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Optimal system wide design for bioprocesses
~
Computers and Chemical Engineering Supplement (1999) S51-S54 t) 1999 Elsevier Science Ltd. All rights reserved PH: S0098-1354199/ooI55·6
Pergamon
Optimal System Wide Design for Bioprocesses M.A. Steffens, E.S. Fraga and I.D.L. Bogle Department of Chemical Engineering, University College, London, UK WC1E 7JE Abstract The advantages of automated process synthesis and design via optimisation have long been recognised in the chemical industries. Applying synthesis procedures to design and optimise whole processes leads to the generation of better solutions than sequential approaches. While the biotechnology sector also stands to gain from the same benefits little work on synthesis algorithms for bioprocesses exists. In this paper we describe a bioprocess synthesis algorithm which is based on an implicit enumeration algorithm and has previously been used for chemical process synthesis. The algorithm uses physical properties data to screen candidate units at each stage of the synthesis procedure thereby reducing the search space without eliminating valuable solutions. The utility of the algorithm is demonstrated by synthesising a flowsheet for the manufacture and purification of penicillin, a well established bioprocess. Results show that the synthesis algorithm is able to generate a set of system wide optimal flowsheets. In addition many of the alternatives identified by the synthesis algorithm concur with industrial knowledge as reported by Swartz (1985).
Keywords: Process synthesis, Bioprocesses, Optimization. INTRODUCTION THE SYNTHESIS ALGORITHM Bioprocess flowsheets are currently synthesised sequentially using existing engineering knowledge (i.e. design heuristics) and extensive laboratory and pilot scale studies. When using this approach each unit can be designed optimally but it is difficult to do the same for the entire flowsheet, The design characteristics for one unit operation may have a strong impact on the performance of another unit in the process. In addition bioprocess flowsheets are relatively large and contain units exhibiting complex behaviour making it difficult for the design engineer to generate the optimal flowsheet. However, strict regulations for biotechnological processes make it particularly important to choose the optimal flowsheet as early as possible in the design process. The work presented in this paper has been developed keeping these difficulties in mind. Process synthesis using optimisation algorithms represents a powerful technique. Numerous optimisation algorithms have been used to solve chemical process synthesis problems (e.g. Grossman and Kravanja, 1995; Westerberg, 1989). However, it is difficult to apply such techniques to bioprocesses for several reasons including: the large range of separation units which may be used; the non-sharp characteristics of many bioprocess separation units; and the complex nature of biostreams. The aims of this paper are twofold: 1. To illustrate and evaluate a synthesis technique which overcomes the problems encountered in bioprocess synthesis.
2. To use a case study to highlight the ability of the synthesis tool to generate flowsheets which are optimal in a system wide, rather than unit by unit, sense.
The bioprocess synthesis method used in this work is based on the Jacaranda implicit enumeration algorithm, implemented in Java, which was developed for chemical process synthesis (Fraga, 1998). Jacaranda simultaneously generates and searches a superstructure in a depth first manner. Unit and stream variables are mapped into the discrete space using user defined discretisation levels. A significant advantage of the Jacaranda package is its ability to generate a list of ranked solutions, not just the optimal one. This allows the design engineer to evaluate a small set of flowsheets in more detail, making the synthesis procedure robust to modelling errors and assumptions. Although the Jacaranda package has been used to synthesise chemical process flowsheets computational constraints limit its application to bioprocesses due to the large number of components and wide range of unit operations which are available. To alleviate this problem we have incorporated a technique which uses physical property information to screen candidate units thereby reducing the size of the synthesis problem, The binary ratio concept developed by Jaksland et ol. (1995) is used to screen units at each level of the synthesis procedure. The idea is that each unit exploits a particular physical property difference between components .for separation. Once this key property is identified for each unit, the ratio between components in a stream can be calculated and used to eliminate units for which it is too small. In this way only units which exploit large property differences between components in a stream are selected. By combining the ability of Jacaranda to generate a list of N best flowsheets with the physical property screening procedure, the synthesis approach can be used to efficiently identify a set of suitable flowsheets
S52
Computers and Chemical Engineering Supplement (1999) S51-S54
Table 1: Unit design methods and assumptions
I Unit Fermentation Rotary drum filtration Membrane filtration Organic extraction Aqueous extraction Centrifugation Ion-exchange Crystallisation
I Design method and assumptions Fed-batch operation Incompressible cake, assume cake solids cone, Small key is completely permeable, large key impermeable Solvent: butylacetate Phases: PEGIPhosphate Assume slurry concentration Assume a residence time Assume purity and yield
I
Source Paul and Thomas (1996) Vogel and Todaro (1997) Ho and Kamalesh (1992) Swartz (1985), Hatton (1985) Guan et aI. (1996) Vogel and Todaro (1997) Leser (1994) Vogel and Todaro (1997)
Thomas, 1996). Table 1 summarises the unit design A pre-requisite for any synthesis method is to be able methods and assumption used in this paper. to determine the state (i.e. composition, temperature etc) of the stream(s) which leave each unit. THE CASE STUDY In bioprocesses, two different approaches are used: splitting or fractionating units. The former operate In this section we use a case study on the production in a more traditional chemical engineering sense, that of penicillin to demonstrate and evaluate the bioprois by splitting the incoming stream into two with cess synthesis technique. The penicillin production significantly different composition, hence achieving process is relatively large scale and its design is well separation. The latter, however, generally oper- established. The purification section of the process ate batchwise and produce several fractions or cuts. is characterised by an organic liquid-liquid extraction Chromatography columns, where the various compo- unit which is commonly used in antibiotic production nents are eluted sequentially, are a particularly com- processes. Figure 1 shows a fairly recent industrial mon example of a fractionating unit. scale flowsheet (Swartz, 1985). for further analysis.
Units which operate in the stream splitting sense are designed -!Ising a similar concept to that used in shortcut distillation design. That is, two 'key' components are selected having ordered the components in a unit's feed stream according to the key physical property for each unit under consideration. The composition of the effluent streams can then be estimated using mass balances along with the design equations specific to each unit (Table 1). The output streams of fractionating units, such as chromatography columns, are more difficult to predict. The elution profile must be estimated so that the amount of each contaminant which leaves with the desired product can be calculated. A typical BioStream contains many different types of complex BioChemicals which interact with each other and with the column. For this reason an empirical approach for estimating contaminant levels is used (Leser, 1994). The technique has been developed for ion-exchange, gel filtration and hydrophobic interaction chromatography columns. In addition to separation units we have included a model for designing and calculating the effluent characteristics of the fermenter. The fermenter design procedure solves a dynamic model to determine the final state of the batch or fed-batch fermentation. Substrate and oxygen consumption are also predicted throughout the fermentation period. A structured dynamic model for penicillin production via Penicillium chrysogenum was used in this work (Paul and
Production of penicillin usually begins with the aerobic fermentation of P. chrysogenum in batch fermenters. A carbon source (e.g. sucrose) and various nutrients such as corn steep liquor, ammonium sulfate and inorganic salts are required for bacterial growth and product synthesis. As the penicillin is produced it is secreted from the cells into the surrounding medium and reaches a concentration of around 20 to 35 gil. The broth is then filtered using a rotary vacuum drum filter to remove the cells which are washed to remove any entrapped penicillin. The filtered broth is acidified and contacted with a solvent (e.g. butyl or amyl acetate) which results in the selective transfer of the penicillin into the organic phase. A back extraction step may be used to return the penicillin to the aqueous phase. Depending on product specifications carbon adsorption to remove pigments and other impurities may be the next separation step. Finally an excess of potassium or sodium acetate is added in a mixing tank to induce crystallization. A centrifuge or drum filtration unit then collects the crystals which are washed and dryed to produce .the final product. Details of the parameters used for synthesis are summarised in Table 2. Note that the feed subsrate concentration and flow can assume different values during synthesis. This allows us to determine the effect of fermentation conditions on the optimal flowsheet. To rank flowsheets the capital and operating costs were estimated for each unit using information
Computers and Chemical Engineering Supplement (1999) SSI-SS4
553
Figure 1: Typical Penicillin Manufacturing Flowsheet
from various sources including Reisman (1988), P~ ters and Timmerhaus (1991) and Vogel and Todaro (1997). Total cost is defined as the sum of the capital cost depreciated over 10 years plus the operating cost ($/yr). To define product specifications we assume that the penicillin will be sold as bulk crystal which may be further purified for therapeutic use. Thus we require a stream containing crystals with no more than 10% moisture and 5% impurities within the crystals.
RESULTS AND DISCUSSION
the additional substrate remaining in the fermenter effluent stream. Thus we see there is a trade off between increasing productivity in the fermenter and increasing purification costs. This result illustrates the ability of the synthesis algorithm to consider the system as a whole, instead of a unit by unit basis, and generate an optimal system wide flowsheet.
CONCLUSIONS The case study presented in this paper shows that the synthesis algorithm is well suited for generating bioprocess flowsheets. A ranked list of N flowsheets is generated which makes the synthesis technique an ideal tool for screening flowsheets prior to more detailed analysis via simulation or pilot plant studies. We have shown that optimal system wide bioprocesses can be generated because the algorithm considers all possible connections between units. Thus we can optimise the fermenter characteristics at the same time as the downstream processing flowsheet. This is an important outcome because the fermenter design parameters often have a significant impact on the optimal purification flowsheet. This is difficult to achieve using more traditional, sequential synthesis methods.
The three best flowsheets generated by the synthesis algorithm are presented in Figure 2. Significant differences between the industrial flowsheet (Figure 1) and the optimal one identified by the synthesis algorithm can be seen. Firstly we note that the carbon adsorption and filtration process has not been included in the synthesised flowsheet. This is because we have used relatively loose product specifications. Carbon adsorption represents one way of achieving higher purity crystals. In addition a membrane filtration U11it is used instead of rotary drum filtration which has a lower capital but higher operating costs. Swartz (1985) have identified the following flowsheet modifications as having the potential to reduce the operating costs of the traditional penicillin production process: ACKNOWLEDGEMENTS
1. membrane filtration instead of rotary drum fil- The work was carried out as part of the Centre for tration of the broth. Process Systems Engineering and financial support 2. whole broth processing via organic extraction from the Engineering and Physical Sciences Research Council is gratefully acknowledged. (i.e, no initial filtration step) .
3. ion-exchange in place of two-phase extraction. The synthesis algorithm identifies membrane filtration, whole broth processing and cation exchange in the top three alternatives (Figure 2). Note that the flowsheet ranking is heavily dependant on cost information which is often approximate at such an early stage in the design process. However, this is not a problem because the algorithm provides a list of solutions , not just the optimal one. Fermenter feed characteristics were also considered during synthesis. Figure 2 shows that the feed glucose concentration and flow were both set to the minimum values in all three flowsheets. Although increasing the glucose concentration may increase productivity it also increases separation costs because of
REFERENCES Fraga, E. S. 1998. The Generation and Use of Partial Solutions in Process Synthesis. Transactions of the Institute of Chemical Engineers 76(A1): 45-54. Grossman, I. E. and Kravanja, Z. 1995. Mixed Integer Non-linear Programming Techniques for Process Systems Engineering . Computers and chemical engineering 19(5uPP1.): S83-S88. Guan, Y. X., Zhu, Z. Q. and Mei, L. H. 1996. Technical Aspects of Extractive Purification of Penicillin Fermentation Broth By Aqueous 2-Phase Partitioning. Separation Science and Technology 31(18): 2589-2597.
554
Computers and Chemical Engineering Supplement (/999) 55/-554
Table 2: Fermentation details (Swartz, 1985)
Innoculum component Glucose Ammonium sulfate Lard oil antifoam Sodium Phenylacetate P. Chrysogenum
I Concentration (g/L) I Fermenter char. 100.0 0.5 2.5 5 4.0
Initial volume Fermentation time Feed flow Glucose cone.
Value 100 in 3 250 hrs 60 or 100 l/hr 400 or 600 gil
Figure 2: The Best Three Flowsheets as Identified by the Synthesis Algorithm ~/L.
1st Cry, u ] Crystal rl1ttl lion
Fcrmc nlCr
d:y ing
HoI is
Penicillin
pmellC'
2nd Crys:A1:imioo
CJ)....1 fillr2ticn
Fcrmcn:
Srcnllllll\o-cu. md,s:ilIatio"
3rd
Fcrmcnter
Hatton, T. A. 1985. Liquid-Liquid Extraction of Antibiotics, pp. 439-449. In: M. Moo-Young (eds.), Comprehensive Blo/technology: the principles, applications and regulations of Bio/technology in industry, agriculture and medicine, ed., Pergamon, Oxford.
Paul, G. C. and Thomas, C. R. 1996. A Structured Model For Hyphal Differentiation and Penicillin Production Using Penicillium-Chrysogenum. Biotechnology and Bioengineering 51(5): 558-572.
Peters, M. S. and Timmerhaus, K. D. 1991. Plant design and economics for chemical engineers . 4th ed. Hersbach, G. J . M., van der Beek, C. S. and van McGraw Hill, New York. Dijck, P. W. M. 1984. The Penicillins: Properties, Reisman, H. 1988. Economic analysis of fermentaBiosynthesis and Fermentation, pp. 45-140. In: E. tion processes. ed. CRC Press, Boca Raton. J . Vandamme (eds.), Biotechnology oflndustrial AnPenicillins, pp. 7Swartz, R. W. 1985. tibiotics, ed., Marcel dekker, New york. 47. In : M. Moo-Young (eds.), Comprehensive Ho, W. S. and Kamalesh, K. S. 1992. Membrane Bio/technology: the principles, applications and regHandbook. 1st ed. Van Nostrand Reinhold, New ulations of Bio/technology in industry, agriculture York. and medicine, 1 ed., Pergamon, Oxford . Jaksland, C. A., Gani, R. and Lien, K" M. 1995. SepVogel, H. C. and Todaro, C. L. 1997. Fermentation aration process design and synthesis' based on therand Biochemical Engineering Handbook. Principles, modynamic insights. Chemical engineering science Process Design and Equipment. 2nd ed. Noyes pub50(3) : 511-530. lications , Westwood, New Jersey. Leser, E. W. 1994. Prot-ex: an expert system for seWesterberg, A. W. 1989. Synthesis in engineering lecting the sequence of processes for the downstream design. Computers and chemical engineering 13(4purification of proteins. PhD Thesis, The University 5): 365-376. of Reading, Reading.
Computers and Chemical Engineering Supplement (1999) S51-S54 t) 1999 Elsevier Science Ltd. All rights reserved PH: S0098-1354199/ooI55·6
Pergamon
Optimal System Wide Design for Bioprocesses M.A. Steffens, E.S. Fraga and I.D.L. Bogle Department of Chemical Engineering, University College, London, UK WC1E 7JE Abstract The advantages of automated process synthesis and design via optimisation have long been recognised in the chemical industries. Applying synthesis procedures to design and optimise whole processes leads to the generation of better solutions than sequential approaches. While the biotechnology sector also stands to gain from the same benefits little work on synthesis algorithms for bioprocesses exists. In this paper we describe a bioprocess synthesis algorithm which is based on an implicit enumeration algorithm and has previously been used for chemical process synthesis. The algorithm uses physical properties data to screen candidate units at each stage of the synthesis procedure thereby reducing the search space without eliminating valuable solutions. The utility of the algorithm is demonstrated by synthesising a flowsheet for the manufacture and purification of penicillin, a well established bioprocess. Results show that the synthesis algorithm is able to generate a set of system wide optimal flowsheets. In addition many of the alternatives identified by the synthesis algorithm concur with industrial knowledge as reported by Swartz (1985).
Keywords: Process synthesis, Bioprocesses, Optimization. INTRODUCTION THE SYNTHESIS ALGORITHM Bioprocess flowsheets are currently synthesised sequentially using existing engineering knowledge (i.e. design heuristics) and extensive laboratory and pilot scale studies. When using this approach each unit can be designed optimally but it is difficult to do the same for the entire flowsheet, The design characteristics for one unit operation may have a strong impact on the performance of another unit in the process. In addition bioprocess flowsheets are relatively large and contain units exhibiting complex behaviour making it difficult for the design engineer to generate the optimal flowsheet. However, strict regulations for biotechnological processes make it particularly important to choose the optimal flowsheet as early as possible in the design process. The work presented in this paper has been developed keeping these difficulties in mind. Process synthesis using optimisation algorithms represents a powerful technique. Numerous optimisation algorithms have been used to solve chemical process synthesis problems (e.g. Grossman and Kravanja, 1995; Westerberg, 1989). However, it is difficult to apply such techniques to bioprocesses for several reasons including: the large range of separation units which may be used; the non-sharp characteristics of many bioprocess separation units; and the complex nature of biostreams. The aims of this paper are twofold: 1. To illustrate and evaluate a synthesis technique which overcomes the problems encountered in bioprocess synthesis.
2. To use a case study to highlight the ability of the synthesis tool to generate flowsheets which are optimal in a system wide, rather than unit by unit, sense.
The bioprocess synthesis method used in this work is based on the Jacaranda implicit enumeration algorithm, implemented in Java, which was developed for chemical process synthesis (Fraga, 1998). Jacaranda simultaneously generates and searches a superstructure in a depth first manner. Unit and stream variables are mapped into the discrete space using user defined discretisation levels. A significant advantage of the Jacaranda package is its ability to generate a list of ranked solutions, not just the optimal one. This allows the design engineer to evaluate a small set of flowsheets in more detail, making the synthesis procedure robust to modelling errors and assumptions. Although the Jacaranda package has been used to synthesise chemical process flowsheets computational constraints limit its application to bioprocesses due to the large number of components and wide range of unit operations which are available. To alleviate this problem we have incorporated a technique which uses physical property information to screen candidate units thereby reducing the size of the synthesis problem, The binary ratio concept developed by Jaksland et ol. (1995) is used to screen units at each level of the synthesis procedure. The idea is that each unit exploits a particular physical property difference between components .for separation. Once this key property is identified for each unit, the ratio between components in a stream can be calculated and used to eliminate units for which it is too small. In this way only units which exploit large property differences between components in a stream are selected. By combining the ability of Jacaranda to generate a list of N best flowsheets with the physical property screening procedure, the synthesis approach can be used to efficiently identify a set of suitable flowsheets
S52
Computers and Chemical Engineering Supplement (1999) S51-S54
Table 1: Unit design methods and assumptions
I Unit Fermentation Rotary drum filtration Membrane filtration Organic extraction Aqueous extraction Centrifugation Ion-exchange Crystallisation
I Design method and assumptions Fed-batch operation Incompressible cake, assume cake solids cone, Small key is completely permeable, large key impermeable Solvent: butylacetate Phases: PEGIPhosphate Assume slurry concentration Assume a residence time Assume purity and yield
I
Source Paul and Thomas (1996) Vogel and Todaro (1997) Ho and Kamalesh (1992) Swartz (1985), Hatton (1985) Guan et aI. (1996) Vogel and Todaro (1997) Leser (1994) Vogel and Todaro (1997)
Thomas, 1996). Table 1 summarises the unit design A pre-requisite for any synthesis method is to be able methods and assumption used in this paper. to determine the state (i.e. composition, temperature etc) of the stream(s) which leave each unit. THE CASE STUDY In bioprocesses, two different approaches are used: splitting or fractionating units. The former operate In this section we use a case study on the production in a more traditional chemical engineering sense, that of penicillin to demonstrate and evaluate the bioprois by splitting the incoming stream into two with cess synthesis technique. The penicillin production significantly different composition, hence achieving process is relatively large scale and its design is well separation. The latter, however, generally oper- established. The purification section of the process ate batchwise and produce several fractions or cuts. is characterised by an organic liquid-liquid extraction Chromatography columns, where the various compo- unit which is commonly used in antibiotic production nents are eluted sequentially, are a particularly com- processes. Figure 1 shows a fairly recent industrial mon example of a fractionating unit. scale flowsheet (Swartz, 1985). for further analysis.
Units which operate in the stream splitting sense are designed -!Ising a similar concept to that used in shortcut distillation design. That is, two 'key' components are selected having ordered the components in a unit's feed stream according to the key physical property for each unit under consideration. The composition of the effluent streams can then be estimated using mass balances along with the design equations specific to each unit (Table 1). The output streams of fractionating units, such as chromatography columns, are more difficult to predict. The elution profile must be estimated so that the amount of each contaminant which leaves with the desired product can be calculated. A typical BioStream contains many different types of complex BioChemicals which interact with each other and with the column. For this reason an empirical approach for estimating contaminant levels is used (Leser, 1994). The technique has been developed for ion-exchange, gel filtration and hydrophobic interaction chromatography columns. In addition to separation units we have included a model for designing and calculating the effluent characteristics of the fermenter. The fermenter design procedure solves a dynamic model to determine the final state of the batch or fed-batch fermentation. Substrate and oxygen consumption are also predicted throughout the fermentation period. A structured dynamic model for penicillin production via Penicillium chrysogenum was used in this work (Paul and
Production of penicillin usually begins with the aerobic fermentation of P. chrysogenum in batch fermenters. A carbon source (e.g. sucrose) and various nutrients such as corn steep liquor, ammonium sulfate and inorganic salts are required for bacterial growth and product synthesis. As the penicillin is produced it is secreted from the cells into the surrounding medium and reaches a concentration of around 20 to 35 gil. The broth is then filtered using a rotary vacuum drum filter to remove the cells which are washed to remove any entrapped penicillin. The filtered broth is acidified and contacted with a solvent (e.g. butyl or amyl acetate) which results in the selective transfer of the penicillin into the organic phase. A back extraction step may be used to return the penicillin to the aqueous phase. Depending on product specifications carbon adsorption to remove pigments and other impurities may be the next separation step. Finally an excess of potassium or sodium acetate is added in a mixing tank to induce crystallization. A centrifuge or drum filtration unit then collects the crystals which are washed and dryed to produce .the final product. Details of the parameters used for synthesis are summarised in Table 2. Note that the feed subsrate concentration and flow can assume different values during synthesis. This allows us to determine the effect of fermentation conditions on the optimal flowsheet. To rank flowsheets the capital and operating costs were estimated for each unit using information
Computers and Chemical Engineering Supplement (1999) SSI-SS4
553
Figure 1: Typical Penicillin Manufacturing Flowsheet
from various sources including Reisman (1988), P~ ters and Timmerhaus (1991) and Vogel and Todaro (1997). Total cost is defined as the sum of the capital cost depreciated over 10 years plus the operating cost ($/yr). To define product specifications we assume that the penicillin will be sold as bulk crystal which may be further purified for therapeutic use. Thus we require a stream containing crystals with no more than 10% moisture and 5% impurities within the crystals.
RESULTS AND DISCUSSION
the additional substrate remaining in the fermenter effluent stream. Thus we see there is a trade off between increasing productivity in the fermenter and increasing purification costs. This result illustrates the ability of the synthesis algorithm to consider the system as a whole, instead of a unit by unit basis, and generate an optimal system wide flowsheet.
CONCLUSIONS The case study presented in this paper shows that the synthesis algorithm is well suited for generating bioprocess flowsheets. A ranked list of N flowsheets is generated which makes the synthesis technique an ideal tool for screening flowsheets prior to more detailed analysis via simulation or pilot plant studies. We have shown that optimal system wide bioprocesses can be generated because the algorithm considers all possible connections between units. Thus we can optimise the fermenter characteristics at the same time as the downstream processing flowsheet. This is an important outcome because the fermenter design parameters often have a significant impact on the optimal purification flowsheet. This is difficult to achieve using more traditional, sequential synthesis methods.
The three best flowsheets generated by the synthesis algorithm are presented in Figure 2. Significant differences between the industrial flowsheet (Figure 1) and the optimal one identified by the synthesis algorithm can be seen. Firstly we note that the carbon adsorption and filtration process has not been included in the synthesised flowsheet. This is because we have used relatively loose product specifications. Carbon adsorption represents one way of achieving higher purity crystals. In addition a membrane filtration U11it is used instead of rotary drum filtration which has a lower capital but higher operating costs. Swartz (1985) have identified the following flowsheet modifications as having the potential to reduce the operating costs of the traditional penicillin production process: ACKNOWLEDGEMENTS
1. membrane filtration instead of rotary drum fil- The work was carried out as part of the Centre for tration of the broth. Process Systems Engineering and financial support 2. whole broth processing via organic extraction from the Engineering and Physical Sciences Research Council is gratefully acknowledged. (i.e, no initial filtration step) .
3. ion-exchange in place of two-phase extraction. The synthesis algorithm identifies membrane filtration, whole broth processing and cation exchange in the top three alternatives (Figure 2). Note that the flowsheet ranking is heavily dependant on cost information which is often approximate at such an early stage in the design process. However, this is not a problem because the algorithm provides a list of solutions , not just the optimal one. Fermenter feed characteristics were also considered during synthesis. Figure 2 shows that the feed glucose concentration and flow were both set to the minimum values in all three flowsheets. Although increasing the glucose concentration may increase productivity it also increases separation costs because of
REFERENCES Fraga, E. S. 1998. The Generation and Use of Partial Solutions in Process Synthesis. Transactions of the Institute of Chemical Engineers 76(A1): 45-54. Grossman, I. E. and Kravanja, Z. 1995. Mixed Integer Non-linear Programming Techniques for Process Systems Engineering . Computers and chemical engineering 19(5uPP1.): S83-S88. Guan, Y. X., Zhu, Z. Q. and Mei, L. H. 1996. Technical Aspects of Extractive Purification of Penicillin Fermentation Broth By Aqueous 2-Phase Partitioning. Separation Science and Technology 31(18): 2589-2597.
554
Computers and Chemical Engineering Supplement (/999) 55/-554
Table 2: Fermentation details (Swartz, 1985)
Innoculum component Glucose Ammonium sulfate Lard oil antifoam Sodium Phenylacetate P. Chrysogenum
I Concentration (g/L) I Fermenter char. 100.0 0.5 2.5 5 4.0
Initial volume Fermentation time Feed flow Glucose cone.
Value 100 in 3 250 hrs 60 or 100 l/hr 400 or 600 gil
Figure 2: The Best Three Flowsheets as Identified by the Synthesis Algorithm ~/L.
1st Cry, u ] Crystal rl1ttl lion
Fcrmc nlCr
d:y ing
HoI is
Penicillin
pmellC'
2nd Crys:A1:imioo
CJ)....1 fillr2ticn
Fcrmcn:
Srcnllllll\o-cu. md,s:ilIatio"
3rd
Fcrmcnter
Hatton, T. A. 1985. Liquid-Liquid Extraction of Antibiotics, pp. 439-449. In: M. Moo-Young (eds.), Comprehensive Blo/technology: the principles, applications and regulations of Bio/technology in industry, agriculture and medicine, ed., Pergamon, Oxford.
Paul, G. C. and Thomas, C. R. 1996. A Structured Model For Hyphal Differentiation and Penicillin Production Using Penicillium-Chrysogenum. Biotechnology and Bioengineering 51(5): 558-572.
Peters, M. S. and Timmerhaus, K. D. 1991. Plant design and economics for chemical engineers . 4th ed. Hersbach, G. J . M., van der Beek, C. S. and van McGraw Hill, New York. Dijck, P. W. M. 1984. The Penicillins: Properties, Reisman, H. 1988. Economic analysis of fermentaBiosynthesis and Fermentation, pp. 45-140. In: E. tion processes. ed. CRC Press, Boca Raton. J . Vandamme (eds.), Biotechnology oflndustrial AnPenicillins, pp. 7Swartz, R. W. 1985. tibiotics, ed., Marcel dekker, New york. 47. In : M. Moo-Young (eds.), Comprehensive Ho, W. S. and Kamalesh, K. S. 1992. Membrane Bio/technology: the principles, applications and regHandbook. 1st ed. Van Nostrand Reinhold, New ulations of Bio/technology in industry, agriculture York. and medicine, 1 ed., Pergamon, Oxford . Jaksland, C. A., Gani, R. and Lien, K" M. 1995. SepVogel, H. C. and Todaro, C. L. 1997. Fermentation aration process design and synthesis' based on therand Biochemical Engineering Handbook. Principles, modynamic insights. Chemical engineering science Process Design and Equipment. 2nd ed. Noyes pub50(3) : 511-530. lications , Westwood, New Jersey. Leser, E. W. 1994. Prot-ex: an expert system for seWesterberg, A. W. 1989. Synthesis in engineering lecting the sequence of processes for the downstream design. Computers and chemical engineering 13(4purification of proteins. PhD Thesis, The University 5): 365-376. of Reading, Reading.