工艺放大过程中需要考虑事项列表processscaleupconsiderationchecklist.docx

1、工艺放大过程中需要考虑事项列表processscaleupconsiderationchecklistProcess scale up consideration check list工艺放大需要考虑的因素清单1. purpose 目的:This list is a compilation of the thoughts of the process engineering group. Its purpose is to share ideas from the group with all in an attempt to use the best collective thinking

2、to improve the success of scale up of the process from lab to pilot plant. This does not consider improvements that may be made to the process by changing operations in the process. 这个清单是工艺组的思想汇总。它的目的是通过收集组内最好的思想来提高从实验室到中试车间放大的成功率。这个清单不考虑通过改变工艺的操作的提高。2. general discussion: 总论No check list will allow

3、 the engineer to successfully scale up the lab process without doing the detailed considerations.如果不做详细的考虑，没有一个检查清单可以使得工程师将实验室的工艺成功的放大。An all inclusive checklist might have two questions:所有包含的清单可能有两个问题 ：- have all important effects been considered? 所有重要影响因数是否已经被考虑到？- will the conditions of the demon

4、stration run be reproduced well enough in the pilot plant for a successful run. 描述的条件在中试车间中是否能够成功的生产出来？If the answers to both of these is “Yes”, the scale up should be successful.如果这两个回答都是“是”，放大时成功的。3. General effects 通常的影响:As professional chemists and engineers doing the scale up we must make the i

5、mportant judgements needed to be successful. There is never enough time to gather all possible data or to simulate the PP equipment exactly in the lab. Critical judgements must be made.作为资深的化学师和工程师在进行工艺放大时，我们必须做一些重要的判断，而这些判断为成功的工艺放大所必须的。不可能有足够的时间来收集所有可能的数据或者在实验室中来准确的评估中试设备。必须做出关键的评估。Below is a list

6、of parameters that may be important at any step in the operation:以下是参数清单，这些参数在运行的每一步中都很重要。- Time 时间- Temperature 温度- PH - pressure/ vacuum 压力/真空- Materials of construction 材质- stirring 搅拌- concentrations 浓度As you are well aware, combinations of these variables can also be important. In a heterogeneo

7、us reaction stirring may have a major effect on reaction rate. In crystallization the rate of cooling may be significant. In most reactions the profile of temperature versus time is rate of cooling may be significant. The basic variables (and their combinations) really must be considered at each; ev

8、en this partial list of variables may not be too helpful in avoiding common scale up problems associated with various common actions done in the pilot plant.如果你能很好的意识到，将几种重要的变量合并。在非均相的反应体系中，搅拌可能是最主要的影响反应收率的因素。在结晶过程中，降温速率影响会很明显。必须考虑基础的变量（和他们的综合影响）的影响。下面列表中的变量可能不是特别有帮助去解决在中试车间放大过程中的问题。The best way to

9、determine that the scale up operation will be successful is to use the pilot plant expected conditions in the demonstration run. This will often be significantly different from the way the PRD chemist usually makes the lab runs.最好的方法去定义成功放大的操作是使用在中试车间放大的条件去做演示实验。这个方法明显区别于实验室化学师在实验室里做的实验。The followin

10、g is a list of important considerations for common activities in the Pilot Plant. This is a living document and should be up dated every time a new scale up effect is recognized.下面的列表列出了在中试车间生产过程中需要考虑的一些因素，这是一个动态的文档，在放大生产过程中出现的因素都可以更新到此表中。OSHA =occupational safety and health act administration 职业安全与

11、卫生条例管理局美Operation and Concern操作和注意事项 Acceptable ( based on demo run if practical)可以接受（基于测试批次）Chemical characteristics学性质Do amounts of the materials cross the OSHA *PSM threshold values?物料的使用量是否超过OSHA要求*PSM阈值Do raw materials require special safety precautions?原料是否需要特殊的安全警示？Have lab test been done wit

12、h all potential peroxide formers if they will be concentrated in the process?在浓缩过程中，实验室是否进行所有可能的过氧化物形成的测试？Are raw materials all released?所有的原材料是否已经放行？Are all air emissions within permit limits?所有的气体释放在允许的限值之内？Charging 投料Can charge be made in same time as lab? (Physical limitations and heat of reacti

13、on considerations)投料是否可以向在实验室中一次投完？（考虑物理限制和反应热）Must solids be dispersed well to avoid forming clumps?固体必须分散的很好从而避免结块？ Is subsurface charging needed?需要液面以下投料吗？What characteristics of the materials need special consideration ( category 4, highly potent, allergenic, mutagenic, toxics, etc.)?什么样的原材料特性需要

14、特殊的考虑？（4类化合物，高活性的，致畸的，基因毒性，有毒的，等）What are the required tolerances in the amount to be added加入的量可以承受多大的公差范围？What are the limitations in the addition sequence?加料顺序有什么限制？Is limitation of oxygen to very low levels necessary?是否需要很低的氧气含量？Is limitation of water into the reactor crucial?反应釜中的水的限制？Stirring 搅

15、拌Will agitation keep the solids suspended?搅拌是否能够使固体悬浮在反应液中Is the stirrer geometry adequate to agitate the entire suspension?搅拌桨的几何形状是否能够使整个悬浮液充分搅拌？Will process be successful after level in reactor falls below agitator?反应液是否降到搅拌桨以下？Will excessive agitation cause fine crystals?过量的搅拌导致晶体变细？ Will excess

16、ive agitation cause emulsion?过量的搅拌导致乳化？Will stirring left on unattended cause the reactor contents to heat to an excessive level?如果无人看守状态下，搅拌是否使得反应加热到过热状态？Reacting 反应What special equipment is need? ( solids charging devices, provisions for additions of very small amounts, gas spargers, special agita

17、tors, high or low temperature) 是否需要特殊的设备（固体加料器，加入很少量的固体，喷气器，特殊的搅拌，高或者低温）Is the level adequate at all times for temperature measurement?反应液面足够进行温度测量，即在温度探头之上？Do volume changes demand transfer to a second larger or smaller reactor?反应体积需要转移到第二个更大或者更小的反应釜中？Can the needed time/temperature profile be achi

18、eved?需要的时间/温度的曲线是否可以达到？Have the dynamics of heating/cooling in pilot plant equipment been considered?中试车间设备的加热冷却状态需要考虑？Have exotherms been anticipated?放热是否可以预料到？Can charges be added in the same time as in lab demo?在实验室里是否可以在同一时间内全部投料完毕？Can the equipment accommodated the rate of gas generation withou

19、t over pressuring?设备是否可以适用于反应的放气速度而不会导致超压？Does the generated gas need to be scrubbed or vented directly because of flammability?生成的气体需不需要洗涤塔或者因为易燃的原因而直排 ？Can pH be controlled adequately?pH值是否可以完全的控制好？Will reaction mass remain stirrable through the reaction? ( freezing point, precipitates) 在整个反应过程中反应

20、液可以搅拌（凝固点，沉淀物等）Will time lag between addition of a pH adjustment material and detection by an in-process pH meter result in problems?在滴加调节pH值的物质和检测中控的pH计的结果是否有时间的滞后？Is stirring adequate ( especially with mass transport controlled reactions)?搅拌是否充分（特别是物料转移控制的反应）Is pressure adequately controlled?压力是否可

21、以充分的被控制？ Will all materials of construction give an acceptable product? ( metals)所有使用的材质是可以接受的？ （金属）Will the reaction harm the equipment? (glass lining or metal)反应对设备是否有危害？（搪玻璃或者金属）Are by-products formed (even in small amounts) which will cause a safety, hygiene or ecological problem?副产物（即使是小量）的形成导致

22、安全，职业卫生或者环境问题？Have hold points been identified? 停止点是否已经被辨识出来In-Process Controlling 中控Can a representative sample be taken?是否可以取代表性的样品？If the reaction mixture is more than one phase, will differences in the relative amount of the phase cause the in process control to give a wrong result?如果反应液不止一相，中控取

23、到的不同层的样品比例是否会影响结果？Does the PMP have enough definition of the test?批记录是否有定义足够的测试信息？Has the time to get the IPC result been considered?做中控的时间是否考虑到？Is the acceptance criteria clear and definitive?可接受的标准是否有清晰和明确的定义？Is the action to take if the IPC fails well defined?如果中控失败，是否有额外的处理措施？pH adjustments pH调节

24、Is the concentration of the adjusting agent appropriate for the adjustment ( control wise)调节剂的浓度是否适合调节（滴加控制）What are the consequences of an over addition of the adjusting agent?如果滴加过量的调节剂有什么后果？What is the final acceptable PH range?最终可以接受的PH值范围？How steep is the pH versus material addition curve?加料过程中

25、pH值曲线坡度怎样？What if the adjustment takes much longer in the pilot plant than in the lab.?在中试车间调节pH值比实验室长多少时间？Liquid phase separations 液相分离Can the expected top later under some circumstance actually be on the bottom? (density change because of variation in composition or temperature)要保证两相有清晰的界面(因为萃取过程中

26、因为组分或者温度原因导致密度上的变化)Are emulsions ( rag layers) a problem?会不会有乳化问题？Is a filtration needed to improve phase separation?过滤是否有助于相分离？Should temperature be raised or salts added to improve separation?提高温度或者加盐是否能够有助于相分离？Is the correct place to send the rag layer specified?中间层是否能够决定在哪一层？Does the heavy phase

27、 cling to the walls of the reactor and contaminate the light phase as it is drained?下层是否会粘在反应釜壁上，污染上层？Is a back extraction needed for either phase?是否需要反萃取？What are consequences of a less than perfect split?如果不能很好的分离会导致什么后果？If separation time is longer in the pilot plant than the lab., is there a pro

28、blem?如果在中试车间分离的时间比实验室长，是否有问题？Distilling 蒸馏Is an adequate end point for the distillation established for the PP?在中试车间，对于精馏，是否能充分的判断结束点。Is the required end point for the distillation achievable in the plant(e.g. content of residual solvents in an oil)?在车间，精馏的终点如何判断（例如：在油状产品中的溶剂含量）？If a mixed solvent i

29、s being distilled before crystallization, is the concentration of each component and the relative amount of mixed solvent to solute well known? Will the PMP include steps to assure that the mixed solvent is correct before crystallization?如果使用混合溶剂，在重结晶之前蒸馏，每个组分的浓度和相关的量是否知道？在批记录中重结晶之前的步骤要确保混合溶剂是正确的？Is

30、 wall temperature important?壁上的温度是否很重要？Does the aterotropes formed? Does pressure influence the azeotropes?是否有共沸产生？压力是否影响共沸？Is pressure adequately controlled?压力控制的是否充分？Does the material foam? Is there water in a separate phase? 物料是否有泡沫？是否有水进入分离相？Will longer time for the distillation than in the lab

31、be detrimental?考虑蒸馏的时间要比实验室长？Will liquid level be high enough to be stirred at all times?考虑死体积？Does the distillation result in a super saturation? Does an unexpected crystallization cause a problem (e.g. product crystallizing early so that no seeding may be done resulting in a low product quality)?是够蒸馏是在过饱和状态下进行？是否意想不到的结晶会导致问题的出现（ 例如：产品结晶较早导致没有晶种得到的产品品质较低）Is a liquid separator (trap) available for the condensate if needed?是否需要加冷阱？Can the material free