化学反应放大中的安全事项
英国皇家化学学会 环境、健康和安全委员会(EHSC)
英国皇家化学学会收到的诸多询问表明，有必要对有关化学反应从实验室到满负荷的商业化生产的安全事项提供一些指南。（英国皇家化学）学会相信，化学家应当对与反应放大有关的安全问题了如指掌、并且应当参与到放大的过程中，以确保有关人员的健康和安全。
本文是为了给那些在有责任将化学反应放大到大生产的实验室中的雇员和管理者提供指南。因此，假设他们理解诸如“风险”和“危害”等基础词汇的含义。本文的目的并不是提供全面的或是标准的指南。希望读者在需要时，去获取更为详细的信息及/或专家的建议。
EHSC 衷心希望收到您有关本文的反馈。您的意见和建议可以发给委员会的秘书，联系方式在本文的最后一页。
1. 简介
在每年报告给HSE 的化学事故（即根据《伤害、疾病与危险事件法规》、又称RIDDOR ，所定义的“危险事件”）中，有20-30起放热反应失控。或许还有没有报告的、以及不符合法律定义的“危险事件”。其中很多可能都是由于放大过程程序不当导致的。
化学反应通常是从小规模的实验室反应做起，然后逐步地通过更大规模的研发，直至转移到商业化生产设备中。在工艺研发的早期阶段使用的化学品的量有限，有关反应（和副反应）的信息通常不全面。通过风险评估和放大程序，可以获取与最终工艺设计有关的信息。
放大程序的失误，以及未采取合适的预防措施会导致工艺失控，然后就会发生放热反应失控、及/或有害物质的生成或泄漏。过去有很多这样的例子，造成了众多的人员伤亡、严重的财产损失、环境危害以及商业损失。
其他由于放大程序不当导致的问题有：
- 由于反应物和溶剂处理不当导致容器内粉尘和蒸汽爆炸； - 容器溢出导致火灾；
- 未能正确地评估危险区域的电器设备的要求，留下可能的火源； - 可燃性蒸汽的自燃，通常发生闪燃；
放大程序的第一也是最关键的步骤，是在概念阶段对所建议的化学反应进行风险评估。
2. 反应风险的评估
对所有新的和变更过的反应的风险评估都应当记录，并且在适当情况下，考虑如下因素：
- 反应物、中间体、产品和废弃物的理化性质；
- 在反应偏离设计参数的情况下，发生有害反应的可能性； - 所用的原料对设备的腐蚀的可能性；
- 火灾和爆炸的风险；
- 与《危害健康物质管制法规》(COSHH) 有关的危害健康的物质评估，以及人员保护设施 (PPE) 评估；
- 主反应和可能的副反应的热化学特性，尤其是放热率；
- 气体产生的速率和容器过压的可能性；
- 放大问题（见下）
- 设备设计特点，包括控制系统，服务需求（如冷却水，惰性气体）以及诸如减压阀、爆破片和通气等等安全设施的适合性和可靠性； - 危害鉴别方法的应用，比如“如果... 应该怎么作”，风险和可操作性研究 (HAZOPS) ，以及定量的风险评估手段；
- 环境影响；
- 新的或变更过的工艺规程；以及
- 操作人员的培训需求；
风险评估的第一阶段是收集数据。可以查找所设计的反应的风险，并且可能的话进行热化学计算。此时应考虑的是反应物的反应基团，并且对同族的反应和反应物进行比较。参考书目中所列的书籍有助于查找这些信息。
对于可能发生放热反应、尤其是反应失控的，在初期就对设计的反应进行热化学分析是非常重要的。现在，对于所有新的反应都要进行行热化学分析。在热化学分析过程中，有很多量热技术可以使用。例如差示扫描量热仪 (Differential scanning calorimetry) 和Carius 管 (Carius Tube)可以用来进行基本的热稳定性测试；恒温量热仪 (Isothermal calorimetry) 主要用来测量反应热和反应动力学；绝热量热仪
(Adiabatic calorimetry) 可以用来检测反应失控的可能性；还可以进行减压通气口尺寸测试 (relief vent sizing test) 等等。
风险评估应当本着消除、减少和控制的原则获取结果。如果所设计的反应的风险不可接受，那么应当考虑其他的合成路线，可能的话采用固有的更安全的方法 (inherently safer methods) 。否则（如果反应一定要这样进行），风险评估应当明确在放大过程的每一阶段用以确保安全操作的控制措施和安全措施。
3. 放大程序
大生产的设计可以通过从实验室的生产到中试生产的放大过程实现。在某些情况下，可以通过多个不断放大的中试设备达到最佳的大生产设计。风险评估也是随着放大逐步前进的。在放大过程中的每一阶段，都应当检查生成的信息，进行风险评估，以决定是否应当进行到下一步。如果决定继续进行，应当明确控制条件和操作条件。
一种化学反应的速度在特定的温度条件下是固定的。但是，反应温度会受到质热传递的影响，后者又受到反应釜的设计和大小的影响。对这些因素进行定量的评估经常是不可能的，一般在目标设备中用水或惰性原料进行试验。如果这样的方法也不行，就要安装反应釜量热仪。
在试管和小烧瓶等等反应仪器中进行的实验生产出了目标分子或产品，但不一定体现出反应的负面信息 -- 比如副产品、有毒或可燃的气体或蒸汽。反应释放的热量可能为仪器或周围环境所吸收而不被注意。原料可能是高纯度的化学品、而非可能含有杂质的工业原料。因此为了克服这一问题，在放大过程中所使用的设备、原料和材料应与大生产的一致，这一点非常关键。在实验室里，反应通常在玻璃仪器中进行。而在放大过程中，工艺可能在其他材质的系统中进行。对某些反应，这一变更很重要，可能会导致意想不到的反应或问题，包括催化或抑制效应。
随着规模的增大，每一步反应所需的时间可能也会增加。要为此留出适当的余地。
中试设备是为了帮助工艺设计放大，而不是用来帮助设计反应机理。它为设计的经济性、操作参数和安全因素提供信息。此外中试设备还可以用来为评估和试销做小规模的生产。应该从中试研究得出信息，用以支持风险评估后关于如下因素的结论：
- 操作条件；
- 设计参数；
- 反应釜、设计和材质；
- 单元反应；
- 材料处理和取样；
- 相的问题；
- 杂质；
- 腐蚀；
- 阻塞；
- 检测；
- 操作程序；
- 工作环境；
- 废物处理和影响
化工品中的杂质可能会导致很多问题。这些问题可以在中试研究阶段找出来。杂质可以是在原料中，或者由于副反应、分解或是聚合等等形成。这些都可能产生意外的结果。系统的渗漏可能会让泵油、密封油或是包括水在内的热交换媒介等无用的东西进入（到反应中）。这些会妨碍反应进行，还会导致其他的问题。有些杂质会催化不受欢迎的爆炸反应、或许它们本身的热稳定性就不好。
中试研究还会揭露腐蚀的问题，这可能与反应的杂质或者是一些次要的部件 - 如垫圈和隔膜有关联。
在大小不同的设备中放大，反应的结果会有变化。很明显，使用完全相同的原料和操作条件，在同一个反应釜中进行的反应将生产出差异极其微小的产品。这一点在发酵过程最为明显。
中试设备应该由有技术资质的、经过适当培训的人员来操作。中试生产中其他未知和未预见到的危险可以通过操作人员的更好的操作和技术控
制所解决。但是必须记住，无论反应釜大小，中试设备发生事故也可能造成严重的后果。
因此，化学反应放大的正确完成是非常重要的。进而才能实现安全地在大生产设备中满负荷生产。
4. 安全操作
从工艺风险评估和放大研究中所得的信息，使我们能决定确保安全操作的工艺控制条件。实现安全操作的主要选择有：
固有的更安全的方法 (inherently safer methods)，使用危害性较低的材料或者其他反应路线来消除或减少有害物质；
预防措施，例如使用传感器，转移，（温度、压力、搅拌、冷却水失效）报警等等过程，以及其他可以激发自动补救措施的控制系统；
保护措施，例如减压阀、爆破片和通气，反应抑制，破碎降温，排空或终止，或者是二次保护以降低反应失控的后果；
对于控制和保护措施，没有万能钥匙式的方案。无论选择哪种方法，都要考虑到最坏的情况，并在尽可能的情况下减少风险。
选择的方案也必须有合适的职业健康和安全管理系统 (occupational health and safety management system) 的支持。职业健康安全和管理系统包括操作程序，操作人员的培训和监督以及人员的维护，厂房和设备的维护，设备变更的控制，软件以及紧急情况下的操作程序。在风险评估人员、设备工艺人员以及维护保养人员之间的良好的沟通和配合是非常重要的，只有这样才能使得每一个相关人员充分掌握操作参数和工艺设备的限度。
当工艺进行到大规模操作阶段，遵守操作参数和程序是很重要的。如果原材料有任何变更或偏差，就要进一步进行风险评估。
5. 结论
从实验室工艺放大到满负荷大生产设备的过程，必须对所有新型的和变更过的反应进行充分和适当的风险评估。需要有合适的工艺控制和保护措施，以降低放热反应失控的风险、并且/或者把产生和释放有毒物质的风险降到尽可能低的水平。这不仅仅是为了确保满足法律的要求，更为了避免因化学反应失控导致的生产中断、成本增加、人身伤害和其他可能的损失。
6. 参考书目 （略）
VERSION 1/3/99
ENVIRONMENT, HEALTH AND SAFETY COMMITTEE
NOTE ONSAFETY ISSUES IN THE SCALE UP OF
CHEMICAL REACTIONS
Enquiries received by the Royal Society of Chemistry indicate that there is a need toprovide some basic guidance on safety issues raised by the scale up of chemicalreactions from laboratory scale to full sized commercial plant. The Society believesthat chemists should be fully aware of the safety problems associated with the scaleup of chemical processes and should contribute to the scale up procedure in order toensure the health and safety of all persons involved.
This Note is designed to provide guidance to members who either manage
laboratories or are employed in laboratories where the scale up of chemical reactionsis undertaken. Therefore it assumes familiarity with basic terms such as ‘risk’ and ‘hazard’. The Note is not intended to be a full or definitive guide and readers areurged to obtain more detailed information and/or expert advice if this is required.The Note was prepared by a Working Party of the Environment, Health and SafetyCommittee (EHSC) of the Royal Society of Chemistry. The Society is a registeredCharity. Its Royal Charter obliges it to serve the public interest by acting in anindependent advisory capacity. In order to meet this obligation the members of theEHSC are drawn from a wide range of backgrounds and serve on the committee asindividual experts and not as representatives of their employers.The EHSC is eager to receive feedback on this Note. Comments can be sent to the
Committee Secretary whose details are given on the last page.
1. INTRODUCTION
Of the chemical incidents reported to HSE each year as dangerous occurrencesunder RIDDOR some 20 to 30 are exothermic runaways. There may be otherchemical incidents which are either not reported or which do not fit the legal
Chemical processes usually originate on a small scale in the laboratory andtheir development is normally carried out by conducting the reactions onsuccessively larger scale before transferring to full size production plant. Inthe early stages of process development limited quantities of chemicals areused and full information about the reaction or side reactions is not usuallyavailable. Risk assessment studies and the scale up procedure enable furtherinformation to be obtained which is relevant to the final process plant design.Failure to scale up properly and to take appropriate precautions may lead tothe loss of process control which in turn may result in a runaway exothermicreaction and /or the generation or release of toxic materials. There have been anumber of such failures in the past which have led to multiple fatalities, severedamage to property, environmental damage and business loss.
Other problems which have arisen from inadequate scale up proceduresinclude for example :
• dust and vapour explosions inside vessels due to the mishandling of reactantsand solvents
• fires due to overfilling of vessels
• failure to correctly assess electrical equipment for use in hazardous areasidentifying all possible sources of ignition
• autoignition of flammable vapours, usually resulting in a flash fire.
The first and most critical step in the scale up procedure is to undertake a riskassessment of the proposed chemical process at the concept stage. Where
appropriate this should include a study of the thermochemistry of the proposedreaction.
2. ASSESSMENT OF REACTION HAZARDS
The risk assessment undertaken on all new or modified reactions should berecorded and should involve the consideration, where appropriate, of thefollowing:
• the physical and chemical properties of the reactants, intermediates,products and wastes
• the possibility of hazardous reactions if there are deviations from setparameters
• the potential for the substances in use to corrode plant
• the fire and explosion hazards
• the health hazards and associated COSHH and Personal ProtectiveEquipment (PPE) assessments
• the thermochemistry of both of the desired and potential undesiredreactions, in particular the rate of heat output
• the rate of gas generation and the potential for vessel over-pressurisation• scale-up problems (see below)
• plant design characteristics, including control systems, service needs (egcooling water, inert gas) and the adequacy and reliability of safety devicessuch as pressure relief valves, bursting discs, vents, etc
• the application of hazard identification methods, such as ‘What If’studies, Hazard and Operability Studies (HAZOPS) and quantified risk assessmenttechniques;
• environmental effects;
• new or modified process instructions; and
• the training needs of operators.
The first stage in the risk assessment is data collection. This will enable
desktop screening of the hazards of the proposed reaction to be undertaken andif possible thermochemical calculations to be carried out. In this exerciseconsideration should be given to the reactive group(s) of the reactants andcomparisons should be made with analogous substances or reactions. Anumber of publications are cited in the Bibliography which may be useful inthis desktop screening exercise.
Where there is potential for an exothermic reaction, particularly a runawayreaction, it is essential that a study of the thermochemistry of the proposedreaction is undertaken at an early stage. It is current best practice to subject allnew processes to thermochemical investigations. Various calorimetrictechniques are available which can be used in such a study. For exampledifferential scanning calorimetry or Carius tube studies can be used for basicthermal stability screening tests. Isothermal calorimetry can be used mainly tomeasure reaction kinetics and heats of reaction. Adiabatic calorimetry can beused to examine the potential for runaways. Relief vent sizing tests can also becarried out.
As a result of the risk assessment the principles of elimination, reduction andcontrol should be applied. If the risks associated with the proposed reaction areunacceptable then an alternative route to the product should be considered, ifpossible using inherently safer methods. If however the reaction is to proceedthe risk assessment should specify the control measures and safety procedureswhich should be adopted to ensure the safe operation at all stages of the scale-up process.
3. SCALE-UP PROCEDURE
The design of a commercial plant can be accomplished by scaling up fromlaboratory equipment using pilot plant. In some cases several pilot plants ofincreasing size may be used to effect the best design for the larger plant. Riskassessment is an evolving process as scale-up progresses. At each stage of the
scale up procedure the information generated should be used to review the riskassessment to enable a decision to be made as to whether or not to proceed tothe next stage. If the process is to proceed the risk assessment should specifythe controls and operating conditions required.
The rate of a chemical reaction is fixed at any given temperature but
temperature may be influenced by mass transfer and heat transfer, which are inturn affected by the size and design of the reactor. It is not always possible totheoretically assess these effects on a quantitative basis and in such cases it isusual to carry out trials with water or inert substances in the intended plant. Ifthis is not feasible purpose built reactor calorimeters will be required.
Laboratory experiments, carried out in test tubes, small flasks etc., produce arequired chemical or product but do not necessarily indicate side effects of thereaction, i.e. by-products, release of gases or vapours which may be toxic orflammable. Heat releases may be absorbed by the equipment or surroundingsand not noticed. The chemicals used may be pure materials rather than bulkcommercial chemicals, which may contain traces of impurities. Therefore inorder to overcome this problem it is essential that the apparatus, materials andchemicals used at all stages of the scale up accurately reflect those that will beused in the final plant. In the laboratory reactions are usually carried out inglass vessels but the scaled up process may well be carried out in containersmade of other materials. With some reactions such changes may be importantand could result in unexpected reactions or problems including catalytic orinhibition effects.
As scale increases the time required to carry out each operation is also likelyto increase and appropriate allowance should be made for this.
Pilot plant is used to assist in the scale up of the chemical process designrather than the mechanical design. It provides information for economicdesign, operating parameters, and safety considerations. In addition pilot
plants can be used in small scale production for evaluation and trial marketing.Information should be obtained from pilot plant studies to confirm thedecisions made as a result of the risk assessment stage in relation to :• operating conditions;
• design parameters;
• reactor problems, design, materials of construction;
• unit operations problems;
• materials handing and sampling problems;
• thermal instability and other decomposition;
• Phase problems;
• impurities;
• corrosion;
• fouling;
• analytical problems;
• operating procedures;
• working and environment problems; and
• effluent and waste disposal problems.
Impurities in the chemicals used can cause many problems which can be
identified in pilot plant studies. Impurities can occur in the feedstock or arise
from side reactions, decompositions, polymerisations, etc. which can cause
unexpected effects. Leaks into the system may bring in unwanted materials
such as pump lubricant, seal fluids or heat transfer media, including water.
These may lead to blockages and other problems. Some impurities can
catalyse undesirable explosive reactions or may be thermally unstable
themselves.
Pilot plant studies can reveal corrosion problems. These can be associated with
minor components such as gaskets and diaphragms or with impurities in the
reactants.
Scaling up in various size plants can produce variations in reactions, and
apparently identical reactors can give slightly different products with
apparently the same feed materials and operating conditions. This is most
marked in fermentation processes.
Pilot plants should be operated by technically qualified and appropriately
trained competent personnel. The extra unknown or unforeseen hazards
associated with pilot plant should be compensated for by better
instrumentation and technical control by the operators. It must be
remembered, however, that accidents on pilot plant despite their size can still
have serious consequences.
It is important, therefore, that scale-up of chemical reactions is done correctly
so that the eventual reactions can be carried out safely in full size production
plant.
4. SAFE OPERATION
Information obtained from the risk assessment of the chemical process and the
scale-up studies will enable decisions to be made on the most appropriate
controls to ensure a safe operation. The main options which could be
considered for a safe operation are:
• inherently safer methods which use less hazardous materials or alternativereaction routes to eliminate or reduce hazards;
• preventative measures such as process controls using sensors, trips, alarms(temperature, pressure, stirrer, cooling water failure) and other control
systems which initiate automatic remedial action; and
• protective measures such as pressure relief valves, vents, reactioninhibition, crash cooling, drown out/quenching or secondary containment
which will limit the consequences of a runaway reaction.
There is no single best option for controls and protective measures that can be
applied in all cases. Whichever option is chosen it must cater for the worst
credible scenario and reduce the risk as far as is reasonably practicable.
The option chosen must also be supported by appropriate occupational health
and safety management systems which cover operating procedures, the
training and supervision of operators and maintenance personnel, the
maintenance of plant and equipment, the control of plant modifications,
software and emergency procedures. It is essential that there is good
communication and co-operation between the risk assessment team, the
process plant team and maintenance personnel so that everyone concerned is
fully aware of the operating parameters and limitations of the process plant.
Once the process is operational it is important to adhere to the agreed
operating parameters and procedures. If there is to be any deviation or change
in raw materials, further risk assessments should be undertaken.
5. CONCLUSION
It is essential that suitable and sufficient risk assessments are undertaken of all
new and modified reactions during the scale-up of laboratory processes to full
sized commercial plant. Appropriate process controls and protective measures
are needed to reduce the risk of a runaway exothermic reaction and/or the
generation or release of toxic materials to a level which is as low as reasonably
practicable. This not only ensures that legal requirements are complied with
but also avoids the disruption, cost, potential damage and injuries that can be
caused by the loss of control of chemical reactions.
6. BIBLIOGRAPHY
• Royal Society of Chemistry, “EHSC Note on Individual LegalResponsibility for Health and Safety”, 1995.
• Royal Society of Chemistry, “EHSC Note on Risk Assessment at Work”,
1997.
• Health and Safety Executive [HSE] leaflet IND(G)254 “Chemical
Reaction and the Risk of Thermal Runaway”.
• Association of the British Pharmaceutical Industry [ABPI] “Guidelines forChemical Reaction Hazard Evaluation”, 2nd Edition.
• J G Lowenstein “The Pilot Plant”, Chemical Engineering, Dec 9/23, 1985
pp 62-76.
• HSE/Institution of Chemical Engineers [IChemE] video “Control ofExothermic Chemical Reactions”.
• IChemE “Chemical Reaction Hazards – a guide to safety”, Ed J Barton
and R Rogers, 2nd Edition 1998.
• “Bretherick’s Handbook of Reactive Chemical Hazards”, 5th Edition, Ed.
Urben, Butterworth Heinemann, 1995
• National Fire Protection Association “Manual of Hazardous Chemical
Reactions”, 4th Edition, 1971.
• A Starkie and S Rowe ‘Taking the heat’, ‘Chemistry in Britain’, February1996.
• 'Pilot Plants and Scale-Up of Chemical Processes II', Ed. W. Hoyle, RSC,
March 1999.This Note was prepared by a Working Party of the RSC Environment, Health and Safety Committee [EHSC].The members of the Working Party were :
Mr G J DickesMr T G R Farthing
Mr R W Hazell [Secretary]
Dr G V MacHattie [Co-chairman]
Dr R Owen
Mr D M Sanderson
Dr I Wrightson [Co-chairman]
The Working Party gratefully acknowledges the assistance of the following individuals and organisations inthe preparation of this Note, though of course the views expressed remain the responsibility of the RSC :• The Health and Safety Executive (HSE)
• Dr J Bickerton
• Mr K D Jackson
• Dr J D Jones
• Mr P G Lambert
• Dr I M McRobbie
• Dr A J Starkie
• Dr W Hoyle
This Note is also available on the RSC website http://www.rsc.org
The Environment, Health and Safety Committee welcomes comments on this Note. Comments shouldbe sent to the Committee Secretary:
Mr R W Hazell
Health, Safety and Environment Officer
The Royal Society of Chemistry
Burlington House
Piccadilly
London W1V 0BN
• Direct Tel : 0171 440 3337
• Switchboard : 0171 437 8656
• Fax : 0171 437 8883
• E-mail : [email protected]
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1 l:\ehscnote\Scale up of Chemical Reactions 1 March 99
化学反应放大中的安全事项
英国皇家化学学会 环境、健康和安全委员会(EHSC)
英国皇家化学学会收到的诸多询问表明，有必要对有关化学反应从实验室到满负荷的商业化生产的安全事项提供一些指南。（英国皇家化学）学会相信，化学家应当对与反应放大有关的安全问题了如指掌、并且应当参与到放大的过程中，以确保有关人员的健康和安全。
本文是为了给那些在有责任将化学反应放大到大生产的实验室中的雇员和管理者提供指南。因此，假设他们理解诸如“风险”和“危害”等基础词汇的含义。本文的目的并不是提供全面的或是标准的指南。希望读者在需要时，去获取更为详细的信息及/或专家的建议。
EHSC 衷心希望收到您有关本文的反馈。您的意见和建议可以发给委员会的秘书，联系方式在本文的最后一页。
1. 简介
在每年报告给HSE 的化学事故（即根据《伤害、疾病与危险事件法规》、又称RIDDOR ，所定义的“危险事件”）中，有20-30起放热反应失控。或许还有没有报告的、以及不符合法律定义的“危险事件”。其中很多可能都是由于放大过程程序不当导致的。
化学反应通常是从小规模的实验室反应做起，然后逐步地通过更大规模的研发，直至转移到商业化生产设备中。在工艺研发的早期阶段使用的化学品的量有限，有关反应（和副反应）的信息通常不全面。通过风险评估和放大程序，可以获取与最终工艺设计有关的信息。
放大程序的失误，以及未采取合适的预防措施会导致工艺失控，然后就会发生放热反应失控、及/或有害物质的生成或泄漏。过去有很多这样的例子，造成了众多的人员伤亡、严重的财产损失、环境危害以及商业损失。
其他由于放大程序不当导致的问题有：
- 由于反应物和溶剂处理不当导致容器内粉尘和蒸汽爆炸； - 容器溢出导致火灾；
- 未能正确地评估危险区域的电器设备的要求，留下可能的火源； - 可燃性蒸汽的自燃，通常发生闪燃；
放大程序的第一也是最关键的步骤，是在概念阶段对所建议的化学反应进行风险评估。
2. 反应风险的评估
对所有新的和变更过的反应的风险评估都应当记录，并且在适当情况下，考虑如下因素：
- 反应物、中间体、产品和废弃物的理化性质；
- 在反应偏离设计参数的情况下，发生有害反应的可能性； - 所用的原料对设备的腐蚀的可能性；
- 火灾和爆炸的风险；
- 与《危害健康物质管制法规》(COSHH) 有关的危害健康的物质评估，以及人员保护设施 (PPE) 评估；
- 主反应和可能的副反应的热化学特性，尤其是放热率；
- 气体产生的速率和容器过压的可能性；
- 放大问题（见下）
- 设备设计特点，包括控制系统，服务需求（如冷却水，惰性气体）以及诸如减压阀、爆破片和通气等等安全设施的适合性和可靠性； - 危害鉴别方法的应用，比如“如果... 应该怎么作”，风险和可操作性研究 (HAZOPS) ，以及定量的风险评估手段；
- 环境影响；
- 新的或变更过的工艺规程；以及
- 操作人员的培训需求；
风险评估的第一阶段是收集数据。可以查找所设计的反应的风险，并且可能的话进行热化学计算。此时应考虑的是反应物的反应基团，并且对同族的反应和反应物进行比较。参考书目中所列的书籍有助于查找这些信息。
对于可能发生放热反应、尤其是反应失控的，在初期就对设计的反应进行热化学分析是非常重要的。现在，对于所有新的反应都要进行行热化学分析。在热化学分析过程中，有很多量热技术可以使用。例如差示扫描量热仪 (Differential scanning calorimetry) 和Carius 管 (Carius Tube)可以用来进行基本的热稳定性测试；恒温量热仪 (Isothermal calorimetry) 主要用来测量反应热和反应动力学；绝热量热仪
(Adiabatic calorimetry) 可以用来检测反应失控的可能性；还可以进行减压通气口尺寸测试 (relief vent sizing test) 等等。
风险评估应当本着消除、减少和控制的原则获取结果。如果所设计的反应的风险不可接受，那么应当考虑其他的合成路线，可能的话采用固有的更安全的方法 (inherently safer methods) 。否则（如果反应一定要这样进行），风险评估应当明确在放大过程的每一阶段用以确保安全操作的控制措施和安全措施。
3. 放大程序
大生产的设计可以通过从实验室的生产到中试生产的放大过程实现。在某些情况下，可以通过多个不断放大的中试设备达到最佳的大生产设计。风险评估也是随着放大逐步前进的。在放大过程中的每一阶段，都应当检查生成的信息，进行风险评估，以决定是否应当进行到下一步。如果决定继续进行，应当明确控制条件和操作条件。
一种化学反应的速度在特定的温度条件下是固定的。但是，反应温度会受到质热传递的影响，后者又受到反应釜的设计和大小的影响。对这些因素进行定量的评估经常是不可能的，一般在目标设备中用水或惰性原料进行试验。如果这样的方法也不行，就要安装反应釜量热仪。
在试管和小烧瓶等等反应仪器中进行的实验生产出了目标分子或产品，但不一定体现出反应的负面信息 -- 比如副产品、有毒或可燃的气体或蒸汽。反应释放的热量可能为仪器或周围环境所吸收而不被注意。原料可能是高纯度的化学品、而非可能含有杂质的工业原料。因此为了克服这一问题，在放大过程中所使用的设备、原料和材料应与大生产的一致，这一点非常关键。在实验室里，反应通常在玻璃仪器中进行。而在放大过程中，工艺可能在其他材质的系统中进行。对某些反应，这一变更很重要，可能会导致意想不到的反应或问题，包括催化或抑制效应。
随着规模的增大，每一步反应所需的时间可能也会增加。要为此留出适当的余地。
中试设备是为了帮助工艺设计放大，而不是用来帮助设计反应机理。它为设计的经济性、操作参数和安全因素提供信息。此外中试设备还可以用来为评估和试销做小规模的生产。应该从中试研究得出信息，用以支持风险评估后关于如下因素的结论：
- 操作条件；
- 设计参数；
- 反应釜、设计和材质；
- 单元反应；
- 材料处理和取样；
- 相的问题；
- 杂质；
- 腐蚀；
- 阻塞；
- 检测；
- 操作程序；
- 工作环境；
- 废物处理和影响
化工品中的杂质可能会导致很多问题。这些问题可以在中试研究阶段找出来。杂质可以是在原料中，或者由于副反应、分解或是聚合等等形成。这些都可能产生意外的结果。系统的渗漏可能会让泵油、密封油或是包括水在内的热交换媒介等无用的东西进入（到反应中）。这些会妨碍反应进行，还会导致其他的问题。有些杂质会催化不受欢迎的爆炸反应、或许它们本身的热稳定性就不好。
中试研究还会揭露腐蚀的问题，这可能与反应的杂质或者是一些次要的部件 - 如垫圈和隔膜有关联。
在大小不同的设备中放大，反应的结果会有变化。很明显，使用完全相同的原料和操作条件，在同一个反应釜中进行的反应将生产出差异极其微小的产品。这一点在发酵过程最为明显。
中试设备应该由有技术资质的、经过适当培训的人员来操作。中试生产中其他未知和未预见到的危险可以通过操作人员的更好的操作和技术控
制所解决。但是必须记住，无论反应釜大小，中试设备发生事故也可能造成严重的后果。
因此，化学反应放大的正确完成是非常重要的。进而才能实现安全地在大生产设备中满负荷生产。
4. 安全操作
从工艺风险评估和放大研究中所得的信息，使我们能决定确保安全操作的工艺控制条件。实现安全操作的主要选择有：
固有的更安全的方法 (inherently safer methods)，使用危害性较低的材料或者其他反应路线来消除或减少有害物质；
预防措施，例如使用传感器，转移，（温度、压力、搅拌、冷却水失效）报警等等过程，以及其他可以激发自动补救措施的控制系统；
保护措施，例如减压阀、爆破片和通气，反应抑制，破碎降温，排空或终止，或者是二次保护以降低反应失控的后果；
对于控制和保护措施，没有万能钥匙式的方案。无论选择哪种方法，都要考虑到最坏的情况，并在尽可能的情况下减少风险。
选择的方案也必须有合适的职业健康和安全管理系统 (occupational health and safety management system) 的支持。职业健康安全和管理系统包括操作程序，操作人员的培训和监督以及人员的维护，厂房和设备的维护，设备变更的控制，软件以及紧急情况下的操作程序。在风险评估人员、设备工艺人员以及维护保养人员之间的良好的沟通和配合是非常重要的，只有这样才能使得每一个相关人员充分掌握操作参数和工艺设备的限度。
当工艺进行到大规模操作阶段，遵守操作参数和程序是很重要的。如果原材料有任何变更或偏差，就要进一步进行风险评估。
5. 结论
从实验室工艺放大到满负荷大生产设备的过程，必须对所有新型的和变更过的反应进行充分和适当的风险评估。需要有合适的工艺控制和保护措施，以降低放热反应失控的风险、并且/或者把产生和释放有毒物质的风险降到尽可能低的水平。这不仅仅是为了确保满足法律的要求，更为了避免因化学反应失控导致的生产中断、成本增加、人身伤害和其他可能的损失。
6. 参考书目 （略）
VERSION 1/3/99
ENVIRONMENT, HEALTH AND SAFETY COMMITTEE
NOTE ONSAFETY ISSUES IN THE SCALE UP OF
CHEMICAL REACTIONS
Enquiries received by the Royal Society of Chemistry indicate that there is a need toprovide some basic guidance on safety issues raised by the scale up of chemicalreactions from laboratory scale to full sized commercial plant. The Society believesthat chemists should be fully aware of the safety problems associated with the scaleup of chemical processes and should contribute to the scale up procedure in order toensure the health and safety of all persons involved.
This Note is designed to provide guidance to members who either manage
laboratories or are employed in laboratories where the scale up of chemical reactionsis undertaken. Therefore it assumes familiarity with basic terms such as ‘risk’ and ‘hazard’. The Note is not intended to be a full or definitive guide and readers areurged to obtain more detailed information and/or expert advice if this is required.The Note was prepared by a Working Party of the Environment, Health and SafetyCommittee (EHSC) of the Royal Society of Chemistry. The Society is a registeredCharity. Its Royal Charter obliges it to serve the public interest by acting in anindependent advisory capacity. In order to meet this obligation the members of theEHSC are drawn from a wide range of backgrounds and serve on the committee asindividual experts and not as representatives of their employers.The EHSC is eager to receive feedback on this Note. Comments can be sent to the
Committee Secretary whose details are given on the last page.
1. INTRODUCTION
Of the chemical incidents reported to HSE each year as dangerous occurrencesunder RIDDOR some 20 to 30 are exothermic runaways. There may be otherchemical incidents which are either not reported or which do not fit the legal
Chemical processes usually originate on a small scale in the laboratory andtheir development is normally carried out by conducting the reactions onsuccessively larger scale before transferring to full size production plant. Inthe early stages of process development limited quantities of chemicals areused and full information about the reaction or side reactions is not usuallyavailable. Risk assessment studies and the scale up procedure enable furtherinformation to be obtained which is relevant to the final process plant design.Failure to scale up properly and to take appropriate precautions may lead tothe loss of process control which in turn may result in a runaway exothermicreaction and /or the generation or release of toxic materials. There have been anumber of such failures in the past which have led to multiple fatalities, severedamage to property, environmental damage and business loss.
Other problems which have arisen from inadequate scale up proceduresinclude for example :
• dust and vapour explosions inside vessels due to the mishandling of reactantsand solvents
• fires due to overfilling of vessels
• failure to correctly assess electrical equipment for use in hazardous areasidentifying all possible sources of ignition
• autoignition of flammable vapours, usually resulting in a flash fire.
The first and most critical step in the scale up procedure is to undertake a riskassessment of the proposed chemical process at the concept stage. Where
appropriate this should include a study of the thermochemistry of the proposedreaction.
2. ASSESSMENT OF REACTION HAZARDS
The risk assessment undertaken on all new or modified reactions should berecorded and should involve the consideration, where appropriate, of thefollowing:
• the physical and chemical properties of the reactants, intermediates,products and wastes
• the possibility of hazardous reactions if there are deviations from setparameters
• the potential for the substances in use to corrode plant
• the fire and explosion hazards
• the health hazards and associated COSHH and Personal ProtectiveEquipment (PPE) assessments
• the thermochemistry of both of the desired and potential undesiredreactions, in particular the rate of heat output
• the rate of gas generation and the potential for vessel over-pressurisation• scale-up problems (see below)
• plant design characteristics, including control systems, service needs (egcooling water, inert gas) and the adequacy and reliability of safety devicessuch as pressure relief valves, bursting discs, vents, etc
• the application of hazard identification methods, such as ‘What If’studies, Hazard and Operability Studies (HAZOPS) and quantified risk assessmenttechniques;
• environmental effects;
• new or modified process instructions; and
• the training needs of operators.
The first stage in the risk assessment is data collection. This will enable
desktop screening of the hazards of the proposed reaction to be undertaken andif possible thermochemical calculations to be carried out. In this exerciseconsideration should be given to the reactive group(s) of the reactants andcomparisons should be made with analogous substances or reactions. Anumber of publications are cited in the Bibliography which may be useful inthis desktop screening exercise.
Where there is potential for an exothermic reaction, particularly a runawayreaction, it is essential that a study of the thermochemistry of the proposedreaction is undertaken at an early stage. It is current best practice to subject allnew processes to thermochemical investigations. Various calorimetrictechniques are available which can be used in such a study. For exampledifferential scanning calorimetry or Carius tube studies can be used for basicthermal stability screening tests. Isothermal calorimetry can be used mainly tomeasure reaction kinetics and heats of reaction. Adiabatic calorimetry can beused to examine the potential for runaways. Relief vent sizing tests can also becarried out.
As a result of the risk assessment the principles of elimination, reduction andcontrol should be applied. If the risks associated with the proposed reaction areunacceptable then an alternative route to the product should be considered, ifpossible using inherently safer methods. If however the reaction is to proceedthe risk assessment should specify the control measures and safety procedureswhich should be adopted to ensure the safe operation at all stages of the scale-up process.
3. SCALE-UP PROCEDURE
The design of a commercial plant can be accomplished by scaling up fromlaboratory equipment using pilot plant. In some cases several pilot plants ofincreasing size may be used to effect the best design for the larger plant. Riskassessment is an evolving process as scale-up progresses. At each stage of the
scale up procedure the information generated should be used to review the riskassessment to enable a decision to be made as to whether or not to proceed tothe next stage. If the process is to proceed the risk assessment should specifythe controls and operating conditions required.
The rate of a chemical reaction is fixed at any given temperature but
temperature may be influenced by mass transfer and heat transfer, which are inturn affected by the size and design of the reactor. It is not always possible totheoretically assess these effects on a quantitative basis and in such cases it isusual to carry out trials with water or inert substances in the intended plant. Ifthis is not feasible purpose built reactor calorimeters will be required.
Laboratory experiments, carried out in test tubes, small flasks etc., produce arequired chemical or product but do not necessarily indicate side effects of thereaction, i.e. by-products, release of gases or vapours which may be toxic orflammable. Heat releases may be absorbed by the equipment or surroundingsand not noticed. The chemicals used may be pure materials rather than bulkcommercial chemicals, which may contain traces of impurities. Therefore inorder to overcome this problem it is essential that the apparatus, materials andchemicals used at all stages of the scale up accurately reflect those that will beused in the final plant. In the laboratory reactions are usually carried out inglass vessels but the scaled up process may well be carried out in containersmade of other materials. With some reactions such changes may be importantand could result in unexpected reactions or problems including catalytic orinhibition effects.
As scale increases the time required to carry out each operation is also likelyto increase and appropriate allowance should be made for this.
Pilot plant is used to assist in the scale up of the chemical process designrather than the mechanical design. It provides information for economicdesign, operating parameters, and safety considerations. In addition pilot
plants can be used in small scale production for evaluation and trial marketing.Information should be obtained from pilot plant studies to confirm thedecisions made as a result of the risk assessment stage in relation to :• operating conditions;
• design parameters;
• reactor problems, design, materials of construction;
• unit operations problems;
• materials handing and sampling problems;
• thermal instability and other decomposition;
• Phase problems;
• impurities;
• corrosion;
• fouling;
• analytical problems;
• operating procedures;
• working and environment problems; and
• effluent and waste disposal problems.
Impurities in the chemicals used can cause many problems which can be
identified in pilot plant studies. Impurities can occur in the feedstock or arise
from side reactions, decompositions, polymerisations, etc. which can cause
unexpected effects. Leaks into the system may bring in unwanted materials
such as pump lubricant, seal fluids or heat transfer media, including water.
These may lead to blockages and other problems. Some impurities can
catalyse undesirable explosive reactions or may be thermally unstable
themselves.
Pilot plant studies can reveal corrosion problems. These can be associated with
minor components such as gaskets and diaphragms or with impurities in the
reactants.
Scaling up in various size plants can produce variations in reactions, and
apparently identical reactors can give slightly different products with
apparently the same feed materials and operating conditions. This is most
marked in fermentation processes.
Pilot plants should be operated by technically qualified and appropriately
trained competent personnel. The extra unknown or unforeseen hazards
associated with pilot plant should be compensated for by better
instrumentation and technical control by the operators. It must be
remembered, however, that accidents on pilot plant despite their size can still
have serious consequences.
It is important, therefore, that scale-up of chemical reactions is done correctly
so that the eventual reactions can be carried out safely in full size production
plant.
4. SAFE OPERATION
Information obtained from the risk assessment of the chemical process and the
scale-up studies will enable decisions to be made on the most appropriate
controls to ensure a safe operation. The main options which could be
considered for a safe operation are:
• inherently safer methods which use less hazardous materials or alternativereaction routes to eliminate or reduce hazards;
• preventative measures such as process controls using sensors, trips, alarms(temperature, pressure, stirrer, cooling water failure) and other control
systems which initiate automatic remedial action; and
• protective measures such as pressure relief valves, vents, reactioninhibition, crash cooling, drown out/quenching or secondary containment
which will limit the consequences of a runaway reaction.
There is no single best option for controls and protective measures that can be
applied in all cases. Whichever option is chosen it must cater for the worst
credible scenario and reduce the risk as far as is reasonably practicable.
The option chosen must also be supported by appropriate occupational health
and safety management systems which cover operating procedures, the
training and supervision of operators and maintenance personnel, the
maintenance of plant and equipment, the control of plant modifications,
software and emergency procedures. It is essential that there is good
communication and co-operation between the risk assessment team, the
process plant team and maintenance personnel so that everyone concerned is
fully aware of the operating parameters and limitations of the process plant.
Once the process is operational it is important to adhere to the agreed
operating parameters and procedures. If there is to be any deviation or change
in raw materials, further risk assessments should be undertaken.
5. CONCLUSION
It is essential that suitable and sufficient risk assessments are undertaken of all
new and modified reactions during the scale-up of laboratory processes to full
sized commercial plant. Appropriate process controls and protective measures
are needed to reduce the risk of a runaway exothermic reaction and/or the
generation or release of toxic materials to a level which is as low as reasonably
practicable. This not only ensures that legal requirements are complied with
but also avoids the disruption, cost, potential damage and injuries that can be
caused by the loss of control of chemical reactions.
6. BIBLIOGRAPHY
• Royal Society of Chemistry, “EHSC Note on Individual LegalResponsibility for Health and Safety”, 1995.
• Royal Society of Chemistry, “EHSC Note on Risk Assessment at Work”,
1997.
• Health and Safety Executive [HSE] leaflet IND(G)254 “Chemical
Reaction and the Risk of Thermal Runaway”.
• Association of the British Pharmaceutical Industry [ABPI] “Guidelines forChemical Reaction Hazard Evaluation”, 2nd Edition.
• J G Lowenstein “The Pilot Plant”, Chemical Engineering, Dec 9/23, 1985
pp 62-76.
• HSE/Institution of Chemical Engineers [IChemE] video “Control ofExothermic Chemical Reactions”.
• IChemE “Chemical Reaction Hazards – a guide to safety”, Ed J Barton
and R Rogers, 2nd Edition 1998.
• “Bretherick’s Handbook of Reactive Chemical Hazards”, 5th Edition, Ed.
Urben, Butterworth Heinemann, 1995
• National Fire Protection Association “Manual of Hazardous Chemical
Reactions”, 4th Edition, 1971.
• A Starkie and S Rowe ‘Taking the heat’, ‘Chemistry in Britain’, February1996.
• 'Pilot Plants and Scale-Up of Chemical Processes II', Ed. W. Hoyle, RSC,
March 1999.This Note was prepared by a Working Party of the RSC Environment, Health and Safety Committee [EHSC].The members of the Working Party were :
Mr G J DickesMr T G R Farthing
Mr R W Hazell [Secretary]
Dr G V MacHattie [Co-chairman]
Dr R Owen
Mr D M Sanderson
Dr I Wrightson [Co-chairman]
The Working Party gratefully acknowledges the assistance of the following individuals and organisations inthe preparation of this Note, though of course the views expressed remain the responsibility of the RSC :• The Health and Safety Executive (HSE)
• Dr J Bickerton
• Mr K D Jackson
• Dr J D Jones
• Mr P G Lambert
• Dr I M McRobbie
• Dr A J Starkie
• Dr W Hoyle
This Note is also available on the RSC website http://www.rsc.org
The Environment, Health and Safety Committee welcomes comments on this Note. Comments shouldbe sent to the Committee Secretary:
Mr R W Hazell
Health, Safety and Environment Officer
The Royal Society of Chemistry
Burlington House
Piccadilly
London W1V 0BN
• Direct Tel : 0171 440 3337
• Switchboard : 0171 437 8656
• Fax : 0171 437 8883
• E-mail : [email protected]
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