This paper discusses the usage of computing machine simulation tools for patterning a pilot scale monoclonal antibody production in a contract fabricating organisation ( CMO ) . A batch procedure simulation package named SuperPro Designer v6.0 ( Intelligen, 2005 ) is employed to pattern and execute the programming undertaking for a 1000 L monoclonal antibody production as a base instance theoretical account. In order to increase the works throughput, optimisation schemes are proposed with alternate procedure apparatuss that utilize idle equipment in the works. As such, the CMO is able to bring forth six more batches per twelvemonth and hence cut down its payback clip to about two old ages. This optimized scheme is following used as drawn-out base instance where uncertainness analysis is carried out with Monte Carlo simulation. From the analysis, it is determined that cell civilization clip in the bioreactors have the greatest impact in accomplishing the targeted works throughput and profitableness.

To heighten fabrication efficiency and hence concern fight in the pharmaceutical industry, assorted design and optimisation techniques have been developed in the past decennaries. Computer-aided procedure simulation ( CAPS ) is one of such tools that has gained good attending in recent old ages in bettering fabrication efficiency. It involves the usage of computing machines to execute steady-state heat and mass reconciliation, every bit good as size and costing computations for a procedure ( Westerberg et al. , 1979 ) . Most frequently, it enables the designation of losing parametric quantities and predicts the behaviour of an incorporate procedure under changing operating conditions. CAPS has been normally used in the majority and petrochemical industries since the late 1960 ‘s. However this tool is comparatively new to other fabrication industries. For case, in biochemical production, the usage of CAPS has merely been reported since center 1990s ( Petrides, 1994 ; Petrides et al. , 1995 ) . More late, CAPS were besides being used in pharmaceutical production ( Petrides et al. , 2002a, Tan et al. , 2006 ) , specialty chemical fabrication ( Athimulam et al. , 2006 ) ; nutrient and drink processing ( Bon et al. , 2010 ; Alshekhli et al. , 2011 ) , every bit good as H2O intervention processes ( Petrides et al. , 2001 ) .

More late, the incorporation of economic analysis and debottlenecking maps into CAPS tools enable the procedure interior decorators to place economic “ hot-spot ” of a procedure at the early conceptual design phase. Assorted options can so be incorporated and evaluated with CAPS tools to cut down capital and/or runing costs in order to increase production throughput ( Koulouris et al. , 2000 ; Petrides et al. , 2002b ) .

In this work, a pilot scale monoclonal antibody fabricating procedure in a contract fabricating organisation ( CMO ) is modeled utilizing SuperPro Designer v6.0 ( Intelligen, 2005 ) . To increase production throughput, different optimisation schemes with alternate procedure apparatuss are proposed and evaluated utilizing SuperPro Designer. This optimized scheme is following used as an drawn-out base instance where uncertainness analysis is carried out with Monte Carlo simulation to quantify hazards in meeting targeted works throughput and profitableness.

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BASE CASE SIMULATION

The production of monoclonal antibody ( MAb ) from mammalian cell civilization is simulated as a base instance theoretical account in SuperPro Designer, with the simulation flowsheet shown in Figure 1. The MAb production consists of upstream ( which consists of Inoculum Preparation and Cell Culture subdivisions ) and downstream processing ( consists of Recovery and Purification subdivisions ) .

Supporting operations such as media readying, pre-operation and post-operation stairss, i. e. cleansing in topographic point ( CIP ) and sterilisation in topographic point ( SIP ) are besides considered in the theoretical account. Buffer readying, nevertheless, is non modeled for simpleness. It is assumed that all buffers, cleansing and storage solutions ( apart from that of the machine-controlled CIP rhythms ) are prepared in progress prior to the operation and stored in disposable bags.

The MAb production starts with inoculum readying in two spinster flasks ( in the Inoculum Preparation subdivision ) , each of 1 L working volume. Once the desired cell denseness is achieved, the inoculant is transferred from the spinster flasks to the 5 L bioreactor ( 00.05.D001 ) . The media solution for spinster flasks is transferred straight from the makers ‘ packaging, while the media solution for 5 L bioreactor is prepared in a chromium steel steel readying armored combat vehicle ( 01.03.T001 ) , together with the media for the subsequent bioreactors ( in the Cell Culture subdivision ) . The media solution is sterilized by go throughing through a 0.2 Aµm unfertile filtration unit ( 01.15.F002/3 ) . Media solution for 5 L bioreactor ( 00.05.D001 ) and 30 L bioreactor ( 02.05.D001 ) is collected in disposable bags and transported into the designated production country, while media for 200 L bioreactor ( 02.06.D001 ) and 1000 L bioreactor ( 02.07.D001 ) is transferred straight into the recipient bioreactor via the piping panel.

Upon the completion of the transportation, the media solution is stored in the bioreactors at 4 A°C until the start of cell civilization. Storage at low temperature is made possible by using ethanediol as the chilling agent. As the 1000 L production bioreactor is operated in fed-batch manner, merely 500 L of media solution is transferred at the start of cell civilization. Another 300 L of media solution is prepared individually in the readying armored combat vehicle ( 01.03.T001 ) and fed into the bioreactor during the cell civilization. The cell civilization in the 5 L, 30 L and 200 L bioreactors takes 3 yearss each, whilst the 1000 L bioreactor takes 15 yearss. The volume of concluding cell civilization stock is about 1000 L, incorporating about 1 kilograms of MAb.

Upon the completion of the cell culturing procedure, the content of the bioreactors are tranferred to the Recovery subdivision. Biomass and other suspended compounds ( denoted as drosss ) in the civilization stock are removed utilizing a disposable deepness filter system ( POD-1 ) . The deepness filter country is estimated as 15.4 M2 and the filtration rate is set to 38.5 L/min. It is estimated that 5 % of the MAb is lost into the solid waste watercourse during the filtration measure. The clarified solution is directed to a chromium steel steel nomadic procedure vas ( 02.23.T001 ) . However, due to its limited capacity, the vas can merely incorporate 200 L of the clarified solution, while the staying 800 L is collected in two units of 500 L disposable bag. This is followed by 10-fold concentration and 5 times diafiltration of the clarified solution utilizing a 4.5 M2 filtration system ( 02.16.D001 ) , with filtrate flux set to 140 L/m2h. Permeate of the diafilter is pooled in the nomadic procedure vas, which is so transferred into disposable bags to be sent to the Purification subdivision.

In the Purification subdivision, Protein A chromatography is carried out in two rhythms utilizing a chromatography system of 45 cm-diameter column ( 02.09.D001 ) . The operating parametric quantities are set as follow:

Bed height: 20 centimeter ( i.e. a bed volume ( BV ) of 31.81 L )

Resin adhering capacity: 25 g of product/L of rosin

Merchandise is recovered in 5 BV ‘s of low pH Buffer B

Merchandise recovery output: 90 %

Linear speed: 200 cm/h for all operations

Entire buffer demands:

Buffer A: 13 BV ‘s ( for equilibration and wash out unbound )

Buffer B: 10 BV ‘s ( for merchandise elution and column regeneration )

Wash Buffer: 3 BV ‘s ( for intermediate column wash )

The eluant from Protein A chromatography is collected in a 100 L disposable bag and incubated for 45 proceedingss for virus inactivation. Subsequently, the protein solution is transferred into a 150 L chromium steel steel procedure armored combat vehicle ( 03.23.T001 ) . Tris solution is added into the armored combat vehicle to set the pH value of the protein solution for neutralization. The solution so undergone 5-fold concentration followed by 5 times diafiltration ( 03.16.D001 ; with 1.5 M2s filter country and filtrate flux of 140 L/m2.h ) . The concentrated protein solution from each rhythm of Protein A chromatography is pooled in a temperature-controlled disposable bag system ( ALG-1 ) .

The following merchandise purification measure is flow-through mode anion exchange chromatography ( IEX ) utilizing a chromatography system with 25 cm-column ( 03.09.D001 ) . In flow-through manner, it is the drosss that bound to the rosin alternatively of the merchandise. Therefore, the merchandise is captured during lading operation and non during elution. The IEX operating parametric quantities are set as follows:

Bed height: 10 centimeter ( i.e. BV of 3.14 L )

Linear speed: 200 cm/h for all operations

Entire buffer demands:

Buffer A: 13 BV ‘s ( for equilibration and wash out unbound )

Buffer B: 10 BV ‘s ( for elution and column regeneration )

The protein solution that flowed through the IEX chromatography column is so filtered utilizing a nanofilter for remotion of virus residues. This is followed by 5-fold concentration and 5 times diafiltration of the protein solution utilizing a filtre ( 04.16.D001 ; with 0.42 M2s filter country and filtrate flux of 140 L/m2.h ) . Permeate of ultrafiltration is collected in a 150 L chromium steel steel procedure armored combat vehicle ( 04.23.T001 ) and transferred into a 20 L disposable bags for smoothing measure in cation exchange chromatography ( CEX ) .

Polishing measure in the CEX is executed in four rhythms utilizing a chromatography system with 20 cm-diameter column ( 04.09.D001 ) . The operating parametric quantities are set as follow:

Bed tallness is 20 centimeter. Therefore, the BV is 6.28 Liter

Resin binding capacity is 40 g of product/L of rosin

Merchandise is recovered in 5 BV ‘s of Buffer B

Merchandise recovery output is 90 %

Linear speed is 200 cm/h for all operations

Entire buffer demands:

Buffer A: 13 BV ‘s ( for equilibration and wash out unbound )

Buffer B: 10 BV ‘s ( for merchandise elution and column regeneration )

The eluted solution is collected in the same procedure armored combat vehicle ( 04.23.T001 ) used in the preceding process. The solution is so concentrated 2-fold and diafiltered 5 times with merchandise preparation buffer ( i.e. PBS ) , besides utilizing the same filtration system ( 04.16.D001 ) . However, different set of membrane cassettes are used for this process. The concentrated protein solution eventually passed through a 0.2 Aµm unfertile filter for bioburden decrease prior to bulk make fulling into an appropriate merchandise container.

In this base instance theoretical account, different attacks are used to stand for the three major chromatography stairss ; pre-operation, operation and post-operation. This is peculiarly important for chromatography processs with multiple rhythms. Pre-operation and post-operation activities are done merely one time per batch and non repeated in each chromatography rhythm. Therefore, the lone manner to stand for these activities is by utilizing a separate unit process that utilizes the same equipment. For case, process P-41 is dedicated for CEX operation that consist of four rhythms per batch, while P-41a and P-41b each represents pre-operation and post-operation activities for CEX that are merely performed one time per batch. Another attack is to utilize multiple unit processs to stand for the multiple rhythms and to include the pre-operation activities in the first rhythm and the post-operation activities in the last rhythm. This is well easy for little figure of rhythms like in this instance ; Protein A chromatography that has merely two rhythms ( P-26 and P-31 ) . Otherwise, this attack is instead complicated and may ensue in a complex flowsheet.

We following treatment the scheduling facet of the batch procedure patterning. In the mold model of SuperPro Designer, programming of all operations in each unit process is set up based on the apparatus clip, procedure clip, and get down clip ( Intelligen, 2005 ) . Setup clip is the readying clip required before an operation takes topographic point. This involves equipment readying or operation apparatuss such as connexion of bobbin pieces and hosieries, every bit good as the transportation of stuff from one treating country to another. On the other manus, procedure clip represents the existent processing continuance of the operation, whereas start clip denotes the beginning of the operation.

Note that procedure clip for certain operations is dependent upon other operations of the same or different process. This inter-dependency is represented utilizing the Master-Slave Relationship characteristic in SuperPro Designer ( Intelligen, 2005 ) . For illustration, the transportation in inoculum operation in process P-13 is set to follow the continuance of transportation out operation in Procedure P-12. In this instance, the transportation out operation in Procedure P-12 behaves as the Master operation, whilst transportation in inoculum operation in process P-13 behaves as the slave operation.

Note that in order to accurately stand for the procedure agenda, the start clip of certain operations are given a clip displacement, chiefly to avoid imbrication of operations when using the same equipment. For case, CIP operation in process P-24 has a start clip displacement of 2.50 hours after the old operation ( Blushing ) ends. This is to let the completion of CIP 1000L operation in process P-13 that uses the same CIP Unit. Similar clip displacement attack is besides applied for CIP operations in processs P-33 and P-38. On the other manus, multiple usage of procedure armored combat vehicle 04.23.T001 for processs P-38 and P-42, every bit good as filtration system 04.16.D001 for processs P-39 and P-43, consequence in a clip displacement of 4.5 hours for transportation out operation in process P-40. This clip displacement ensures that sufficient clip is allocated to wholly clean these two equipment prior to the start of the ulterior processs. Scheduling of the base instance theoretical account is represented in the Gantt chart as shown in Figure 2.

From the base instance simulation theoretical account, the works batch clip is determined as 679.72 hours. This is the clip required from the readying of inoculant in the spinster flasks to the concluding filtration of merchandise in a individual batch. A new batch is initiated every 634.67 hours, which corresponds to the minimal rhythm clip calculated by SuperPro Designer. The 1000 L bioreactor ( 02.07.D001 ) of process P-13 is identified as the programming constriction. On an one-year footing, the works processes a sum of 12 batches, or a sum of 7.62 kilograms of MAb. For every batch, the MAb recovery output is determined as 64 % . In other words, 640 g of MAb is recovered from the 1000 L bioreactor ‘s civilization stock.

Table 1 shows the sum of natural stuffs required for the MAb production. As shown. big sum of RO Water is being utilized for each batch, chiefly for CIP operations. A sum of 5,650 kilograms WFI is besides used for CIP operation ( i.e. as concluding rinse ) . Apart from the machine-controlled CIP operations, all buffers, cleansing and storage solutions are besides prepared from WFI. However, the sum of WFI used for the makeup of these buffers and solutions are non shown in the tabular array, but can be calculated from its mass composing, as defined in the stock mixtures databank.

To execute economic analysis of the MAb production, declarative values from the CMO are used. These include the cost of natural stuffs, consumables, public-service corporations, waste disposals and labor, every bit good as other economic rating parametric quantities such as depreciation period, income revenue enhancement rate, etc. The entire capital cost investing estimated by SuperPro Designer utilizing its constitutional economic rating theoretical account ( Intelligen, 2005 ) is estimated as $ 36 million. This appraisal is inline with the CMO ‘s existent capital investing. The works gross is calculated based on the production rate of MAb in stream S-208 at a merchandising monetary value of $ 1,500/gram. With a unit production cost of about $ 1,000/gram of the purified MAb, the undertaking yields a payback clip of 5.18 old ages, with a gross border of 32.45 % and return on investing ( ROI ) of 19.32 % . The after-tax internal rate of return ( IRR ) is 12.27 % and the net nowadays value ( NPV ) is $ 13 million ( based on price reduction involvement of 7 % ) . As an inducement to advance the growing of biotechnology, the CMO is exempted from income revenue enhancement for the first 10 back-to-back old ages the company derived statutory income from its concern. Therefore, the income revenue enhancement rate of the theoretical account is set to 0 % .

Figure 3 shows the interruption down of the works one-year operating cost. The facility-dependent cost is the chief subscriber, accounting for 74 % of the operating cost. This is common for high value-added merchandises that are manufactured in little measures. Consumables are in the 2nd place with 13 % of the entire operating cost, which include disposable bags for storage of media and buffers, every bit good as chromatography rosins and membrane filters that need to be replaced on a regular footing. Natural stuffs and laboratory/QA/QC constituents each contributes 5 % of the entire cost, followed by labor cost at 3 % . In this instance, the labor cost is set to $ 5.75 per hr for equipment operation, integrating factors for periphery benefits, runing supplies cost, supervising cost and disposal cost based on the constitutional theoretical account in SuperPro Designer ( Intelligen, 2005 ) . On the contrary, the cost of labor for laboratory/QA/QC plants is defined as 15 % of the entire labor cost and is inclusive of the laboratory/QA/QC cost. The laboratory/QA/QC cost besides covers elaborate costing of all trials based on the defined frequence and cost per trial, either on an one-year or per batch footing. Tables 2 and 3 provide the sectional lists of laboratory/QA/QC trials considered in the base instance theoretical account. A subdivision named Facility is created in the simulation theoretical account to include the one-year operating cost in keeping the installation and public-service corporation systems.

Optimization STRATEGIES

In order to increase the works throughput and profitableness, two optimisation schemes are proposed. These optimisation schemes, nevertheless, are merely limited to the bing works and the equipment housed within it. This is because the CMO has no purpose to buy new equipment due to infinite restraint in the works. Apart from the equipment used in the base instance theoretical account, the following idle equipment, which is designed for the processing of smaller batch size ( 200 L ) , may be utilized in the optimized theoretical account.

Stainless steel readying armored combat vehicle ( 01.04.T001 ) of 300 L working volume

Chromatography column ( diameter = 10 centimeter, height = 50 centimeter )

Chromatography column ( diameter = 30 centimeter, height = 50 centimeter )

Optimization Strategy 1 suggests an alternate apparatus for media readying where the idle readying armored combat vehicle 01.04.T001 is used in add-on to readying armored combat vehicle 01.03.T001. Alternatively of fixing the media for 5 L, 30 L, 200 L and 1000 L bioreactors in a individual armored combat vehicle ( 01.03.T001 ) , the media is prepared in both 01.03.T001 and 01.04.T001. This apparatus is illustrated in Figure 4. Preparation armored combat vehicle 01.04.T001 is assigned to fix the media for 5 L, 30 L and 200 L bioreactors in process P-45, while readying armored combat vehicle 01.03.T001 is dedicated to fix media for 1000 L bioreactor in process P-4. This scheme allows the start of a new batch every 491.60 hours ( about 6 yearss earlier than the basal instance ) , and later increases the works throughput to 18 batches per twelvemonth. The simulation consequence indicates that 15.10 % addition in runing cost is observed, chiefly due to more cleaning operations and the ingestion of the 0.2 Aµm filters in the sterilisation of media. However, this addition is easy compensated by the important addition in the figure of batches processed per twelvemonth. Furthermore, this alternate apparatus could cut down the hazard of taint of media in the 1000 L bioreactor, since the media readying is scheduled merely before the transportation of inoculant. This is in contrast with the base instance theoretical account where the media is prepared in progress and stored at 4 A°C in the bioreactor for about 10 yearss before the transportation of inoculant. Figures 5 and 6 show the difference in the equipment tenancy for both theoretical accounts and the earlier start of a new batch.

Apart from cut downing the minimal rhythm clip, the procedure can be farther optimized utilizing Strategy 2. In this scheme, the batch clip is reduced by minimising the figure of rhythms for cation exchange chromatography ( CEX ) in process P-41. This is made possible by utilizing a larger column so that more merchandises can be loaded in every rhythm. Alternatively of four rhythms in Optimization Strategy 1, process P-41 is carried out in merely two rhythms utilizing a column of 10 centimeters larger in diameter. The comparing between the process apparatus for Optimization Strategies 1 and 2 is given in Table 4. When utilizing a larger column, more chromatography rosin is required to pack the column. However, the rosin is replaced less often as a effect to the less figure of rhythms per batch. Furthermore, fewer buffers will be consumed for the process. These nest eggs are reflected by a 1.04 % decrease in the operating cost as compared to Optimization Strategy 1 ( see Table 5 ) .

Table 5 shows the consequences of throughput analysis and economic rating for the simulation theoretical accounts of the base instance, Optimization Strategies 1 and 2. By comparing the economic consequences, it is evident that Optimized Strategy 2 with higher Return on invested capital and lower payback clip would be the best solution to increase the CMO ‘s works throughput and profitableness. This theoretical account, henceforward denoted as the drawn-out base instance, which are used as the footing for uncertainness analysis, as described in the undermentioned subdivision.

Uncertainty ANALYSIS

The simulation theoretical account constructed utilizing SuperPro Designer is of deterministic nature. This means that the theoretical account will supply consistent end products and does non see the random fluctuation of the inputs. For the simulation theoretical accounts discussed in earlier subdivisions, mean value has been used for the varying procedure input ( e.g. cell civilization clip ) . In this subdivision, uncertainness analysis is performed on the drawn-out base instance theoretical account utilizing Monte Carlo simulation. The simulation quantifies the hazards in meeting targeted works throughput and profitableness due to uncertainnesss in operational parametric quantities and variableness in the cost of natural stuffs and consumables.

Monte Carlo simulation is carried out by incorporating SuperPro Designer with an Excel add-in application called Crystal Ball ( Intelligen, 2005 ) . The model for incorporating the two tools is shown in Figure 7. The chance distributions of the unsure input parametric quantities for Monte Carlo simulation are defined in Crystal Ball. When running the Crystal Ball application, random values for these parametric quantities are generated utilizing the Monte Carlo method harmonizing to their assigned distribution. For each simulation test, the random values of the unsure input parametric quantities are sent to SuperPro Designer, which will so execute assorted computations for the procedure flowsheet. This includes stuff and energy balances, programming and capacity use computations, cost appraisal and economic rating. The values of the end product variables from SuperPro Designer are so sent back to Crystal Ball as prognosiss. The input and end product variables are linked to each other in an Excel spreadsheet utilizing VBA books written in C linguistic communication ( Intelligen, 2005 ) .

Figure 8 shows the flowsheet of the drawn-out base instance theoretical account, corresponds to the consequences of Optimization Strategy 2. As mentioned in earlier subdivision, the works processes a sum of 18 batches of MAb per twelvemonth. The simulation consequences besides determine that the unit production cost is estimated as $ 770/kg MAb. Assuming the company has a production mark of 14 successful batches per twelvemonth, and an upper bound of $ 900/kg of MAb for the unit production cost, the above-named analyses show that the company is able to run into its production and unit cost marks. However, it is good to execute uncertainness analysis to help the CMO in quantifying the hazards of non run intoing these marks.

The uncertainness analysis is focused on parametric quantities that may hold direct impact on works throughput ( i.e. figure of batches per twelvemonth ) and profitableness ( i.e. unit production cost ) . The major subscribers to the unit production cost are the costs of facility-dependent, consumable, natural stuff and laboratory/QA/QC. Since production is carried out in an bing works, fluctuation in facility-dependent cost is negligible. The same premise goes to laboratory/QA/QC costs, which do non change much when there are no major alterations in the procedure.

Significant uncertainness, nevertheless, is expected on the cost of natural stuffs and consumables as they are extremely associated with the supply and demand state of affairs, every bit good as the universe economic science. When demand is more than supply, the material monetary value will increase of course, and frailty versa. Furthermore, most natural stuffs and consumables used in the production at the CMO ‘s site are imported. Fluctuation in universe economic sciences will hence hold important impact on the cost of natural stuffs and consumables. Table 6 shows that 1X Media Solution is the most expensive natural stuff, which contributes 79.5 % of the natural stuffs cost. On the other manus, Virus Filter is the most expensive consumable, stand foring about 21.7 % of the consumables cost, followed by Protein A at 17.6 % , as illustrated in Table 7.

The works one-year throughput is determined by the minimal rhythm clip of the programming constriction ( i.e. P-13 ) . Hence, any procedure alteration that increase the rhythm clip of P-13 will ensue in lower degree of one-year batch production. In other words, any variableness in the completion of P-13 will take to uncertainness in the works throughput. This variableness is non limited to operations within P-13 entirely, but besides the variableness in the assorted processs upriver of P-13. Procedures P-3 and P-10 for illustration, poses uncertainness in their operations due to the variableness in the accomplishments of operators during manual equipment apparatus ( 5 L bioreactor and 30 L bioreactor severally ) . The worst instance would be cell civilization taint in these bioreactors, which will necessitate a complete restart of the full process.

Table 8 summarizes the input parametric quantities chosen for the uncertainness analysis and their false chance distributions. Two prognosis variables are considered in the simulation, i.e. the figure of batches per twelvemonth and the unit production cost of the MAb. These variables are chosen based on their significance in production planning and procedure economic sciences. The end product variables of the Monte Carlo simulation are quantified by mean, average, manner, discrepancy, standard divergence and frequence distribution.

The simulation consequences ( i.e. one-year batch production and unit production cost ) are presented in frequence distribution curves for the prognosis variables. After 1,000 simulation tests, the distribution curves for the prognosis variables are usually distributed. The Frequency Chart in Figure 9 reveals that the company is able to accomplish its production mark of minimal 14 successful batches per twelvemonth with a certainty of 87.20 % ( represented in bluish bars of the curve ) . On the other manus, the Frequency Chart in Figure 10 shows that the certainty of run intoing the company ‘s unit production cost mark of $ 900,000 is 87.10 % .

Apart from Frequency Charts, Sensitivity Charts provide overview on the fluctuation of the prognosis variables with regard to the unsure parametric quantities. This is really utile as it allows the company to place which input parametric quantity have the greatest impact on the works throughput and profitableness, and therefore concentrate the attempt to better this parametric quantity. The Sensitivity Charts for the figure of batches per twelvemonth and the unit production cost are given in Figures 11 and 12 severally. Cell civilization clip in P-10 ( i.e. 30 L bioreactor ) has the greatest impact on both the figure of batches per twelvemonth ( accounting for 65.4 % among the factors ) , every bit good as the unit production cost ( contributes to 58.6 % among the factors ) . This is followed by cell civilization clip in P-3 ( i.e. 5 L bioreactor ) . Cell civilization clip in P-13 ( 1000 L bioreactor ) and 1X Media Solution cost besides contribute to the unit production cost, but with much smaller per centum ( 3.6 % and 2.9 % severally ) . Therefore, the company should concentrate its betterment attempts on the operation of 5 L and 30 L bioreactor to hold a better certainty of run intoing its throughput and profitableness marks. Better apprehension of the procedure, good procedure handling, well-trained operators and execution of advanced mechanization can assist to cut down the variableness in the operation of these bioreactors.

Decision

This paper demonstrates how CAPS tools are used in patterning and optimising a pilot scale production of monoclonal antibody. In base instance simulation, SuperPro Designer is used to imitate and schedule the production procedure. Optimization schemes are so proposed and evaluated utilizing the package in order to increase the works throughput and profitableness. Optimization Strategy 2 proves that even without the purchase of new procedure equipment, the one-year throughout of the works can be increased significantly by cut downing the minimal rhythm clip. This is made possible by utilizing alternate equipment apparatuss and using idle equipment available in the works.

An uncertainness analysis survey is so carried out by incorporating SuperPro Designer with a Monte Carlo simulation package known as Crystal Ball. This quantifies the hazard in run intoing the CMO ‘s mark in footings of throughput and profitableness. Uncertainties in operating parametric quantities and variableness in the cost of natural stuffs and consumables are taken into history in the simulation. From the analysis, it is determined that cell civilization clip in the bioreactors have the greatest impact in accomplishing the targeted works throughput and profitableness.

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