F3 Factory Training Module: Methodologies for Conceptual Process Design This training module concerns the conceptual process design methodologies

Transcription

1 F3 Factory Training Module: Methodologies for Conceptual Process Design This training module concerns the conceptual process design methodologies developed in Work Package 3, by a team from several partners within the F3 Factory project, led by Britest Ltd. The work on the associated equipment selection methodology was led by the University of Newcastle. The module is aimed at chemists, engineers and other professionals who work in teams that develop processes, and who are interested in applying modular continuous intensified processing. If you need more information about the F 3 Factory Project in general, take the F3 Factory Overview Training Module, or see the website 1

2 The objectives or learning outcomes of the module are expressed in terms of what you should be able to do at the end of the module, and these are: Explain why it is useful to have a methodology for process development and design. Explain why different circumstances and business drivers mean that a single unified methodology is not possible. Explain how the methodologies should be deployed. State the prerequisites for applying the fast methodology. List the activities in the fast methodology. Explain each of the activities in the fast methodology. List the activities in the full methodology. Explain those activities in the full methodology that are different from those in the fast methodology. To attain these objectives, the structure of the module is as shown here. 2

3 The purposes of the methodologies are given on the slide. It is worthwhile to consider why a methodology for process development and design is useful. A systematic approach to process development and design can help in several ways: By using a systematic approach, the process development team is likely to spot good ideas that could otherwise be missed. Developing a shared understanding of both the business environment and drivers and the science of the process can help the team work more effectively together. Good planning of development activities can save time and effort. 3

4 The methodology is intended to be applied by a process development team, based around a series of team meetings. These meetings form the backbone of a plan do review cycle for carrying out the development work. Experience shows that where a team consists of more than a handful of members, then the meetings will be more effective if they are led by a trained independent facilitator, that is someone who is not part of the development team. A team-based methodology is beneficial because: Different members of the team will have different knowledge of the process. By sharing this knowledge amongst the whole team, a more comprehensive understanding of the process will be attained. Different members of the team will have different experience that can be applied to the development of the process. Professionals educated in different subjects will have different background knowledge and skills. For instance, chemical engineers will typically have a better understanding of mixing and mass transfer than chemists, and chemists will have a better knowledge of reaction mechanisms. A multidisciplinary discussion will ensure that all important aspects of the process are considered. Tips on implementing the methodologies will be given later. 4

5 The methodologies will be illustrated using an example. This uses the model transfer hydrogenation process studied by AstraZeneca in the F 3 Factory project. An intermediate, 3-aminobenzoic acid, is to be made by transfer hydrogenation of 3-nitrobenzoic acid using a mixture of formic acid as hydrogen donor, over a palladium on carbon catalyst. The overall reaction is summarised on the slide. 5

6 The Work Package 3 team originally tried to develop a single methodology to cover all situations. However, when validating the draft version of this with the F 3 Factory industrial partners, it became obvious that the needs of the various process industry sectors were diverse, because of the differing business environments and business drivers. So in trying to meet all eventualities, the single methodology was over-complex. The team developed this diagram to summarise the differences between the sectors. This is organised in terms of a Modularisation Throughput Ratio, as defined on the slide. This can be thought of as the number of modular plants needed to deliver a specified annual output of product. If the value of this is below 1, this indicates that several products could be produced in the same plant using campaign operation. In other words, one product would be produced for a few weeks or months, then the plant would be reconfigured and a second product would be produced, and so on for as many products as are to be produced in the year. If the value of the Modularisation Throughput Ratio is well above 1, this implies that several plants are needed to meet the capacity, for instance by using distributed production. 6

7 Essentially, two cases have been identified: Firstly, a rapid process changeover case, where the Modularisation Throughput Ratio is below about 1. Here the drivers are likely to be minimising process development costs, minimising process development time, minimising campaign length, and re-use of production assets (for instance PEAs) for multiple products. Here, a fast methodology is needed to meet the business needs. Secondly, a row housing case, where the Modularisation Throughput Ratio is well above 1, so several identical plants are required. Here, the modular approach will compete with a world-scale plant (and its economies of scale), so the rationale for modularisation will be either distributed production, or (if identical plants are to be sited in the same location) flexibility to meet uncertain market demand (for instance for a new product). Here, the need to compete with a world-scale plant means that the design must be carefully optimised and the equipment must be tailored to the particular process needs. To match these two cases, two methodologies have been developed, a fast methodology for fast implementation of new processes in the rapid process changeover case, and a full methodology that incorporates rigorous process optimisation and tailored PEA design. 7

8 The fast methodology is intended for projects where rapid changeover of processes is needed, in other words where conventional practice would implement the process in an existing batch multi-purpose plant. The fast methodology is only suitable when the following pre-requisites apply: specially-tailored PEAs are not needed to achieve the required process efficiency, the process is constructed from a catalogue of existing PEAs, and a lab-scale analogue of each PEA in the catalogue is available for process validation and optimisation. A quick reference document about the methodologies is provided, and should be referred to when working through this training module, and when using the methodologies. 8

9 This slide gives an overview of the activities in the fast methodology. The methodology starts when an initial trigger causes a new process development project to start. This could be a business trigger (for example identification of a new market opportunity) or a technical trigger (for example a new discovery or invention of a new product). The team then carries out the activities shown, until a conceptual design is ready for final design and implementation. These activities will be now be described, in order. 9

10 The first activity in the methodology is to define the project parameters. The aim is to define the parameters for the technical evaluation and conceptual process design, so that the team understands: why the process is being developed, the key success factors, the business environment and the project and process constraints. This helps to ensure that all the team members are aligned in their goals and approach. The team should use the checklist provided in the quick reference document to share knowledge and agree project parameters and constraints. The outputs of activity A should be reviewed briefly at the start of each team meeting during process development. This will remind the team of their aims, but will also help the team identify if anything has changed since the start of the project. 10

11 Taking our example process, and using the checklist to guide the discussion, the project team identified the following parameters for the project: 30 kg of the 3-aminobenzoic acid product are needed in 3 months time as an intermediate for making a drug in development. If the drug is successful in trials, it is expected that between 2 and 10 tonnes per year would be required. The product is to be the methanesulphonic acid salt of 3-aminobenzoic acid, with 98% purity. The starting material is commercial grade 3-nitrobenzoic acid. The throughput must be sufficient to give 30 kg of material in a maximum campaign length of one week, i.e. at least 0.18 kg/h. Transfer hydrogenation is to be used to avoid the need to use hydrogen gas, which cannot be used in the facility where the process is to be sited. The product will be recovered by precipitation. Note that this is a fictionalised example to illustrate the methodology. In fact, the synthesis of 3- aminobenzoic acid was a model reaction used in developing and tailoring the F 3 Factory concept to meet AstraZeneca s needs. 11

12 The aim of Activity B is to collect and share enough information about the fundamental science of the process to allow successful process development. The checklist can help the team identify important aspects of the process that need to be understood. It is useful to draw up qualitative or semi-quantitative models of the process, for instance showing the reaction mechanisms and their interactions with mass transfer processes. A very important aspect of this activity is to identify gaps in knowledge, to agree priorities for collecting information to fill these gaps, and to decide how to collect the information. Experimentation is always essential, but some information can be found more effectively using other means such as consulting published sources (either computerised or traditional) or by calculation. Remember that a month in the lab saves a morning in the library. 12

13 Looking at our example process, the team used information collected about the process to draw up this outline reaction mechanism. Note that there are two intermediates, a nitroso species and a hydroxyamino species. Allowing either of these intermediate species to accumulate is undesirable: The nitroso species can react with the product amine to give an undesired azo impurity. The hydroxyamino species is potentially dangerously unstable, and would be a hazard if present in large concentrations. Nomenclature of diagram Pd H is H adsorbed onto the Pd/C catalyst R NO 2 is 3-nitrobenzoic acid (the substrate) R NO is 3-nitrosobenzoic acid R NHOH is 3-(hydroxyamino)benzoic acid R NH 2 is 3-aminobenzoic acid (the desired product) R N=N R is the undesired azo impurity 13

14 Propylene carbonate was identified as a suitable solvent because both the substrate and product are soluble enough in this solvent, and it has a high boiling point so there are no issues with vapour formation at high reaction temperatures. Triethylamine can be added to the reaction mixture to prevent the formic acid forming a second phase. The product can be recovered as its methanesulphonic acid salt, which will precipitate. Note that the triethylamine methanesulphonic acid salt is expected to be soluble in the mixture. A key question for experimentation was the reaction time needed to give complete conversion. Another action was to check whether there was any accumulation of the nitroso and hydroxyamino species during experimentation. Nomenclature of diagram CH 3 SO 3 H is methanesulphonic acid Et 3 N is triethylamine 14

15 After experimentation on the lab scale at different reaction temperatures, the AstraZeneca team discovered that a temperature of 130 C would give complete conversion within a 1 minute residence time in a plug flow reactor. 15

16 The aim of Activity C is to generate a whole process concept, expressed as a block diagram showing the processing operations needed. Development of the whole process concept can be carried out in three steps: choosing a reaction concept, plus preparation of the reaction feeds to make them suitable for reaction, choosing a concept for purifying and isolating the desired product, and brainstorming possibilities for improving the whole process by adjusting the reaction and separation concepts. We will consider each of these sub-activities in turn. 16

17 The aims of this sub-activity are to develop a concept for the reaction, in terms of contacting pattern and operating conditions, and to develop a concept for preparing the feeds for reaction. The standard principles of reaction engineering apply, and these should be used to brainstorm concepts that would deliver a process to meet the business needs, based on the fundamental process understanding gained through activity B. The checklist provided in the quick reference document can help with this. The team also needs to brainstorm the concepts for feed preparation. 17

18 This diagram illustrates the various aspects of a reactor concept, which can be chosen to give the most effective process. The first aspect is the flow pattern, which for a single phase process could be: A plug flow reactor, equivalent to a batch reactor where all feeds are added at the start of reaction. This maximises the concentrations of both reactants, and minimises the reactor volume needed to attain a specified conversion. A reactor with multiple injections, equivalent to a fed batch reactor. This maximises the concentration of reactant A while minimising the concentration of reactant B, which is useful when there is an undesired reaction between B and the product P. A continuous stirred tank reactor (CSTR). This minimises the concentrations of both reactants. For multi-phase processes, there can be different contacting patterns, for instance co-current or counter-current. With two-phase fluid-fluid systems, the phase continuity should also be chosen as part of the reactor concept. Normally, it is advantageous that the main reactions occur in the continuous phase. The heat management strategy of the reactor, e.g. adiabatic or isothermal, should also be chosen. And finally, the reaction conditions, including choice of the excess reactant and its percentage excess, form part of the reactor concept. Further reading: Smith, R, Chemical Process Design. New York, McGraw Hill. Chapter 2, pp Atherton, J H & Carpenter K J, Process Development: Physicochemical Concepts. Oxford, Oxford University Press. pp

19 As well as developing a reaction concept, in many cases the reactants must be prepared to allow a successful reaction to occur. So after developing a reaction concept, the process development team should brainstorm the preparation of the reactor feeds. Processing tasks to prepare the reaction feeds could include, for instance: dissolving solid reactants, suspending insoluble solids as a slurry, for instance a heterogeneous catalyst, mixing immiscible liquids to get the intended phase continuity, adjusting the viscosity of a mixture, for instance by addition of solvent, premixing some of the feed materials, adjusting the ph so that the reactants are in the correct state of protonation, and removing species that cause problems in reaction, for instance eliminating water and oxygen in Grignard reactions, or protecting a catalyst from poisons. 19

20 Let s look at the reaction concept for the example process. This reaction is clean unless accumulation of the nitroso intermediate occurs, so there is no need to consider selectivity when choosing a contacting pattern. Simple plug flow will minimise the necessary reactor volume. In general, adiabatic heat management is cheaper and simpler than an isothermal strategy, but here the reduction reactions produce a considerable exotherm, and the hydroxyamino intermediate is known to be thermally unstable, so an isothermal approach is preferred. In principle, a packed bed of catalyst could be used. But due to the reaction exotherm, temperature gradients could exist within the packed bed, and also the catalyst could deactivate over the course of a run, so use of a continuous feed of fresh slurry catalyst gives better reliability and a more robust process. There is no special advantage to a counter-current approach, so the simpler and cheaper co-current flow is preferred. Complete conversion of the 3-nitrobenzoic acid substrate is desired to avoid accumulation of the nitroso and hydroxyamino intermediates, so excess formic acid will be used. The exothermic reaction will start when the reactants contact the catalyst, so mixing of the reactants and catalyst should occur within the reactor where the exothermic heat of reaction can be managed. 20

21 Consider the preparation of the feeds for reaction. The 3-nitrobenzoic acid substrate is solid at ambient temperature, so this needs to be dissolved in solvent to allow reaction to occur. There are no undesired reactions between the 3-nitrobenzoic acid, formic acid and triethylamine in the absence of catalyst, so for simplicity these materials can all be pre-mixed before reaction. The catalyst needs to be slurried in solvent before reaction, to allow it to be fed to the reactor. There are no special requirements for eliminating particular chemical species, for instance water, to avoid reaction problems. However, the reaction mixture should be nitrogen inerted as a safety precaution in case small quantities of elemental hydrogen are released in a side reaction. Continuous solids handling at low flowrates is known to be problematic, so for this process, batch preparation of both the reactant mixture and the catalyst slurry using vessels available in the Large-Scale Laboratory will best meet the business drivers and constraints. 21

22 The aim of this sub-activity is to develop a concept for isolating the required product or products at the required specification. The main principle is to do easy separations first. So firstly, provided that the product is predominately in one phase, separate the other phases that do not contain the product. Then the components can be listed together with their properties (see the quick reference guide for a list of useful properties). This allows easy separations to be readily identified. 22

23 Considering the separation concept, start by doing the simplest separations. Easiest is the phase separation of the offgas, so this is the first process task. Then the catalyst can be removed by filtration. Because the product is to be isolated as the methanesulphonic acid salt, and this is expected to precipitate cleanly, no further separation steps are required before precipitation. After this, the precipitate can be recovered by filtration. The product filter cake will be wet with a solution of reaction products, so a washing step should be included to remove the residual impurities. Finally the product should be dried to remove the solvent. 23

24 The aim of this sub-activity is to consider the reaction and separation concepts together, and to optimise the process as a whole. The optimum whole process is not necessarily the same as the process that would result from optimising the reaction and separations separately. The process team should use its process understanding developed in activity B, together with the checklist given in the Quick Reference document, to brainstorm improvements to the whole process. 24

25 To understand why it is important to optimise the process as a whole, consider this real example from the batch process industry. The reaction in the original process was optimised to give 95% conversion in an 8 hour reaction time. However, during the last two hours of the reaction a lot of impurities were generated by side reactions, so the subsequent separations were complicated and took 48 hours. Also, only 60% of the product was recovered from the reaction mixture, due to losses in separation. By revising the process to have a reaction time of only 6 hours, the reaction conversion dropped to 85%. However, the smaller amounts of impurities generated meant that the subsequent separations were easier, only taking 24 hours. Furthermore, the losses of product in separation were reduced, so that 78% of the product was recovered. Taking the whole process into consideration, the revised option 2 gave both significantly reduced cycle time and higher overall process yield. Although this example is taken from a batch process, similar considerations apply to continuous processes. A more complicated separation will entail more equipment, and losses of product in waste streams are likely to be higher

26 The ideas behind the whole process design checklist are summarised in this slide. In turn, each solvent, reagent and catalyst used in the process is considered: can the process be improved by eliminating it, substituting it for an alternative, or adding it in a different place? Similarly, considering each processing operation, is the process improved by eliminating it, using a different operation to achieve the same result, or carrying it out in a different place in the process? Finally, can the process be improved by changing significant process parameters, such as the reaction yield, as illustrated in the example you have just seen on the previous slide? 26

27 So to look at the whole process aspects of the AstraZeneca example, this block diagram summarises the process after developing the reaction and separation concepts. The team now considered the whole process design questions. Are there possibilities for improving the process by eliminating separation tasks between reaction stages? In this process, this could only be considered between the React and Precipitate tasks. However, there would be no advantage in not doing the two phase separations at this stage, and in fact not filtering the catalyst would prevent the recovery of pure product by precipitation. Are there opportunities for improving the process by changing reaction conditions? The reaction is very clean, and by taking the reaction to completion the separation is already very simple, so there are no opportunities here. Are there opportunities for improving the process by changing the points at which process materials, solvents, catalysts or reagents are added? Again, the process is very simple, and there are no opportunities for improvement. Are there possibilities for improving the process by changing the choice of solvents, catalysts and/or reagents? The use of hydrogen gas could give a simpler process than transfer hydrogenation, but this is excluded by the parameters specified in Activity A. So to conclude, in this example there are no opportunities for whole process optimisation, but as we have seen in the batch process example just presented, this will not always be the case. 27

28 Now, to finalise the complete whole process design concept, this shows how the initial block diagram for the AstraZeneca example can be converted into PEA blocks. The key processing PEAs are shown in red, and the PEAs for storing and feeding the raw materials and for collecting and storing the various product streams are shown in black. As already discussed, the propylene carbonate solvent, 3-nitrobenzoic acid substrate, triethylamine and formic acid are pre-mixed and fed as one stream to the reactor, with the catalyst slurry being fed as the second stream. Both of these feeds can be made up in the batch vessels of the Large Scale Laboratory. The slurry reactor PEA is assumed to include a facility for gas disentrainment. This process concept can now be taken forward into activity D, PEA selection. 28

29 The aim of activity D is, from a range of existing PEAs, to identify the PEA that is appropriate for carrying out each processing operation shown on the block diagram. 29

30 Firstly, write down the requirements of the equipment, such as: Throughput Volume Residence time Phases present Mass transfer Heat transfer Temperature, pressure, materials of construction, other operability factors A checklist of relevant duties for equipment for mixing, reaction, mass transfer and heat transfer is given in the reference document, based on work done in EU FP6 Project IMPULSE. (Double, 2006) After writing down the process requirements, from the list of PEAs that are available, select the one that most meets the needs. If a relatively small number of PEAs is available to the project team, then no special tools or methodologies should be needed to select an appropriate PEA for each unit operation on the block diagram. It should be relatively easy for the team to identify which of the available PEAs can deliver the task requirements already identified. If the number of different available PEAs is large, then the equipment selection tool developed in F 3 Factory task 3.2, led by the University of Newcastle, could be useful to aid rapid selection of the most appropriate PEA. Reference: Double, JM, Project IMPULSE: equipment selection methodology. Proceedings of CHISA 2006, Aug 2006, Prague, Czech Republic. 30

31 As an example of PEA selection, let s take a look at the example of the slurry reactor for the AstraZeneca process example. Firstly, the requirements of the process concept are written down: The required output and throughput given here are based on a preliminary material and energy balance. The residence time is based on the reaction measurements made as part of activity B. The required reactor volume is calculated from the residence time and throughput. The heat transfer requirement depends on the throughput finally chosen, but it must be sufficient to remove the exothermic heat of reaction. This can be calculated using the normal energy balance and heat transfer equations. The PEA must permit the use of suspended catalyst solids without blocking. The PEA must include provision for offgas disengagement. The PEA must be constructed of materials that resist corrosion from the process materials, and stainless steel or hastelloy are suitable. Finally, the reactor must be suitable for GMP manufacture, for instance it must be readily cleanable and able to be inspected as being clean. 31

32 Comparing the requirements with the available PEAs, the KIT slurry reactor PEA is suitable for the duties specified, and is chosen. 32

33 After choosing the PEAs needed to deliver the process concept, the team must make sure that this results in a viable process, and optimise the process conditions. So activity E has the aims shown on the slide. In a facilitated meeting, the team would plan experiments to run the process in the lab using the lab-scale analogues of the chosen PEAs. The team should decide what measurements to make, additional to those needed for process control, that could aid troubleshooting should unexpected results occur. After the programme of lab-scale validation and optimisation, the team should review the results. It is possible that the results show that the process concept or choice of PEAs is not suitable for full-scale use, in which case the team may decide to revisit activities B, C and D to develop an improved process concept. Alternatively, the team should use the results to decide on appropriate operating conditions for use once the proven process concept is implemented. 33

34 Looking at the AstraZeneca example, the process concept and choice of PEAs developed in activities A to D are validated using lab-scale equipment that has equivalent performance to the full-scale PEA. Note that only the PEAs for the tasks shown in red on the block diagram on slide 27 need to be tested in the laboratory. For instance, the lab-scale slurry reactor can be used to validate and optimise the reaction concept before full-scale operation using the full-scale slurry reactor PEA. After proof of concept and optimisation on the lab scale, the full-scale plant can be assembled, and the usual HAZOP studies and GMP validation completed. Then the required quantity of product can be manufactured in a one-week campaign, as demanded in the project brief. 34

35 In practice, the methodology will be carried out over a number of meetings, the activities will not map one-to-one onto the individual meetings, and there might be some need for iteration. An example of how the activities might map to team meetings is shown here. 1. At the project kick-off meeting, activity A will be carried out to agree the key parameters for the process and project. A plan will be made for information collection (activity B). After the meeting, the team members will carry out the agreed information collection actions. 2. The next meeting will review the information collected (activity B). In this case, important information gaps are identified, so a plan to collect the relevant information is devised, and carried out before the next meeting. 3. The third meeting will review the information collected and update the qualitative process models (activity B), and develop a process concept (activity C). In this case, some key information is needed to allow PEA selection, so a plan of experiments and shortcut calculations is devised, and then carried out by the relevant team members after the meeting. 4. At the fourth meeting, the PEAs can be selected (activity D), and a plan agreed to carry out the experimental process validation and optimisation (activity E). 5. The next meeting will review the results of the activity E experiments. In this case, unexpected results were obtained, so the process understanding is revisited (activity B). Experiments are planned to develop understanding of the unexpected phenomenon, and these are carried out before the next meeting. 6. The results are reviewed, and a further iteration of activities B, C and D is carried out before planning further activity E experiments. 7. After successful process validation and optimisation, the final stages of process implementation are planned. 35

36 Let s now look at the full methodology for conceptual process design. This would be used when the prerequisites for using the fast methodology do not apply. Examples might include: In the distributed manufacture of commodity chemicals where a highly optimised design is needed to compete with existing world-scale plants (in other words, the row housing case). In a rapid process changeover case where existing PEAs cannot be used, for instance while a company is developing a new F 3 Factory facility, or where significant new capabilities need to be added to an existing F 3 Factory facility. These cases inevitably involve the design of new PEAs, and rigorous chemical and mechanical engineering design cannot be avoided. So the full methodology is more similar to conventional process development and design than the fast methodology. Activities A, B and C are essentially similar to the fast methodology, at least in the initial stages of the project. However, more detailed and precise work is likely to be needed in these activities, if the business drivers require a highly-optimised process. Also, more detailed business optimisation is likely to be needed for the row housing case, where production and capital costs are the dominating business drivers. The main differences between the full methodology and the fast methodology already described are in activities F and G, which replace activity E of the fast methodology. In this training module, we will address the full methodology by considering its differences from both the fast methodology and conventional chemical engineering design. 36

37 The aims of activity F are: to develop the flowsheet based on the whole process concept (block diagram) developed in Activity C, to validate the process concept as being workable for a commercial process realised via the F 3 Factory approach, and to optimise the flowsheet, including optimisation of processing conditions. This activity is very similar to the flowsheet development and optimisation carried out in the chemical engineering design of a traditional process, and as in the classical case there are two basic approaches that can be used: 1. A quantitative model-based approach, using standard flowsheeting software. 2. A semi-empirical approach, relying on experiments that simulate the process under varying operating conditions. Either approach needs to: predict the full-scale behaviour of each of the reactors and other processing tasks included on the flowsheet in terms of its material and energy balance, given its operating conditions, and predict the full-scale performance of the whole process in terms of its material and energy balance, given a set of operating conditions. If good fundamental data are available, such as Arrhenius parameters for all of the reactions occurring (both desired and undesired), then a quantitative model-based approach is appropriate, because this gives good robustness and quick evaluation of different operating conditions. However, if the process is more complicated, then it can be more time- and cost-efficient to perform experiments that simulate the process and use these to develop correlations for mass balance modelling. 37

38 The aims of activity G are: firstly, for those parts of the process that are not suitable for implementation using existing available PEAs, to divide the flowsheet into sections, each of which will be converted to a single PEA, and secondly, for each identified section of the flowsheet, to design a PEA. This is largely standard chemical engineering design, based on the following ideas: Firstly, a PEA should provide the equipment for a complete process operation, including its instrumentation and control. So, for instance a PEA would not normally be created for a single pump. Secondly, common operations should use the same design of PEA, so, for instance, there can be identical liquid feed units, each consisting of a storage vessel, pump and associated instrumentation and control system. 38

39 There are some extra considerations for PEA design compared with standard chemical engineering design. PEAs should be designed to meet the standards developed in the F 3 Factory project. Equipment must be of physical dimensions that are smaller than the PEA framework into which they are to be fitted, so equipment size needs to be taken into consideration during the design process. This might require non-standard configurations of equipment. The team needs to consider the possible re-use of the PEAs. 1. Flexibility in use: For instance, a reactor might be constructed of sections that could be connected in different ways (e.g. series or parallel) to allow different throughputs and residence times. 2. Range of operation parameters: If two or more PEAs are being designed for a similar operation, but for different values of their key characteristic duty (e.g. throughput), then the ranges should overlap rather than leaving a gap in the operating range covered. 3. Materials of construction: It might be that the use of a different material of construction might make the PEA more flexible for use in other processes. However, the trade off between an increased cost for a more widely suitable material of construction and flexibility of the PEA design should be considered carefully. 4. Provision for flammable atmospheres: There are special considerations concerning the Ex rating of control systems and motors. If all PEAs were built to the most stringent Ex rating (e.g. for hydrogen), then this would considerably increase the cost. There will thus be a trade off between a widely-applicable Ex rate and capital cost. 5. Local regulations: If it is envisaged that the PEA might be used in different locations, then all relevant local regulations need to be considered to make sure that the PEA is acceptable for use in each location. 39

40 Here is an example of a flowsheet. To divide this into PEAs, firstly, common operations are identified: here there are four liquid feeds, and a single design of PEA can be used for each of these. Then the other parts of the flowsheet are also divided into PEAs, as shown. 40

41 As with the fast methodology, the activities of the full methodology will not map directly onto team meetings, and also iteration will be needed. In fact, iteration between activities B, C and F, and the business evaluation activity will be more extensive than in the fast methodology. Iteration will be particularly advantageous for the row housing case, where a modular plant for distributed processing needs to be highly optimised to compete with world scale plants. Experience from the F 3 Factory project shows that benefits can be gained by carrying out these activities almost in parallel, rather than sequentially. 41

42 Finally, let us recap. Two methodologies have been developed for the conceptual design of modular, intensified, continuous processes: a fast methodology, for use when a process is to be developed quickly and implemented using existing off-the-shelf PEAs, and a full methodology, for use when design of new PEAs is required, for instance for highly optimised modular plants designed for distributed manufacture. The methodologies are described in terms of the activities that the process development team needs to carry out to design the process. The two methodologies share activities A, B and C, which are A: defining the project parameters, B: developing a fundamental understanding of the process, and C: developing a process concept as a block diagram. The fast methodology then proceeds with activity D: choosing existing PEAs to carry out each of the tasks in the process concept, and activity E: proving and optimising the process concept using lab-scale analogues of the chosen PEAs. In contrast, the full methodology is more similar to conventional chemical engineering, with activity F: optimising a flowsheet using either a computer modelling or a semi-empirical approach. Activity G then divides this flowsheet into PEAs. Design of the PEAs must take into account the F 3 Factory standards, the space available within the PEA framework, and the possibilities for re-use of PEAs in other processes. Of course, where appropriate, existing PEA designs can be used to implement parts of the process flowsheet. These methodologies should be useful to help your team design processes using the F 3 Factory modular, intensified, continuous process concept. 42

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