of practical experience and theoretical understanding.The process parameter risk assessment is performed iteratively throughout the development lifecycle to prioritize development efforts.Depending upon an organization’s experience and relative level of comfort conducting these risk assessments,they may be performed by a subject matter expert,or by a cross-functional team.Per ICH Q6,the degree of rigor and formality of quality risk management should reflect available knowledge and be commensurate with the complexity and/or criticality of the issue to be addressed.The initial process parameter risk assessment is performed in four basic steps: (1)identify output,(2)identify input process parameters,(3)evaluate the probablerisks,and(4)rank the process parameters by riskscore.The results from the risk assessment guide and prioritize the experimental program used to characterize each unit operation of the cell culture manufacturing process.2.2.1Identification of OutputsCritical quality attributes are the main output analyzed in the initial process parameter risk assessment.Process performance indicators may also be considered.2.2.2Identification of Input Process ParametersThe inputs,or process parameters,are identified based on the operational knowledge and mechanistic understanding of each unit operation in the manu-facturing process.A cause and effect diagram is a useful tool to organize and group process parameters systematically by function.The cause-and-effect diagram is constructed by placing the output(i.e.,product and process attributes of interest)at the right side of the diagram,with the potential design factors(i.e.,process parameters and incoming raw material attributes,e.g.,concentration accuracy)on a series of branches and subbranches extending from the output axis.The process parameters can be grouped by function or process step to ensure no process parameters are overlooked.98 D.M.Marasco et al.The level of branching can be moderated to facilitate efficient communica-tion to ensure the level of detail is appropriate.An example cause-and-effect diagram describing a typical production bioreactor process is given in Fig.2[9].2.2.3Risk AnalysisAfter identifying the relevant process outputs (CQAs)and process inputs (process parameters)for each unit operation,the risks of common cause variability in the input parameters that may affect the output parameters are assessed.The risk analysis is based on first principles,literature information,platform knowledge,manufacturing experience,scientific judgment of the subject matter experts,and molecule-specific empirical knowledge.The process parameters can be classified into two groups:those that have the potential to affect critical quality attributes and those that do not.Process parameters that do not have the potential to affect critical quality attributes may be assigned a low risk score.Typically,low-risk process parameters are not formally studied in laboratory models or designed experiments and are classifiedas Development and Characterization of a Cell Culture Manufacturing Process 99100 D.M.Marasco et al.noncritical with appropriate rationales.The remaining process parameters are classified as high risk,thus,they may have the potential to affect critical quality attributes and require additional evaluation to better understand,reduce,or miti-gate risks.The process parameter risk assessment follows the logic diagram pre-sented in Fig.3.The initial process parameter risk assessment is an integral part of the development of a control strategy;therefore,this assessment should be ade-quately documented.2.2.4Raw Material Risk AssessmentThe risks of variability inherent to the cell culture raw materials used to manu-facture drug substances on CQA(s)are evaluated in the development lifecycle.The raw material components are analyzed to assess the intrinsic risk(use of the correct raw materials)and the extrinsic risk(lot-to-lot variability)on CQA(s)and other quality attributes.The assessment includes the risks introduced from a quality,technical,and procurement perspective.The initial risk assessment occurs prior to the manufacture of pivotal clinical materials,and is reassessed as the process evolves.For example,technology transfer and/or changes in the process or supply chain may initiate a reassessment.The evaluation of raw material risk utilizes a series of weighted risk elements based on their criticality to the product or process,and the risk to the patient.Each raw material is assigned a three-tiered risk score(low=1,medium=3,or high=5)for each risk element using a combination of platform knowledge, manufacturing experience,opinions of the subject matter experts,and molecule-Development and Characterization of a Cell Culture Manufacturing Process101 specific empirical knowledge.The summation of the individual risk scores mul-tiplied by the risk element weight is calculated for each component.These values are used to rank the relative risks for each raw material component.As an example,the risk elements,and their respective weights,are described in table.Description of risk elementsWeight=5•Variability has the potential to affect the drug substance quality attributes•Ability of raw material to introduce bioburden,endotoxin,viral contaminates•Known issues with raw materialWeight=3•Molecular complexity•Potential to affect process performanceWeight=1•Experience with vendor•Manufactured for pharmaceutical industry2.3Risk Mitigation/Initial Process CharacterizationExperimentsFollowing the identification of high-risk process parameters and raw materials,an experimental program is designed to characterize and mitigate the risks of iden-tified process parameters on critical quality attributes within common cause variability.2.3.1Experimental StrategyThe experimental program is designed to characterize the manufacturing process to ensure consistent robust manufacturing capability.The high-risk process parameters are studied in a series of designed experiments intended to understand and mitigate potential risks further.Scale-independent process parameters are explored using a laboratory scale-down model.Scale-dependent parameters may be studied using intermediate or at-scale bioreactors.The experimental program is typically initialized utilizing a highly leveraged design of experiments of a resolution sufficient to identify the main effects and some quadratic effects.Depending upon the number of relevant process parameters identified in the risk assessment process,a single or a series of screening exper-iments can be planned.Multivariate fractional factorial design of experiments of resolution III or IV run using one or several blocks are common.Based on the output from the screening experiment,additional studies may be performed to102 D.M.Marasco et al. characterize parameters further that have a statistically and practically significant effect on critical quality attributes.Prior to designing experiments,the high-risk process parameters should be examined while acknowledging that not all process parameters are independent of each other(i.e.,medium strength and medium osmolality).Potential correlations should be identified and taken into consideration.2.3.2Process Parameter Range of InterestDuring cell culture manufacturing process characterization studies,the target setpoints of process parameters are determined based on process design and def-inition experimentation;process parameter ranges selected are intended to eval-uate the impact of common cause variability in operations on critical quality mon cause variability is defined as the expected level of variability experienced during normal unit operations in a manufacturing environment when executed according to the batch record instructions.The range of interest is determined from the current understanding of the at-scale control capability using a combination of operational variability,or the variance from target setpoints,and the measurement uncertainty of the device(s) that record the process measurement.Theoperationalvariabilityisameasureofperformancederived fromsampling unit operations in the clinical manufacturing or commercial manufacturing facilities.The range encompassing common cause variability is chosen so that the probability of the parameter values being within the range of the target setpoints±operational vari-ability is at least0.995(or99.5%).Generally,six times the operational variability is selectedtoensurethatthevaluesofagivenprocessparameterwillfallwithinthisrange irrespective of the underlying distribution[10].The measurement uncertainty characterizes the dispersion of the values that could be reasonably attributed to the measurement.The measurement uncertainty is designed to reduce the false acceptance rate and is selected to ensure95%of the recorded measurements fall within the desired range.The measurement uncer-tainty is derived from either the measurement system design specification or historic calibration performance[11].The summation of operational variability(containing99.5%of the observed values)and measurement uncertainty(containing95%of the recorded measure-ments)defines the recommended minimum range of interest used to characterize the process,as displayed in Fig.4.2.3.3Laboratory Scale Models for Process CharacterizationIn most scenarios,performing process characterization studies at the manufac-turing scale is not practically feasible due to the cost of operation,and limited availability of large-scale bioreactors.Therefore,laboratory scale models are usedto perform process characterization experiments that define acceptable process ranges and establish predictive relationships between the scale-independent pro-cess parameters and critical product quality attributes.This approach is in align-ment with ICH guidance [4];small–scale models can be developed and used to support process development studies.The development of a model should account for scale effects and be representative of the proposed commercial process.A scientifically justified model can enable a prediction of product quality,and can be used to support the extrapolation of operating conditions across multiple scales and equipment.The cell culture manufacturing process includes a series of shake flasks and conventional stirred-tank or disposable bioreactors to manufacture the unprocessed bulk drug substance.The culture expansion steps have a limited potential for impact on critical quality attributes due to negligible accumulation of product;therefore the focus of the scale-down model is typically on the production bio-reactor unit operation.The bioreactor configuration has five primary control loops intended to measure and control culture temperature,dissolved oxygen,culture pH,agitation rate,and vessel pressure by manipulating caustic and acidic pH control loops,air,oxygen,and carbon dioxide gas flow rates,vessel jacket heat exchanger,and the agitator drive.An example P&ID (piping and instrumentation diagram)is provided in Fig.5.The cell culture process parameters can be separated into two groups including scale-dependent and scale-independent parameters.The operating conditions for scale-independent parameters (i.e.,temperature,pH,dissolved oxygen concen-tration)are conserved across different scales.The scale-dependent parameters (i.e.,agitation rate,gas flow rates,nutrient addition volume)are adjusted to conform to the scaling strategy employed.The scale-dependent parameters included in a bioreactor system are driven by gas–liquid and liquid–liquid mixing with the associated mass and heat transport phenomena.Mixing systems do not scale proportionally in all dimensions;therefore a basis for scaling up mixing unit operations must be chosen by bal-ancing the characteristics that are important to the process under consideration.Scaling strategies are typically based on a combination of geometric similarity,kinematic similarity,dynamic similarity,and/or power per unit volume input.TargetVariability6σr 2σmu2σmu 6σrTypically two of the four methods are selected,allowing the other characteristics to change.Bioreactor unit operations used for mammalian cell culture processes are usually scaled up by conserving the power per unit volume with geometrically similar vessels.When scaling up on the basis of geometric similarity and constant power per unit volume,the relative agitator tip speed and the bulk mixing time increase.Increasing the agitator tip speed may increase the risk of shear damage to the cells;however,prior experiments have demonstrated that the risk of damage is minimal over the normal operating range of interest.Increasing the bulk mixing time will result in an increased risk of vessel heterogeneity which could affect the product’s critical quality attributes and process performance.Equipment design and addi-tional experiments should be considered if there is a high risk of vessel hetero-geneity affecting culture performance or critical quality attributes.In cell culture processes the proper scaling of gas flow rates to control dissolved carbon dioxide and dissolved oxygen levels is not trivial.As the process is scaled up,the mass transport of oxygen increases with vessel volume leading to a decreased volumetric flow rate of oxygen necessary to meet the culture demand.The resulting decrease in volumetric flow rate reduces the capability to remove carbon dioxide.An air balance is required in the sparger line to provide a sufficient volumetric flow for carbon dioxide removal.In addition,the medium chemistry and the profile of metabolic by-products (i.e.,lactate concentration)may lead to a feedforward control strategy based on the interaction between dissolvedoxygen Fig.5Example bioreactor piping and instrumentation diagramand pH control loops.In our system,the gas sparger configuration may be spec-ified so that the amount of gasflow needed to maintain the dissolved oxygen control is the amount of gas needed for carbon dioxide removal.The carbon dioxide management in the at-scale and intermediate-scale bioreactors may be determined through process models that simultaneously solve the chemistry equilibrium and mass transfer equations through the course of the run assuming that the oxygen uptake rate and significant metabolic by-products are defined by the process conditions.The models are used to define a target airflow rate that allows for carbon dioxide off-gassing.The interaction between multiple scale-dependent control loops presents additional challenges when scaling down cell culture processes to the laboratory bench scale.The power per unit volume is difficult to determine as the standard vessel geometry is modified to accommodate the reduced scale.In addition,the ratio between culture volume and surface area in contact with the head space increases,influencing the mass transfer rates for gases.As a result controlling the pCO2concentration at the laboratory scale is difficult to model.Additional experiments may be performed to understand the risks better that elevated carbon dioxide levels have on culture performance and/or product critical quality attributes.The capabilities of the laboratory scale models are monitored throughout the development lifecycle and the risk,whether the scale-down models are repre-sentative of at-scale processes,is analyzed as sufficient large-scale information becomes available.The laboratory-scale models are analyzed by comparing results between the scale-down and at-scale processes for outcomes including critical quality attributes,other product quality attributes,and process performance indicators.The scale comparison data for quality attributes are explored using statistical methods.The data from bioreactors run at process targets in the scale-down model (from process characterization and process design and definition studies)are compared to the data generated from at-scale clinical material manufacturing campaigns.An equivalence test(two-one-sided t test,TOST)with a predefined practical difference is used to test for equivalency between critical and other product quality attributes[12].A practical difference threshold should be sufficient to support the claims,or intended use of the scale-down model.Based on these criteria,the suitability of the scale-down model relative to the at-scale process can be assessed.The process performance indicators are also explored qualitatively by exam-ining the process trends over parisons are made relative to the direc-tionality and closeness of the time-series data.If the performance of the scale-down model is not equivalent,additional analysis should be performed to determine if the process characterization results are sufficient to construct an adequate control strategy.If not,additional work should be performed to develop a better model,or generate additional data to mitigate risks.。
翻译USP61
〈61〉MICROBIAL LIMIT TESTS微生物的限定测试This chapter provides tests for the estimation of the number of viable aerobic microorganisms present and for freedom from designated microbial species in pharmaceutical articles of all kinds, from raw materials to the finished forms. An automated method may be substituted for the tests presented here, provided it has been properly validated as giving equivalent or better results. In preparing for and in applying the tests, observe aseptic precautions in handling the specimens. Unless otherwise directed, where the procedure specifies simply ―incubate,‖hold the container in air that is thermostatically controlled at a temperature between 30and 35,for a period of 24to 48hours.The term ―growth‖ is used in a special sense herein, i. e. ,to designate the presence and presumed proliferation of viable microorganisms.这个篇章提供了目前的可行需氧的微生物的预计数量和不受影响的状态，从所有制药条款里指定的微生物类型，从原材料到毛坯。
stable diffusion prompt 提示词整理
stable diffusion prompt 提示词整理什么是稳定扩散？稳定扩散是一种经济学中的概念，它描述了一种理想的市场现象，其中产品、服务或创新以持续的、平稳的速度在市场上扩散。
这种扩散通常是为了满足消费者需求、提高市场份额或取得市场竞争优势。
在稳定扩散中，产品或服务的需求与供应保持平衡，并通过一系列的市场因素来推动扩散的持续增长。
稳定扩散的关键因素之一是市场需求。
产品或服务需要满足消费者的需求，并具备市场优势。
这可以是创新的技术、价格竞争力、品质保证或其他增加产品或服务价值的因素。
市场需求的稳定和增长是稳定扩散的基础，因为消费者只会购买符合他们需求的产品。
另一个关键因素是市场竞争。
市场竞争鼓励产品或服务提供者不断挖掘创新，以满足消费者的需求。
竞争促使企业不断改进产品或服务的质量、价格和特性，以获取市场优势并吸引更多消费者。
在稳定扩散中，产品或服务供应商必须不断适应市场需求和竞争环境，确保其产品或服务能够持续地满足消费者需求并保持竞争力。
市场营销策略也是稳定扩散成功的关键。
企业需要采取适当的市场营销策略，包括产品定位、推广、定价和分销等，以确保产品或服务能够顺利地扩散到目标市场。
例如，企业可以通过广告、促销和口碑营销等手段向消费者传递产品或服务的价值，并吸引更多消费者采购或使用。
稳定扩散还需要持续的市场监测和反馈。
企业应该关注市场的动态变化，包括竞争对手的行动、消费者需求的变化等。
通过市场监测，企业可以及时调整其产品或服务的策略和优化，以确保持续的扩散。
此外，消费者的反馈也是改进产品或服务的重要依据，企业应该积极倾听消费者的建议和意见，并进行相应的改进。
最后，稳定扩散需要企业具备一定的组织能力和资源。
企业需要拥有良好的管理体系，以确保生产、分销和服务等各个环节的协调和高效运作。
此外，企业还需要投入适当的人力、财力和技术资源，以支持稳定扩散的需求。
总而言之，稳定扩散是一种理想的市场现象，它描述了产品、服务或创新以持续的、平稳的速度在市场上扩散的情况。
招标文件敏感词汇英文
1. Confidential Information- Any information disclosed in this bidding document should be treated as confidential and not disclosed to any third party without the prior written consent of the bidding entity.2. Proprietary Rights- The bidding document and its contents are protected by intellectual property laws and are the proprietary property of the issuing entity.3. Non-Disclosure Agreement- Bidders are required to sign a Non-Disclosure Agreement (NDA) prior to accessing any confidential information contained in the bidding document.4. Solicitation- This document is a solicitation for bids and is not an invitation to negotiate.5. Invitation to Bid- This is an official invitation to all interested parties to submit bids in accordance with the terms and conditions set forth in this document.6. Bidding Requirements- Bidders must comply with all the requirements and conditions specified in this bidding document to be eligible for consideration.7. Bidder's Qualifications- Bidders must meet the specified qualifications, including but not limited to financial stability, technical expertise, and past performance.8. Exclusion Clause- Any bidder who has been disqualified or suspended fromparticipating in government procurement shall not be eligible to submit a bid.9. No Discrimination- The bidding process is open to all eligible bidders without discrimination on the basis of race, color, religion, sex, national origin, age, disability, or any other non-merit factor.10. Pre-Bid Conference- A pre-bid conference will be held to provide bidders with an opportunity to ask questions and clarify any aspects of the bidding document.11. Bidding Procedures- Bidders must follow the specific bidding procedures outlined in this document to ensure their bids are properly received and evaluated.12. Bid Submission- Bids must be submitted in the manner and format specified in the bidding document and must be received by the designated time and date.13. Bid Opening- The bid opening will be conducted in a public forum at the specified time and location.14. Bid Evaluation Criteria- The evaluation of bids will be based on the criteria outlined in the bidding document, which may include price, technical qualifications, and past performance.15. Bid Bond- Bidders may be required to submit a bid bond as a guarantee that they will be responsible for any damages resulting from their bid.16. Performance Bond- The successful bidder may be required to provide a performance bond to ensure the completion of the project in accordance with the terms of the contract.17. Liquidated Damages- The bidding document may include provisions for liquidated damages in the event of a bidder's failure to fulfill their obligations under the contract.18. Force Majeure- The bidding document may include clauses that excuse performance due to unforeseen events beyond the control of the parties involved.19. Change Orders- Any changes to the scope of work or terms of the contract must be documented in a change order and agreed upon by both parties.20. Warranty- The successful bidder shall warrant the quality and performance of the goods or services provided under the contract.21. Insurance Requirements- Bidders and the successful bidder may be required to maintain certain types of insurance throughout the duration of the project.22. Payment Terms- The bidding document will specify the payment terms and procedures for the successful bidder.23. Dispute Resolution- The bidding document may include a dispute resolution mechanism to address any disagreements that may arise during the performance of the contract.24. Compliance with Laws- Bidders and the successful bidder must comply with all applicable laws, regulations, and standards in the performance of the contract.25. Equal Opportunity Clause- The bidding document may include an equal opportunity clause to ensure that the contract does not discriminate against any group of people.26. Sustainability Requirements- The bidding document may include sustainability requirements that the bidder must meet in the execution of the project.27. Performance Review- The bidding document may outline the process for reviewing the performance of the successful bidder during the term of the contract.28. Acceptance of Terms- By submitting a bid, the bidder acknowledges and agrees to all the terms and conditions set forth in the bidding document.29. No Warranties- The issuing entity makes no warranties, express or implied, regarding the information contained in the bidding document.30. Last Date for Questions- Bidders must submit any questions regarding the bidding document by the specified date and time.31. Bid Cancellation- Bidders may cancel their bid at any time prior to the bid opening, but must notify the issuing entity in writing.32. Post-Bid Clarifications- The issuing entity reserves the right to request additional information or clarification from bidders after the bid opening.33. No Oral Modifications- No modifications to the bidding document or contract terms will be binding unless made in writing and signed by both parties.34. Contract Award- The contract will be awarded to the bidder whose bid is determined to be the most advantageous to the issuing entity, based on the evaluation criteria.35. No Return of Bids- Once a bid is submitted, it will not be returned to the bidder.36. Bidding Schedule- The bidding schedule, including deadlines for submission, review, and award, is outlined in the bidding document.37. Bid Security- Bidders may be required to provide security for their bid, such as a cash deposit or a bank guarantee.38. Bid Withdrawal- Bidders may withdraw their bid at any time prior to the bid opening, but must do so in writing.39. Technical Specifications- Detailed technical specifications are provided in the bidding document and must be met by the successful bidder.40. Quality Assurance- The successful bidder must implement a quality assurance program to ensure compliance with the specified standards.41. Environmental Considerations- The bidding document may include environmental considerations that the bidder must take into account during the project.42. Training and Development- The successful bidder may be required to provide training and development opportunities for their employees working on the project.43. Community Involvement- The bidding document may outline requirements for community involvement and social responsibility during the project.44. Intellectual Property Rights- The successful bidder may be required to transfer certain intellectual property rights to the issuing entity upon completion of the project.45. Endorsements- Bidders may be required to provide endorsements or certifications from relevant authorities or organizations.46. Review Period- The bidding document may specify a review period for the evaluation of bids.47. Feedback- Bidders may request feedback on their bids after the bid opening, but the issuing entity is not required to provide detailed feedback.48. Communication Protocol- The bidding document may outline the communication protocol to be followed by bidders and the issuing entity during the bidding process.49. Responsible Bidding- Bidders are expected to engage in responsible bidding practices and avoid any form of corruption or unethical behavior.50. Technical Evaluation Committee- The bidding document may describe the composition and role of the technical evaluation committee responsible for assessing bids.51. Award Criteria- The bidding document will clearly define the criteria used to determine the successful bidder.52. Appeal Process- Bidders may appeal the decision of the issuing entity regarding the award of the contract.53. Contract Execution- The successful bidder will be required to execute the contract within the specified timeframe.54. Performance Monitoring- The issuing entity may conduct periodic performance monitoring to ensure the contract is being fulfilled.55. Post-Contract Review- A post-contract review may be conducted to assess the overall performance of the successful bidder.56. Continuity of Services- The successful bidder must ensure the continuity of services throughout the duration of the contract.57. Subcontracting- The bidding document may include provisions regarding the subcontracting of work under the contract.58. Performance Milestones- Specific performance milestones may be established to track the progress of the project.59. Change in Ownership- Any change in ownership of the bidder must be reported to the issuing entity.60. Certificate of Insurance- Bidders must provide a certificate of insurance as evidence of compliance with insurance requirements.61. Regulatory Compliance- The successful bidder must comply with all relevant regulatory requirements throughout the project.62. Audit Rights- The issuing entity reserves the right to conduct audits to verify compliance with the contract terms.63. Exclusivity Clause- The bidding document may include an exclusivity clause that prevents the successful bidder from engaging in similar work for competitors.64. Termination Clause- The bidding document may outline the terms and conditions for terminating the contract.65. Dispute Resolution Mechanism- The bidding document may specify the dispute resolution mechanism to be used in the event of a disagreement.66. Fulfillment of Contract- The successful bidder must fulfill all obligations under the contract in accordance with the specified terms.67. Project Completion- The successful bidder will be responsible for the successful completion of the project within the agreed timeframe.68. Risk Management- The successful bidder must implement a risk management plan to address potential project risks.69. Transparency- The bidding process and contract execution must be transparent and open to scrutiny.70. Intellectual Property Protection- The successful bidder must protect any intellectual property developed during the project.71. Product Quality- The successful bidder must ensure the quality of the products or services provided under the contract.72. Customer Satisfaction- The successful bidder must strive to achieve customer satisfaction throughout the project.73. Training and Development- The successful bidder may be required to invest in the training and development of their workforce.74. Community Impact- The bidding document may include provisions to mitigate any negative impacts on the local community.75. Environmental Protection- The successful bidder must adhere to environmental protection standards throughout the project.76. Sustainability- The successful bidder must demonstrate a commitment to sustainability in their project execution.77. Continual Improvement- The successful bidder must continually improve their processes and practices to enhance project outcomes.78. Health and Safety- The successful bidder must prioritize health and safety on the project site.79. Fair Labor Practices- The bidding document may include requirements for fair labor practices.80. Project Management- The successful bidder must employ effective project management techniques to ensure project success.81. Innovation- The successful bidder is encouraged to introduce innovative solutions to improve project outcomes.82. Collaboration- The successful bidder must foster a collaborative environment with all stakeholders.83. Risk Sharing- The bidding document may include provisions for risk sharing between the bidder and the issuing entity.84. Post-Implementation Review- A post-implementation review may be conducted to assess the long-term impact of the project.85. Feedback Mechanism- The successful bidder must establish a feedback mechanism to receive input from stakeholders.86. Knowledge Transfer- The successful bidder may be required to transfer knowledge gained during the project to the issuing entity.87. Technology Transfer- The successful bidder may be required to transfer certain technologies to the issuing entity upon completion of the project.88. Intellectual Property Rights Assignment- The successful bidder may be required to assign certainintellectual property rights to the issuing entity.89. Confidentiality Agreement- The successful bidder may be required to enter into a confidentiality agreement with the issuing entity.90. Performance Evaluation- The successful bidder's performance will be evaluated periodically to ensure compliance with the contract.91. Continual Improvement Program- The successful bidder must implement a continual improvement program to enhance project performance.92. Project Monitoring and Control- The successful bidder must establish effective monitoring and control mechanisms to manage the project.93. Quality Assurance Plan- The successful bidder must develop and implement a quality assurance plan to ensure project quality.94. Health and Safety Plan- The successful bidder must develop and implement a health and safety plan to protect workers and the public.95. Environmental Management Plan- The successful bidder must develop and implement an environmental management plan to minimize environmental impact.96. Sustainability Plan- The successful bidder must develop and implement a sustainability plan to promote sustainable practices.97. Training and Development Plan- The successful bidder must develop and implement a training and development plan to enhance workforce capabilities.98. Community Impact Assessment- The successful bidder must conduct a community impact assessment to identify potential benefits and risks.99. Stakeholder Engagement Plan- The successful bidder must develop and implement a stakeholder engagement plan to involve all relevant parties.100. Risk Management Plan- The successful bidder must develop and implement a risk management plan to identify, assess, and mitigate project risks.101. Project Closure Plan- The successful bidder must develop and implement a project closure plan to ensure a smooth transition and handover.102. Feedback and Improvement Mechanism- The successful bidder must establish a feedback and improvement mechanism to continuously improve project outcomes.103. Performance Monitoring and Reporting- The successful bidder must monitor project performance and provide regular reports to the issuing entity.104. Compliance with Contract Terms- The successful bidder must ensure compliance with all contract terms and conditions throughout the project.105. Ethical Conduct- The successful bidder must conduct themselves ethically and in accordance with applicable laws and regulations.106. Conflict of Interest Policy- The successful bidder must comply with a conflict of interest policy to avoid any conflicts of interest.107. Equal Opportunity Policy- The successful bidder must comply with an equal opportunity policy to ensure non-discrimination.108. Whistleblower Policy。
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© Stefan Leue 2005
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Markov Chain Models
♦ Continuous Time
8 A continuous time Markov chain (CTMC) is a quintuple (S, s0, P, E, L), where – (S, s0, P, L) is a DTMC and – E : S → R>0 is a function assigning each state an exit rate, ie.g., E := {(s0, 3), (s1, 0), (s2, 5)} – exit rates are exponentially distributed 0
Outline
♦ Motivation ♦ Probability Measures for Optimizing Search ♦ Approximation based on Uniformisation ♦ Directed Probabilistic Reachability Analysis ♦ Case Study ♦ Conclusion and Outlook
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© Stefan Leue 2005
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Probabilistic Timed Reachability
♦ Property Violation
8 According to CSL semantics, validity of φ can be decided by comparing the probability bound p with cumulated reachability probability – probability measure of the (tree-shaped) infinite cylinder set containing all paths that reach ϕ-state within t time units – can be computed by transient analysis where all ϕ-states are made absorbing (CSL model checking à la Baier et al.)
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Property Specification
♦ Timed Pobabilistic Reachability
8 The probability to reach a state s violating a state proposition ϑ, i.e., satisfying ϕ := ¬ ϑ, within the time interval [0, t], does not exceed a probability p ∈ [0, 1]. 8 Specification using Continuous Stochastic Logic (CSL)
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Probabilistic Timed Reachability
♦ Search Algorithms
8 What do standard state space search algorithms deliver when applied to stochastic models? Path-length optimizing search (BFS, Best-First, A*) Depth-First Search (DFS) we want this!
© Stefan Leue 2005
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Markov Chain Models
♦ Discrete Time
8 A discrete time Markov chain (DTMC) is a quadruple (S, s0, P, L), where – S is a finite set of states, and – s0 ∈ S is an initial state – P : S × S → R is a probability matrix, satisfying that for each state, the sum of the probabilities of outgoing probabilistic transitions is 1. – L : S → 2AP is labeling function, which assigns each state the subset of valid atomic propositions. – i.e., a Kripke structure augmented with probabilistic information
♦ What constitutes a good counterexample?
8 In typical non-stochastic transition systems: – good = short
♦ How to obtain good (short) counterexamples?
8 Breadth-First Search (BFS). 8 Directed Explicit-State Model Checking (DESMC), uses heuristics guided search (e.g., Greedy BestFirst or A*).
Counterexamples for Timed Probabilistic Reachability
Stefan Leue
University of Konstanz Chair for Software Engineering Stefan.Leue@uni-konstanz.de http://www.inf.uni-konstanz.de/~soft 17 August 2005 SUNY Stony Brook Copyright © Stefan Leue 2005
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Joint work with...
♦ Husain Aljazzar
8 University of Konstanz
♦ Holger Hermanns
8 Saarland University
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© Stefan Leue 2005
♦ Approach
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Explicit-State Model Checking
♦ Explicit-State model checking (ESMC)
8 checks state properties by exploring the state space using graph search algorithms like DFS and BFS. 8 If an error is found, an offending system run is returned, which helps in explaining why the property is violated.
P<p : Transient probability does not exceed p. ♦· t : Timed reachability within [0, t]
♦ CSL Model Checking (according to Baier et al.)
8 recursively determines sets of states satisfying CSL subformulae 8 efficient and numerically stable 8 based on uniformisation 8 Weakness: – CSL model checking (like many other stochastic model checking approaches) do not return "counterexamples" iproblematic for system debugging 8 state space search on the CTMC to find offending system runs
3 5
♦ Probabilities in DTMCs and CTMCs
8 steady-state probabilities: – system is considered "in the long run", i.e., when equilibrum has been reached 8 transient-state probabilities: – system is considered at a given time instant t
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8 Need search algorithms that optimize (maximize) probability mass along single paths.
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© Stefan Leue 2Why Stochastic Model Checking?
8 Stochastic models are widely used to model and analyze system performance and dependability. – communication protocols, embedded systems, etc. 8 Various model checking approaches for stochastic models have been presented. 8 Our point of reference: CSL Model checking – Baier, C., Haverkort, B., Hermanns, H., Katoen, J.P.: ModelChecking Algorithms for Continuous-Time Markov chains. IEEE Transitions on Software Engineering 29, 2003 iContinuous Stochastic Logic (CSL) for expressing real-time probabilistic properties of Continuous Time Markov Chains (CTMCs) has been proposed. * Probabilitstic, timed extension of CTL. iEfficient approximative algorithms to model check CSL formulae have been developed (e.g., by the above authors).