The main objective of this work is to model and debottleneck a pharmaceutical production of an anti-allergic cream. The base case process has a minimum cycle time of 29 hours which is equivalent to 66 batches/year. Four schemes were proposed for process debottlenecking due to the anticipated increase of the product demand of 150% in the market. By carrying out throughput analysis study, schemes that fulfil the debottlenecking objective were determined. Out of the four debottlenecking schemes, Scheme 4 was chosen, which proposed a new blending tank and intermediate tank, showed a production increase of over 150%

Abdul Aziz, Ramlan

Foo, Dominic Chwan Yee

Kumaresan, Sivakumar

Tan, Jully

English

Universiti Teknologi Malaysia Institutional Repository

)ia pei". -.r: . '3e.-,J ,,:t n,*,J - il lv*cri,i,r-riEVALUATION OF PIIARMACEUTICAL CREAM PRODUCTIONDEBOTTLENECKING SCHEMESJully Tan,Doninic C.Y. Foo' Sivakurnar Kutnaresar, Ramlan A. AzizChenical Engineering Pilat Plant, Uni|e6iti Tetnologi MalaysiaI I 3I0 Sl'dai, J ohor, Malatsia|abiulMa|vahoocduk: ctfoo@.cepb t|n dljs hi 1e@ c e pp. ut n. n1) ; r anlad@ c e D:D!4!utIAbstracr The main objective ofthis work is to model and debotileneck a phannaceuticalproduction of an anti-allergic cream. The base cas€ process has a rninimum cycle time ofi9 hours which is equivalent to 66 batchestear. Four schemes were proposed forproc$s debottlenecking due to the anticipated increase ofthe product demand of 150%in the ma*et. By carrying out throughp$ analysis study, sohemes that ftlfil thedebottlenecking objective were determined. Out of the four debottleneoking schemes,Scheme 4 was choseq which proposed a new blending tank and intermediare ftnk,showed aproducrion i crease ofover 150%.Keywordsr Barch, modelling, optinisatio[ throughput,schedulingI. ]NTRODUCTIONComputer Aided Prooess Design (CAPD) andsimulation tools have been widely used in the bulkand petrochemical industries since the early 1960's.It involves the use of computers to perform steady_stat€ h€at and mass balancing a! well as lizing a:ndcosting calcularions for a process {We$erberg er a/.1979). However the use of these CAPD andsimulation tools has only emerged in thepharmaceutical ma.ufacturing in the past decade(Petrides, et ,1, 195; Hwa4, 1997; Emst et aI.,1997; Koulouris, er al, 20OOt Petides, et al , ZO0Za,b; Ol\ et al., 2004). Colnpared to tbe readilyavailabl€ comnercial process simulato$ in lhe bulkand lerochemical industries, lhere are only a limitednumber of commercial simulators available forpharmaceutical process modelling in the market,*hich include Batches by Batch ProcessTechnolosies, Barch Plus by Aspen Technolo8v,SuperPro Designer by l elligen as well as BatchDesign Kit by Hyproteoh. This situation is mainlydue ro the oonstraints associated with the nodellingof pharmaceutical processes, which include themcomlnon unit operatrons and batlb operation natweof phamaoeutical prooessing. Due to its relativelynew emergenoe, much work needs to b€ done in ihisThis pap€r describes the use ofthe commercial batchproc€ss simulator SuperPro Designer v5.0 in tb€modelling and debohlenecking of an anli-allergiccreain production line at a local phamaceutioalfaciliry. Due to the increasing customer demand ofth€ anti-allergic cream product, the pharnaceuticalfacilit management t€am is looking for a.ltemativeexpansion sohemes lo iDcrease the curent productionraie as the Foduction oapacitj is limited by thecunent operaling oondition and e4uipment setuP.Hence, a debottleneoking study is needed for anincreas€ in production.2. BACKGROUND THEORYln order to jnoease the prooess throughput theproc€ss bottleneck that limits the curreDt pJoducrionneed to be identified. Bottlenecks de processlimitations fta1 are related to eith€r equipmeDt orresource such as deinand for various utilities, labour,rav materiat, etc. H€nc€, proc€ss debottleteckingcan b€ defined a! the identifcation and removal ofobstacles in the attempt to increase the plantthroughput (Koulouh, et at, 2000). In batchmarufeturing, two types of process bottl€n€cks canbe oategorised. These are the equipm€nt capacrty'related size bottlenerk (an equipmett tlut is limited insiz€) as well as th€ scheduling bottleneck (due to thelong occupancy of an equipmenl during a Process)Tle abilit to identiS and remove processbottlenecks that create obstacles in a nanufaoturingprocess will increase plant throughput and tulfrlA good roolro identiry bath p.oces5 bonleneck is viaa throughput aralysis study. Thrcughput analysismeasures the equipment utilisation in a batch processwith two variables, i.e. the capacity utilisation andequipment uptime (Koulouris, €t dl, 2000; Petrides,et al.,2002a). Capac;iy utilisadon is defmed as thepercerlage of the curent operaling load of anequipment relative to its itaximum load On the otherhand, equipme uprime neasures $e effectivetess ofa piece of equipnent that is utilised iD lime lt isgiven as tle p€rcentage of the equ;pnent utilisariontime over th€ plant cycle time Tle Prodlct ofequipment capaoit utilisation and its uptine definesthe combined utilisation of the respective quipment(Koulouris, er at , 2000; P etides, et al., 2002a)- 'theprocessing step with the highest combined utilisationis identified as the process bottleneck. Simulattontools that are capable of tracking caPacit utilisationand equipment 'rptime om facilitate the identificationof process bottlenecks and the development of thesoenaiios for process debottlene.king. By using the"what if' scenario, prooess altematives can besinulated via the use of simulation tools to revealpotential cand;dates for lhe debonlenecting srud)3. MODEL DEVELOPMENTFig. I shows the base case simulatio' flowsheet forth€ production of anriallergic cream modelled inSuperPro Design€r v5.0. Du€ to the nature of theprocess that is operated in batch mode, tbe base casesimulation model was developed to rcflect tbe actualoperating condition of the cutrent production i, theexisting pharmaceutioal manufacturing facili9.Fig. 1. Base case simuladon flowsheet for lheproduction of anti'allergic oreamln Lhe baqe case process. rhere are nine majorprocessing sleps in three diferent sub-sections Thisincludes raw material melting in the Pre-mix'ngSection, Main Blending Section, as well as filling,cartoning, pekaging (shrink wrapping) and shipmentpackaging in the Pa.kaging sectio.s. Fifty tttooperation weeks were taken as the basis of this work.Tuo barches of emuhibins wax 'LSw) and romstabiliser (FS) are independently heated in the beati.gprocedures P-l (oarried out in Jacketed Heate.V-101)and P-2 (in Jackered Heater V-102) to approximately100'c b€fore the ernulsifier GMUL) and ointnentrOIN) are added.D€ionised rDn water is heated in the electric heaterEH-101 (procedure P-3) before beins transfened rntothe Main Blending Tank, V-103 (P-4) in the MainBlending Section. An antirnicrobial agent (AM) hn€xt added into the hot DI water. The mixtore in thejacketei heater V-101 and V-102 is then tansfenedinto V-103 and all insredients in V-103 are blendedfor a uniform composition. The mixture is then lefr inan air-conditioned dispensing foon to be narurallycooled to room temperature. This cooling operationtook approxnnately 19 hours to accomplish due to theslow rate of natual cooling. Upon the completion ofthe cooling ope.atio., the active ingredient (AI) oftheantiallereic crean is finaliy added before rhe produotmixture is sent ro the PackagiDg Section.ln the Packaging Seotion, the anti all€rgic cream isfilled into tbe tubes of 15 g eaoh. The existing fillingnachine is operated ar a speed of 30 tubevmin. Thetubes are then s€nt 10 the canoning packagingprocedure P-? (using a belt conveyer P-6/tsC-101)where the anti-allersic oream in tubes are paokedmalually by two operators into the tube cartons, eachat a speed of 20 cartons/min. Next, 12 oartons ofanti-allergic cream are packed into one wrapper in theskink wrapper (P-8/CBX-101), with a speed of 5lvrapp€r/min. Finally, 6 wrappen are packed tntoeach of the pallet boxes in P-9|BX-102 (equivalent o72 tubes/pallet box) before they are sent to thewarchouse. Approximately 6 sealed pallet boxes arepacked per minute by the operator manually.As the manufacturing process is carried out in a batchoperation, efforts have be€n mad€ to document hescheduling derails of each processing steps. TheOperation Gantt Chart for the conplet€ recipe of asingle batch operation is shown in Fig. 2. It shouldalso be noted that the process time for certainoperations arc dependant upon other op€rations ofotber procedure (e.g. Transfer-out fiDction in P-4 issel equal to the filling duration of P-5). Hence, th€dwation of this slave operation is set to follow to theduration of the master operation using the Master-Slave Relationship tunction of SuperPro Designer(Intellisen, 2003).The customer denand for this anri-allergic creanproduct is expected to rhe anothet 150% of thecurrent production capaciq in coming y€ats.However, the Focess is currently running at itsmarjmum capadty and any anempl of increasingproduction is not Possible due to the processboitleneck. This calls for a systematic procedure toanalyse the curent producdon facilities and next, todebottleneck the process.Fig. 2. Operaiion Gartt Chart for the base casesimulation.4. BOTTLENECK IDENTIFICATIONSTRATEGIESFrom the base case simulatioq a complete batch ofpharmaceutical cream production has a process batchtime of 40.2 hrs and a minimum cycle tiine of 29 hrs-The minimum cyole tine of the prooess ets the plantanoual Foduction at 66 baLh€s, widr 11,333 tubes ofanti-allergic cream produced per batch. The oapacity,tirne and combined utilisation of all theprocedure/equipment pairs in th€ base cas€simulation. As shown in Fig. 3, the Main BlendirgProcedurE P-4 (V-103) has the highest cornbinedutilisation of all prooedures. The product ofequipment utilisarion and uptine leads to the highestoombined utilisation of 84.1% for P-4lV-103, andheroe ;t is identified as the overall process bottleneckAfter id€ irying the Main Blending Procedure P-4(V-103) as the process bottleneck, debottleneckingstrategies will nexr be focused on reducing €;ther thesize or time utilisation ofthis procedure/equipmentFig. 3. Capac;ty, time and co'nbined utilhation forunit prooedures in base case simulation.5, DEBOTTLENECKING SCHEMESAfter identifying the candidate for processdebodlenecting. rhe feasibiliD of variousd€bottlene.king schemes were evaluated lsingsuperPro Designer. Four debottlerecking scheneswerc matysed in which all schemes were uppliedfocusing on reducing the equipment uptinre of P-4,^r'-I 03 as the process time bottlereck.For debottlenecking Schene l, a new intermediat€tank V-104 is installed after the Main Blendingvessel. fie TransfeFout opemlion in P-4lV - I 03 is nolonger crnstrajned by rhe slow filling operation inFiller P-5FL-101. Upon the completion on theblending operations in P-4,^r'-103, the Foductmixiure is transfened into the newly added V-104 fort€mporary storage, while waiting for the fillingoperation to complete. Simulation results showedftat rhe annual production for $is scheme isdetermined as 87 batches, wi$ rhe rcduction ofminimum cycl€ time that limits the nurnber of annualproduction from 29 hrs (in the base case simularion)to 21.6 hrs. This conesponds roan increase ofannualproduction rate of 32%, but is insufficient to tulfilprojected cuitomer demands.Schem€ 2 focuses on ihe reduction of coolingoperation of P-4,^r'-103 instead. A mulriftnctionalblerding tank with a cooling systeDr (purchase cost ofLSD 255.000) is installed to replace tle mainblending tank. This reduces the cooling tirne of theproduct mixture fton th€ cunent 19 hours to 5 hours.Chilled water is us€d as cooling agent to cool tbemixlure from 85'C to room temperature. This leadsto the reduction of rnininum cycle time lo 15 hrs.Hence, sn increase of 83.3ol" is achieved for annualproduction as conpared to the base case, i.e. fiom 66to 121 batches. How€v€r, P-4fr'-103 remains as theovenll process bottleneck although its combiredutilisation valu€ bas be€n reduc€d from the ourrent84.2To to 79.3o/o (as the uptime was reduced from94"/' to 88o/o). Further deboftlenecking can only beachieved if the long durarion of ils Transfer-outoperation (to filler P-5,GL-101) can be rcduoed.Scheme 3 explored the reduction of P-4lv-103uptime fiom a different perspective wh€re a new filler(50 tubes/min; purchase cost of USD 300,000) isinstalled in addiiion to the new multifunctionalblending lank in Scheme 2 to acc€lerate the fillingrate. AD annual p.odoction of 147 batches with aminimum cycle time of 12 hrs is achi€ved.Simulation result! showed that altlough the durationof Tnnsfer-oul operation in P4/V-103 can bereduc€d significadly, dre combined utilisation valueof P-4,ry-103 is only ieduced slightly to 77.10%o(*on 793avo) in Schene 2). Th€ resultins annuatproduction is determined as 147 batches, i.e. anADother debottlerecking altemativ€ focusing onreducin8 the overall uptime ofP-4/V-103 is preseniedir Soheme 4 (Fig. 4). Instead of installi.g a newfilling machine a! in Scheme 3, an intermediatestorage tsnl( (v-104; plrrchase crst of usD10,000) isadded here in addition to fte installation of a newBl€nding Tank (P-4,^/-103) Sinulatiot resuh,showed thar the annual produclion ior !his scheme i<173 batches lvith a mjnimum cycle time reduoed 1o9.9 hts. Ttis co esponds to an inc.ease of annualproduction rate of 162%, fulfilling the fthrre marketFig. 4. Debottlenetking Scheme 4installatiori of intermediate tankmultitunctioml blending tank.It should also be noted that after tbe installation ofintermediate storage tank P-10^r'-101, the nai,blending tank (P-4,^/-103) is no longer the processbottleneck. Thh is consistent witb the finding ofKoulouris e/ al (2000), where new bofileneckequipment will emerge after the current bottleneck isovercome. Debotttenecking efons are stopped atthisscheme as the debotdenecking objective is reached,i.e. achieving the 150% increase in produotion ascompared to curent Production6. CONCLUSIONIn this worlq cornputeFaided Proc€ss design (CAPD)- and sirnulation tools ate used in the syst€maticidentification of th€ process bottleneck and adebottlenecking study. A local phannaceutical casestudy of anti-allergic cream productior is used iodemonstraie the effectiveness of th€ tools. The baseoase ard four debottleneckng schemes are simulatedusing SuperPro Desiger. lt is shown that wjtll tbereduction of equipment uptime of the Focess timebotdeneck, the annual prooess ihroughpd is increasedsignificantly. The study resulted in a debotdeneckingscherne that achieves the cunent produotion ne€ds.andREFERENCESErnst, S., O.A. Gano, S. Winkler, S., G.Venkataraman, R. Langer, C.L. Cooney and R.Sasisekharan, (1997) Process sirnu,ation forrecombinant protein production: oost estimationand sensitivity analysis for Heparinase Iexqessed in Escherichia coli. Biotechnologl qndBioe nsine et ins, 53(6), w. 57 5 -s82.Hwang, F. (1997). Batch pharmaceutical prooessd€sign and simJlation. 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Evaluation of pharmaceutical cream production debottlenecking schemes

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Evaluation of pharmaceutical cream production debottlenecking schemes

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