Monoclonal Antibody Production

This example analyzes the production of a therapeutic monoclonal antibody using animal cell
culture. The recipe analyzed produces 19 kg of purified product per batch. Three SuperPro
esigner files are included in this example!
Mab7_0a.spf: This is the simplest file of the three. "t represents the core Mab process
#buffer preparation $ holding% deli&ery lines% transfer panels not included'. (or reference
and guidelines on ho) to model a simple Mab production process the user should refer to
section * of this file.
Mab7_0b.spf: This file is based on the pre&ious file but it also includes modeling of
buffer preparation and holding acti&ities% transfer panels% and buffer deli&ery lines. "t
explains ho) to specify e+uipment sharing )ithin these and pro&ides tips on ho) to
model single,cycle operations in multi,cycle unit procedures. (or information on all the
abo&e the user should refer to section - of this file.
Mab7_0c.spf: The process of this file is the same as the pre&ious one. The difference
bet)een the t)o files is in the number of upstream trains used. "n this case a cycle time
reduction exercise is performed by increasing the number of bioreactor trains. This is the
implementation design and thus a full economic analysis is performed to e&aluate
profitability. (or information on ho) to specify staggered e+uipment in order to reduce
cycle times and ho) to perform cost of goods analysis% please refer to sections . $ / in
this file.
Section 1 belo) pro&ides a brief description of the basic features of the monoclonal antibody
process #Mab7_0a.spf'. All files for this example can be found in the 0!1Program
(iles1"ntelligen1SuperPro esigner123AMP42S1MA5.67 subdirectory.
1 8pstream Processing
The upstream section is split in t)o sub,sections% the "noculum preparation section and the
5ioreaction section. (lo)sheet sections in SuperPro are simply set of related unit procedures
#processing steps'.
1.1 "noculum preparation
The inoculum is initially prepared in 99* ml T,flasks. The material is first mo&ed to roller bottles
#9.9 4'% then to 97 4 and subse+uently to 177 4 disposable bag bioreactors. Sterilized media is
fed at the appropriate amount in all of these four initial steps #:.-% 11.;% ;:.-% 1.*.; kg<batch
respecti&ely'. The broth is then mo&ed to the first #1777 4' and second #;777 4' seed bioreactor.
(or the seed bioreactors the media po)der is diluted using =(" in t)o prep tanks #MP,171 $ MP,
179' and then sterilized<fed to the reactors through 7.9 >m dead,end filters #2,171 $ 2,179'.
1.9 5ioreaction section
Serum,free lo),protein media po)der is dissol&ed in =(" in a stainless steel tank #MP,17:'. The
solution is sterilized using a 7.9 m dead,end polishing filter #2,17:'. A stirred,tank bioreactor
#P5?1' is used to gro) the cells% )hich produce the therapeutic monoclonal antibody #Mab'. The
production bioreactor operates under a fed batch mode. To edit the fed batch options the user
should select the Fed Batch tab of the FERMENT-1 (Batch Stoich. Fermentation) operation
dialog. @igh media concentrations are inhibitory to the cells so half of the media is added at the
start of the process and the rest is fed at a constant rate during fermentation. The concentration
of media po)der in the initial feed solution is 1. g<4. The fermentation time is 19 days. The
&olume of broth generated per bioreactor batch is approximately 1*%777 4% )hich contains roughly
:7 kg of product #the product titer is approximately 9 g<4'. The target product titer can be
specified through the Reactions tab of the FERMENT-1 (Batch Stoich. Fermentation) operation
dialogA select the option Calculate to Achieve. The stoichiometry of the reaction is specified by
clicking on the button that looks like a shake flask #in the ?eaction Se+uence box'.
9 o)nstream Processing
5et)een the do)nstream unit procedures there are 7.9 >m dead,end filters to ensure sterility.
The generated biomass and other suspended compounds are remo&ed using a isc,Stack
centrifuge #S,171'. uring this step% roughly 9B of Mab is lost in the solids )aste stream
resulting in a product yield of 9/B. The bulk of the contaminant proteins are remo&ed using a
Protein,A affinity chromatography column #0,171'. The yield on Mab for this step is 97B. The
protein solution is then concentrated *x and diafiltered 9x #in P,91 < (,171'. The yield on product
is 9.B and this is represented by the product denaturation feature of the iafiltration operation.
The concentrated protein solution is then chemically treated for 1.* h )ith Polysorbate /7 to
inacti&ate &iruses #in P,99 < C,111'. An "on 2xchange chromatography step follo)s #P,9; 1 0,179'
)ith a yield on Mab of 97B. Ammonium sulfate is then added to the "23 eluate #in P,9* 1 C,179'
to increase the ionic strength for the @ydrophobic "nteraction 0hromatography #P,9- 1 0,17:' that
follo)s. 17B of Mab is lost during the @"0 procedure. A &iral exclusion step #2,17*' follo)s. "t is
a dead,end type of filter )ith a pore size of 7.79 >m. (inally the @"0 elution buffer is exchanged
for the product bulk #P5S' storage buffer and concentrated 1.*,fold #in (,179'. The
approximately /77 4 of final protein solution is stored in t)enty *7 4 disposable storage bags
#0S,171'. 19 kg of Mab per batch are produced approximately. The o&erall yield of the
do)nstream operations is approximately -:B.
DET2! Dumbers bet)een the files may differ slightly due to modeling differences
: Feneral features
"n all the unit procedures% excluding those utilizing disposable containers and columns% an S"P
operation is scheduled before and a 0"P after the main processing. =(" is used for the rinsing
step of the 0"P cycle )hile the 0"P skids are dedicated either to upstream or do)nstream
e+uipment #9 skids for the upstream section and 9 for the do)nstream'. (inally% flush operations
are performed prior to processing in the t)o diafiltration units #(,171 and (,179'.
; Material ?e+uirements
The table belo) displays the material re+uirements in kg<year% kg<batch and kg<kg MP #main
product G purified Mab in this case'. This plant produces approximately 19 kg of therapeutic Mab
per batch. The table belo) )as extracted from the ?T( &ersion of the Streams Mat. Balance
report of the Mab.67a.spf file. The material results of the other t)o files #Mab7_0b.spf,
Mab7_0c.spf' are different because they also include the cleaning of the buffer prep and
holding &essels% )hich are missing from this file. ?eports in SuperPro are generated through the
Re!orts menu of the main menu bar. The format and contents of the reports can be customized
by selecting Re!orts " #!tions from the main menu bar.
B$%& RA' MATER(A%S (ENT(RE )R#CESS)
Ra* Material +,-.r +,-/atch +,-+, M)
"noc Media Sltn ;%91; 9:;.777 19.1/9
=(" 1%7-1%199 *7%*99.-91 9%-:9.7:1
Serum(ree Media 9%;19 ;;/.*91 9:.:-:
Air :99%9*. 19%7;*.*/1 999.7-:
@:PE; #*B )<)' 9:/%;.1 11%:**..:/ *91.*7/
DaE@ #7.* M' 99:%991 17%--9.//: ***.;1.
Prot,A ?eg 5uff 197%-9/ *%.;;.1/: 999.97/
Protein A eluti 979%7;. 9%-91.9-9 *71.1-1
Protein A 2+uil ;:9%:.- 97%999.--7 1%7/9./:/
DaE@ #7.1M' 1:*%.99 -%;--.-77 ::-./:/
"23,2+,5uff -*%.*9 :%1:1.7*9 1-:.79:
"23,=ash,5uff -*%/1/ :%1:;.1.7 1-:.9**
"23,2l,5uff :%.7- 1.-.;.* 9.199
Da0" #1 M' ;7%;.: 1%99..9/1 177.:97
Amm. Sulfate 9%/71 1::.:*9 -.9;.
@"0,2+,5uff 9;%991 1%197.7;9 -1.9//
@"0,=ash,5uff -9%;./ 9%9.*.19: 1*;.9.1
@"0,2l,5uff -7%;1* 9%/.-.//. 1;9./*;
DaE@ #1 M' -*%.79 :%199.777 1-9.9/-
P5S :9%:7. 1%*:/.;:9 /7.1:-
Polysorbate /7 9 7.7.. 7.77;
TETA4 :%9-7%179 1**%9;9.9-9 /%7/-.;:7
There are also resins% membranes and other consumables that are consumed in a Monoclonal
antibody production process. (or information on initialization of consumables% refer to section 9.
* Analysis of the 5ase 0ase #Mab.67a.spf'
The e+uipment in Mab7_0a.spf is in esign Mode% )hich is the default option for ne)ly created
files. "n esign Mode% SuperPro esigner sizes the e+uipment based on amounts of material
processed per batch and operating time allocated to &arious acti&ities. "f you )ish to specify the
size of a specific e+uipment item% right,click on its procedure icon and select E0ui!ment 1ata.
(igure 1 #belo)' displays the e+uipment data dialog of a &essel. Select Set /. $ser (Ratin,
Mode) to specify the &olume of the &essel.
Fi,ure 12 The e0ui!ment data dialo, /o3
The e+uipment occupancy chart for four consecuti&e batches is sho)n in (igure 9. The cycle time
specified by the user is 1; days% )hich results in 91 batches per year #;7: kg of product per
year'. To generate the chart of the figure belo)% select 4ie* " E0ui!ment #ccu!anc. Chart "
Multi!le Batches from the main menu of SuperPro. To change the number of displayed batches%
right,click on the chart and select Set Num/er o5 Batches. To specify the recipe cycle time%
select Tas+s " Reci!e Schedulin, (n5ormation. To copy the e+uipment occupancy chart% make
it the top )indo) and press HAlt I Prnt ScrnJ. That generates a screen &ie) in the clip board that
can be pasted into other application% such as MS =ord. Alternati&ely% you may right,click on the
chart% select Co!. and then mo&e to the destination application and select )aste or )aste
S!ecial. The top lines of the chart represent the occupancy of 0"P #cleaning,in,place' skids used
to clean other e+uipment items. 0"P operations determine the occupancy of 0"P skids.
7 14 21 28 35 42 49 56 63 70 77 84 91 98 105 112 119 126 133 140 14 day
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 wk
DCS-101
DE-107
DF-102
DE-105
V-110
DE-106
V-108
C-103
V-109
DE-110
C-102
V-111
DF-101
DE-109
V-107
C-101
DE-108
DS-101
V-101
V-103
DE-104
V-105
DE-103
V-106
PBR1
DE-102
V-104
SBR2
DE-101
V-102
SBR1
BBS-102
BBS-101
RBR-101
TFR-101
CIP-DSP-2
CIP-DSP-1
CIP-UPS-2
CIP-UPS-1
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Fi,ure 62 The e0ui!ment occu!anc. chart 5or 5our consecutive /atches o5 the /ase case
(Mab7_0a.spf)
The scheduling bottleneck identified is the production bioreactor P5?1% as it has the longest time
occupancy. This information is pro&ided on the Reci!e Schedulin, (n5ormation dialog. "t can be
noted that the do)nstream train has lo) time utilization. To increase column time utilization and
conse+uently reduce the re+uired size the user can specify more than one cycle for each column
operation. To do this the user must right click on the procedure icon in +uestion% select
)rocedure 1ata and specify the number of cycles per batch #(igure :'. The number of cycles
specified for the Protein,A column is ; and for the "23 and the @"0 columns :. Ene can specify
more cycles and subse+uently reduce the size of the column. Too many cycles% ho)e&er% lead to
increased labor cost.
Fi,ure 72 The )rocedure 1ata dialo, /o3 5or the )rotein-A column
"n addition to the e+uipment occupancy chart% SuperPro generates Fantt charts for the &arious
operations and their unit procedures #through Tas+s " 8antt Charts " #!erations 8C'. "n the
Eperations Fantt chart that follo)s #(igure ;'% the tan bar at the top represents the time re+uired
for one full batch. The duration of each section of the flo)sheet is displayed )ith green bars. The
dark blue bars represent the time re+uired for each unit procedure% and the light blue bars
represent indi&idual operations. The Fantt chart is highly customizable. To modify the bar
properties #such as their colors% labels for duration% etc.'% right,click on the empty area of the chart
and select St.les from the drop,do)n list. Then choose a bar type to edit.
0harts such as the Fantt chart and the 2+uipment Eccupancy chart are po)erful tools for cycle
time analysis% debottlenecking% scheduling purposes% and technology transfer.
Fantt charts #for single or multiple batches' can be exported to MS ProKect #see 0hapter - of the
SuperPro manual for information on exporting to MS ProKect'.
Fi,ure 92 #!erations 8antt chart (Mab7_0a.spf)
- Ad&anced Modeling (eatures
-.1 Modeling 0hromatography Steps
The rest of this document focuses on ad&anced modeling features for biopharmaceutical
applications utilized in files Mab.67b.spf and Mab.67c.spf.
"n these t)o files each chromatography step is represented )ith three unit procedures. The
reason for that is because )hen a unit procedure in SuperPro has multiple cycles% that applies to
all operations of the procedure. "f certain operations are done only once per batch #e.g.% column
storage'% the only )ay to represent it is by using a separate unit procedure that utilizes the same
e+uipment. The table belo) explains the )ay the processing is done in the columns!
Pre
Processing
#0ycles<5atch'
Main
Processing
#0ycles<5atch'
Post
Processing
#0ycles<5atch'
Protein A 1 ; 1
"23 1 : 1
@"0 1 : 1
The pre, and post,processing acti&ities do not follo) a cycling pattern. Therefore% they must be
represented )ith different procedures that ha&e one cycle per batch and utilize the same column
as the main chromatography acti&ity. To specify that a pre, or post,processing unit procedure
#e.g.% P,-- or P,-. for Protein,A in Mab.67b.spf' utilizes the same column as the main acti&ity
#e.g.% P,1/ in Mab.67b.spf'% right,click on its icon and select E0ui!ment 1ata. Then% focus on
the Selection box #upper left corner of the dialog' and select 0,171 through the Select drop,
do)n menu.
DET2! The chromatography columns in these t)o files are in ?ating Mode #i.e.% their dimensions
are specified'. Lou may &ie) their dimensions by right,clicking on their icons and selecting
E0ui!ment 1ata. Please note that if the columns are left in esign Mode% then SuperPro )ill
force you to specify a fake 4oad operation for the pre, and post,processing unit procedures.
ThatMs the case because all procedures that are in esign Mode must ha&e an operation that can
size their e+uipment. "n chromatography procedures the 4oad operation is the only one that can
size the column.
-.9 Modeling 5uffer Preparation and @olding
5iopharmaceutical processes are generally designed to be limited by bioreactor capacity.
@o)e&er )hen bioreactor capacity is increased )ith multiple bioreactor trains% constraints may
arise in purification and supporting processes #e.g.% buffer preparation $ holding% cleaning% etc.'.
Such constraints limit plant throughput. Modeling the buffer preparation section of a process is
therefore important. =hen de&eloping such models t)o issues need to be taken into accountA the
material balances and the scheduling both ha&e to be based on the main do)nstream processing
#SP' steps. The user is ad&ised to follo) the methodology described in this section )hen
modeling such processes in SuperPro.
A typical buffer preparation step consists of a preparation &essel #PC' )here the ingredients are
charged and mixed and a holding &essel #@C' )here the prepared buffer is transferred from the
prep,&essel and stored until used by the SP process. The buffer is filtered )hile transferred from
the PC to the @C to ensure sterility. A similar installation is assumed in this example )ith * PC
and / @C &essels. The filters in bet)een are not included in this model for simplicity. 5et)een the
@C and PC there are t)o transfer panels that connect any of the @C )ith any of the PC. The
generic boxes TP,171 and TP,179 represent the transfer panels. (inally% the buffer preparation
e+uipment is installed in a separate room to the SP suite. Therefore% ; buffer deli&ery lines ha&e
been specified% 54,171% 54,179% 54,17:% 54,17; #represented )ith generic boxes' that are
dedicated to supplying buffers to the Protein A% "23% @"0 columns and the diafiltration skids #(,
171% (,179' respecti&ely. The )ay to simulate the occupancy of the transfer panels and the
buffer deli&ery lines )ill be described later in this document.
The fi&e buffer prep &essels are used to prepare more than fi&e different buffers. (or instance%
PC,179 is used to prepare three different buffers. En the flo)sheet each buffer preparation is
represented )ith a different unit procedure. En the 2+uipment Eccupancy chart those procedures
are presented )ith a rectangle #one rectangle for each procedure' on the PC,179 line #since all
three utilize the same e+uipment% but at different times'. The red circles of (igure * sho)n belo)
highlight the three different procedures handled by PC,179. As mentioned in the pre&ious
section% e+uipment sharing by multiple procedures is specified through the Selection box of a
procedureMs E0ui!ment 1ata dialog #upper left corner of the dialog'.
Fi,ure :2 4isuali;in, e0ui!ment sharin, *ith the E0ui!ment #ccu!anc. chart.
-.: Material balances
8nder regular operating conditions the user )ould specify the amount of material that needs to be
charged into a prep tank before transferred into a holding tank and subse+uently used by the
SP process. @o)e&er% the operation that determines the amount of material that needs to be
charged is the SP operation% such as the 2+uilibration operation of a chromatography step. So
)hat is needed is an operation in the holding tank that allo)s the column operation to dra) the
amount of material re+uired. SuperPro has this ability through the )ull-#ut operation.
A Pull,Eut operation is similar% in concept% to a Transfer,Eut operation but )ith one &ery important
differenceA the amount of material being transferred out is not kno)n and therefore not set by the
user but instead computed during simulation by the pulling #consuming' operation that utilizes its
stream. "f the amount of material a&ailable in an @C &essel is less than the amount re+uired by
the consuming operation and all the input streams of the charge operations in the PC procedures
are in Auto-Ad<ust mode #specified by checking the corresponding check box'% the Pull,Eut
operation )ill back,propagate the information for the greater demand and the simulation algorithm
of SuperPro )ill attempt to adKust all inputs streams of that train so that the demand is fully met
The follo)ing table indicates the )ay the operations should be specified in the PC and @C tanks!
)4 Tan+s =4 Tan+s
S"P S"P
0harge Transfer,"n
Agitate Pull,Eut
#"nstead of Transfer Eut'
Transfer,Eut 0"P
0"P
Multiple dra)s of material form the same @C &essel should be handled by multiple pull out
operations in the same @C unit procedure #e.g.% P,:. 1 @C,171' )ith their duration and scheduling
info arranged as described abo&e.
That )ay and by setting the input stream#s' of the train to Auto-Ad<ust mode% the amount of
material is automatically computed depending on the re+uirements of the do)nstream
operation#s'. The )ay to schedule the abo&e operations )ill be dealt )ith in the follo)ing section.
To locate the Auto-Ad<ust option in the stream dialog% refer to (igure -.
DET2! The PC tank procedures include a single charge operation that pumps the buffer into the
tank. "n reality the constituents are added one by one and conse+uently mixed. @o)e&er% )e
recommend this approach #charging the buffer )hich is defined as a stock mixture instead of its
constituents' because it enables you to track the demand of the &arious buffers #as stock
mixtures' as )ell as the demand of the constituents of the buffers.
Fi,ure >2 The auto-ad<ust o!tion in an in!ut stream
-.; Scheduling 5uffer Prep and @olding Eperations
The scheduling of buffer preparation and holding acti&ities should be based on the main
do)nstream operationsA the pull out operations in the @C tanks should be synchronized )ith the
rele&ant do)nstream operation #e.g.% e+uilibration of a chromatography step'. Thus the pull out
operation is used as a scheduling basis for all the other operations in the @C and PC procedures.
Eperations that precede the pull out operation are scheduled relati&e to the start of the pull out
using appropriate negati&e &alues for Start Time Shi5t #top of the Scheduling tap of an
operationMs dialog'. A negati&e Start Time Shift is e+ui&alent to a 4ead Time. This is the only )ay
to handle the e+ui&alent of scheduling based on finish time% )hich is not a&ailable in the current
&ersion of SuperPro.
A description of the recommended approach follo)s!
@C!
A pull out in the @C is set to last as long as the buffer utilizing operation #using a master
sla&e relationship' in the SP process and scheduled to start at the same time. Please
&isit at this point the Eper.0ondMs tab of P844,E8T,1 in P,;:<@C,17: that feeds
regeneration buffer to the Protein A column #0,171'. Lou )ill notice that P844,E8T,1 is
a sla&e of the ?2F2D2?AT2,1 operation in P,1/ #the Protein A step'. That makes the
duration of P844,E8T,1 the same as the duration of ?2F2D2?AT2,1 #spanning all four
cycles on ?2F2D2?AT2,1 in P,1/'. (urthermore% if you &isit the Scheduling tab of
P844,E8T,1% you )ill see that it is scheduled to start at the same time as
?2F2D2?AT2,1 in P,1/.
The T?ADS(2?,"D,1 operation in P,;: #duration -7 min' is scheduled to start based on
the start of the P844,E8T,1 )ith a Start Time Shift of ,: h #i.e.% : h before the start of
P844,E8T,1'. That )ay the buffer is in the @C tank 9 h prior to use #safety margin'.
The S"P,1 operation P,;: #@C tank' )hich has a duration of *7 min is scheduled to start
based on the start of T?ADS(2?,"D,1 )ith a shift of ,*7 min. That )ay% S"P )ill be
finished by the time transfer,in starts.
The 0"P is scheduled to start )hen the Pull out operation has finished.
PC!
Transfer out is set to last as long as the transfer in operation in the @C #using a master
sla&e relationship' and scheduled to start at the same time as transfer,in in the @C.
The rest of the operations are scheduled based on the transfer out according to the )ay
described for the @C #using negati&e Start Time Shifts'
8sing this scheduling methodology% changes in the SP schedule )ill automatically adKust the
scheduling in the buffer prep operations since all @C and PC operations depend directly or
indirectly on the time that the buffer is used by the main SP process.
-.* Modeling eli&ery 4ines and Transfer Panels
As mentioned earlier in this document% the occupancy of transfer panels and buffer deli&ery lines
has to be simulated to ensure that scheduling conflicts do not occur. This is done by representing
such e+uipment items )ith generic boxes that include a =old operation% )hich is synchronized
)ith the operation in +uestion #using the techni+ues described in the pre&ious section'.
(or example% buffer deli&ery line one #54,171' is utilized during the operation of the first column
i.e. it deli&ers the buffers from the buffer preparation area to the SP area. To tackle this issue
since buffer deli&ery line does not exist as a separate unit procedure% the user should use a batch
generic box and name is appropriately #54,171 in this case'. Feneric boxes are selected from
$nits )rocedures " 8eneric Bo3es " Bul+ Flo* " Batch ?t.!e@. Subse+uently% the user should
add three hold operations #in P,.9' one for each of the protein A unit procedures. The first hold
operation should be synchronized )ith the pre,processing acti&ities of 0,171 #represented by P,
-.' using a master sla&e relationship and the same start time. The second hold operation should
be synchronized to all the processing operations in P,1/. (inally the third hold operation should
be synchronized to the post processing acti&ities and skid storage represented by P,--. That )ay
the buffer deli&ery line is occupied )hen a buffer from the 5uffer preparation area is transferred to
the SP process. The other three deli&ery lines should be modeled in a similar )ay.
The user should model Trans5er )anels in the same )ay. 8se batch generic boxes )ith hold
operations that are synchronized )ith the corresponding transfer operations that utilize the
transfer panels. This approach enables you to keep track of the use of simple transfer panels that
can handle a single transfer at a time. 0omplex transfer panels that are e+uipped )ith multiple
bridges and Kumpers and can handle multiple simultaneous transfers can be modeled in detail
using Schedule)ro% the second member of the (ntelli,en Suite. T)o transfer panels )ere used
in this example% TP,171 or TP,179.
DET2! The generic boxes utilized to represent deli&ery lines and transfer panels should be set
under Ratin, mode since @old is not an operation that can size e+uipment. Ether)ise% those
procedures )ill generate error messages during simulation. To choose bet)een Ratin, and
1esi,n mode the user should &isit the e+uipment data dialog box by right,clicking on a procedure
icon and selecting E0ui!ment 1ata #(igure 1'.
-.- Modeling Preparation of 2xcess 5uffer for Safety
"n commercial buffer preparation acti&ities the amount of buffer produced is slightly higher than
the amount needed for safety reasons. This can be accounted for by adding a splitter bet)een
the @C and the SP operation and specifying a certain amount of remo&ed buffer #in this case
*B' in the upper stream. Since this splitting is a dummy operation that is only re+uired for mass
balancing calculations% the user can remo&e the procedure from the scheduling calculations by
selecting the scheduling dialog box under procedure data #right click on the procedure icon and
select Procedure ata' and checking the #mit 5rom Schedulin, box. 4ook at procedures P,:/
and P,:9 in the "23 buffer prep<holding area for more information.
. 0ycle Time ?eduction
The Mab.67b.spf file represents a process running in a plant )ith a single e+uipment line. (igure
. displays the e+uipment occupancy chart for four consecuti&e batches of the process. The top
eight lines correspond to the 0"P skids.
The time bet)een consecuti&e batches #process cycle time' is t)o )eeks. The production
bioreactor #P5?1' )hich has the longest cycle time determines the cycle time of the process. "n
other )ords% the production bioreactor is the time #or scheduling' bottleneck of the process.
"t is ob&ious that under these conditions the purification line is underutilized. The cycle time of the
process can be reduced #and its throughput increased' by adding another production bioreactor
that operates in staggered mode #out of phase' compared to the original #P5?1'. This is done
through the E0ui!ment 1ata dialog of the fermentation procedure #P,11'. 0heck the Sta,,er
Mode box #in the lo)er left corner' and set the number of extra pieces of e+uipment that operate
out of phase )ith the main. The names of the extra e+uipment can be edited by clicking on the
Names button in the same dialog. =hen debottlenecking a facility the extra pieces should be
introduced to the e+uipment that is the scheduling bottleneck. Ence the ne) bioreactor is
specified #P5?1b'% the ne) bottleneck is the tank used to store the media for the fed batch
operation #MP,17;'. "n the same manner a ne) tank is specified #MP,17;b'. (ollo)ing the same
method )hereby a bottleneck is identified and remo&ed one by one the cycle time of the process
is reduced to :.* days #corresponding to file Mab.67c.spf'. (igure / belo) displays the
2+uipment Eccupancy chart for 1* consecuti&e batches of Mab.67c.spf. The first batch is
handled by P5?1 #the original production bioreactor'% the second by P5?1b% the third by P5?1c%
and the fourth by P5?1d. The next four batches follo) the same se+uence. This a&ailability of
multiple bioreactors that operate out of phase reduces the cycle time of the process to :.* days
e&en though each bioreactor continuous to ha&e a cycle time of 1; days. All bioreactor batches
are handled by the single purification line.
The follo)ing total upstream e+uipment is re+uired for a process cycle time of :.* days.
T)o inoculum preparation trains
Three seed bioreactor trains #S5?1%b%c and S5?9%b%c'
(our production bioreactors trains #P5?1% P5?1b% P5?1c% P5?1d'
8nder these conditions the number of batches per year increases to /1 and the annual
throughput to 1%*** kg of purified Mab.
7 14 21 28 35 42 49 56 63 70 77 84 91 98 105 14 day
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 wk
DCS-101
DE-107
DF-102
DE-105
V-110
DE-106
V-108
C-103
BD)-103
V-109
DE-110
*V-105
*V-107
C-102
BD)-102
PV-105
V-111
*V-108
BD)-104
DF-101
*V-106
*V-104
PV-104
DE-109
*V-102
TP-102
*V-103
PV-102
V-107
C-101
BD)-101
PV-103
TP-101
*V-101
PV-101
DE-108
DS-101
V-101
V-103
DE-104
MP-104
DE-103
MP-103
PBR1
DE-102
MP-102
SBR2
DE-101
MP-101
SBR1
BBS-102
BBS-101
RBR-101
TFR-101
CIP-BP-4
CIP-BP-2
CIP-BP-3
CIP-DSP-2
CIP-DSP-1
CIP-BP-1
CIP-UPS-2
CIP-UPS-1
M
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Fi,ure A2 Four consecutive /atches o5 scenario Mab7_0b.spf (one /ioreactor train)
7 14 21 28 35 42 49 56 63 70 77 84 91 98 105 112 119 126 133 140 14 day
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 wk
DCS-101
DE-107
DF-102
DE-105
V-110
DE-106
V-108
C-103
BD)-103
V-109
DE-110
*V-105
*V-107
C-102
BD)-102
PV-105
V-111
*V-108
BD)-104
DF-101
*V-106
*V-104
PV-104
DE-109
*V-102
TP-102
*V-103
PV-102
V-107
C-101
BD)-101
PV-103
TP-101
*V-101
PV-101
DE-108
DS-101
V-101
V-103
DE-104d
DE-104+
DE-104,
DE-104
MP-104d
MP-104+
MP-104,
MP-104
DE-103
MP-103
PBR1d
PBR1+
PBR1,
PBR1
DE-102
MP-102
SBR2+
SBR2,
SBR2
DE-101
MP-101
SBR1+
SBR1,
SBR1
BBS-102,
BBS-102
BBS-101,
BBS-101
RBR-101,
RBR-101
TFR-101,
TFR-101
CIP-BP-4
CIP-BP-2
CIP-BP-3
CIP-DSP-2
CIP-DSP-1
CIP-BP-1
CIP-UPS-2
CIP-UPS-1
M
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Fi,ure B2 Fi5teen consecutive /atches o5 scenario Mab7_0c.spf (5our /ioreactor trains).
/ 0ost Analysis
SuperPro esigner performs thorough cost analysis and generates three pertinent reports
#through the Re!orts menu'. The table belo) displays the key economic e&aluation figures for
the case of Mab.67c.spf #four bioreactor trains'. The table )as extracted from the Economic
Evaluation Re!ort #generated in ?T( format'. (or a plant of this capacity #-7%777 4 of production
bioreactor &olume' that produces 1%*** kg of purified Mab per year% the total capital in&estment is
around N1.1.: million #or N9./- million per m
:
of bioreactor capacity'. The estimated
manufacturing cost is N:11 million per year% )hich translates to a unit cost of N-*<g of purified
Mab. The numbers for the calculation of the ?eturn,En,"n&estment% Payback Time% etc. are
based on a selling price of N977<g of purified Mab.
ECEC$T(4E S$MMARD (6EE> !rices)
Total 0apital "n&estment 1.1%97/%777 N
0apital "n&estment 0harged to This ProKect 1.1%97/%777 N
Eperating 0ost 9:%911%777 N<yr
Production ?ate 1%***.99 kg MP<yr
8nit Production 0ost -7%:/;.;9 N<kg MP
Total ?e&enues :11%7;:%777 N<yr
Fross Margin -9./1 B
?eturn En "n&estment /:..1 B
Payback Time 1.19 years
"?? #After Taxes' .9.*/ B
DPC #at ..7B "nterest' 91-%9:-%777 N
MP O (lo) of 0omponent Mab in Stream (inal Product
(igure 9 belo) displays the annual operating cost breakdo)n. "t is a chart that is automatically
generated )ith the 2conomic 2&aluation ?eport. To include such charts in the report% &isit
Re!orts " #!tions and select (nclude Charts #lo)er left corner of the dialog'. The facility,
dependent o&erhead cost is the most important item accounting for 9.B of the o&erall
manufacturing cost. The cost of consumables is in the second position accounting for 9;.9B.
Fi,ure F2 Annual o!eratin, cost /rea+do*n (Mab7_0c.spf)
The table belo) displays the operating cost breakdo)n per flo)sheet section for the
Mab7_0c.spf case. The table )as copied from the (temi;ed Cost Re!ort #?T( format' that
can be generated by selecting Re!orts " (temi;ed cost ((CR).
S$MMARD )ER SECT(#N
Section G-+, M) G-/atch G-.ear H
"noc Prep 1*%-.7.7*. :77%/-/ 9;%:.7%:9; 9*.9*
5ioreaction 1-%;7..9.- :1*%79: 9*%*1-%/*. 9..1.
Prim ?eco& 9%7*;.-./ :9%;*7 :%19*%;-9 :.;7
Protein,A 19%7;*.99. 9:1%9.9 1/%.::%7:9 19.9*
"23 0hrom 9%:/-.*-9 ;*%/9: :%.11%-:7 :.9*
@"0 0hrom 9%97-.*99 ;9%:-- :%;:1%-1/ :.-*
(inal (iltration -/..7-9 1:%199 1%7-/%*;1 1.1;
0hemical Cirus "nacti&ation 1%.;/.-:: ::%*.; 9%.19%*71 9.97
Ciral 2xclusion 1%9.;.9;/ :.%919 :%7.1%;.7 :.9.
5uffer Preparation *%97:.;;9 99%97. /%799%;.- /.-9
T#TA% >EI7B9.9F1 1I1:FI7F9 F7IF1EIF69 1EE.EE
The 5ioreaction section has the highest contribution to the manufacturing cost #9..1.B of total'%
follo)ed by "noculum Preparation #9*.9*B'% and Protein,A #19.9*B'. ?oughly *:B of the
operating cost is associated )ith the upstream sections and ;.B )ith the do)nstream sections.
DET2! A section in SuperPro is simply a set of unit procedures. "f a long process is di&ided into
sections% the reports of SuperPro pro&ide &arious breakdo)ns per section.
The table belo) pro&ides a breakdo)n of the consumables costs #the second most important
item of the operating cost'. The Protein,A resin is the most important contributor to this cost #.9B
of total'.
C#NS$MAB%ES C#ST (6EE> !rices) - )R#CESS S$MMARD
Consuma/le
$nits Cost
(G)
Annual
Amount $#M
Annual Cost
(G) H
9.9 4 ?oller 5ottle - -;/ item :%/// 7.79
ft 2( 0artridge 1%777 .99 item .99%777 :.97
99* m4 T,(lask 9 1%;*/ item 9%91- 7.71
ft Membrane ;77 19- m9 *7%99- 7.99
*7 4 5ag * 1%-97 item /%177 7.7;
177 4 0ell 5ag :77 ;7* item 191%*77 7.*:
Ciral 2xclusion Membrane 1:%:*- 1-9 item 9%1-:%-.9 9.*1
97 4 0ell 5ag 177 ;/- item ;/%-77 7.91
Protein A -%777 9%.1; 4 1-%9/-%71- .1.*.
@"0 5utyl Sepharose @P 9%7*7 9*; 4 1%9*-%9:7 /.-7
SP,Sepharose @P 1%977 1%1** 4 1%:/*%*/; -.79
T#TA% 99%.*-%777 177.77
The table belo) pro&ides a breakdo)n of the ra) materials costs. Serum (ree Media is the most
expensi&e ra) material. A purchasing price of N:77<kg )as assumed for Serum (ree Media #in
po)der form'.
RA' MATER(A%S C#ST - )R#CESS S$MMARD
Bul+ Ra*
Material
$nit Cost
(G-+,)
Annual
Amount
(+,)
Annual
Cost (G)
H
"noc Media Sltn -.1;. 1/%9*9 11-%*:9 7..1
@:PE; #*B )<)' 7.1;: 9%;19%199 :;;%.:- 9.79
DaE@ #7.* M' 7.9;* 9%1-:%99: *:7%991 :.91
=(" 7.1*7 /%.::%-*; 1%:17%7;/ ..9:
Serum(ree Media :77.777 :-%::9 17%971%.-. -*.9.
DaE@ #7.1M' 7.9;: .%919%*.7 1%99:%.7; 11.-;
Amm. Sulfate /.777 19%:1; 9/%*17 7.-7
Polysorbate /7 1./:: . 19 7.77
Protein A 2+uil 7.1*: 1%991%.1* :7;%-:: 1./;
Protein A eluti 7.1*: /17%19- 19;%:;9 7..*
Prot,A ?eg 5uff 7.1-/ ;/-%:99 /1%*/: 7.;9
Da0" #1 M' 7.:-/ 1/-%;/; -/%-/1 7.;9
"23,2l,5uff 7.:;. 1-%::* *%-.; 7.7:
"23,2+,5uff 7.1/- -.:%91/ 19*%:79 7..-
@"0,2l,5uff 7.:7* 9;9%197 .:%..9 7.;*
@"0,2+,5uff 7.979 ;**%9*: ;1:%.9. 9.*7
P5S 7.1/9 199%:79 9:%*.7 7.1;
2tE@ #17B )<)' 7.917 :-.%*:- ..%1/9 7.;.
T#TA% 6BI1FFIE9: 1>I:69IEF: 1EE.EE
DET2! The estimation of the (acility,ependent o&erhead cost is based on a &ariety of multipliers
that are process and region specific. The default multipliers typically underestimate the (acility,
ependent o&erhead cost for biopharmaceuticals. (or information on ho) to access and modify
those multipliers% please consult the Economic Evaluation chapter of the manual and the
corresponding topic in the @elp (acility of SuperPro.
DET2! Most of the multipliers used in cost analysis can be stored into the 8ser atabase of
SuperPro and retrie&ed for future pertinent )ork. That facilitates standardization and impro&es the
accuracy of cost estimation. (or information on ho) to take ad&antage of the database
capabilities of SuperPro% please consult the S.n)harm1B document in the JECAM)%ES "
SDN)=ARM subdirectory of the SuperPro installation.
9 "nitialization of 0onsumables
5iopharmaceutical processes tend to use large amounts of consumables such as filter cartridges%
chromatographic resins% and disposable bag bioreactors. The cost of consumables is often the
most important item of the manufacturing cost. 0onsumables in SuperPro are associated )ith
e+uipment and can be specified through the Consuma/les tab of the E0ui!ment 1ata dialog
#(igure 17'. 0ertain e+uipment types% such a chromatography columns and membrane filters%
ha&e e+uipment,specific consumables #e.g.% chromatography resins and filter cartridges'
specified through the top box of the 0onsumables tab #e.g.% Membrane box of (igure 17'. All
e+uipment types can utilize other #non,e+uipment specific' consumables specified through the
#ther Consuma/les table.
Fi,ure 1E2 The Consuma/les dialo, /o3
SuperPro is e+uipped )ith a consumables database that can be accessed by selecting
1ata/an+s " Consuma/les. That brings up the dialog of (igure 11. The types of a&ailable
consumables are listed on the left,hand,side of the )indo). The user can add a ne) type of
consumable by right,clicking on All Consuma/le T.!es and selecting Add Consuma/le T.!e.
=hen a consumable type is selected on the left% SuperPro displays the a&ailable instances of that
type on the right. The user may add a ne) instance #e.g.% a ne) filter cartridge' by right,clicking
on the name of the type #on the right' and selecting Add Consuma/le. 0onsumables that are
part of the esigner database of SuperPro are displayed in red color and cannot be modified by
the user. Those that are displayed in green are part of the user database and can be modified by
the user.
uring selection of a consumable through the 0onsumables tab of the 2+uipment ata dialog%
the user has access to all compatible consumables that are already registered in the file and to
those that are a&ailable in the database. =hen a user selects a consumable from the database%
the program makes a copy of that consumable into the SuperPro file #this is called consumable
registration'. "n other )ords% SuperPro does not maintain a li&e link to the obKects in the
0onsumables database% but it simply copies the information from the database. The same logic
applies to all other obKects stored in the SuperPro databases.
Fi,ure 112 The consuma/les data/an+
DET2! Since SuperPro does not maintain a li&e link )ith the consumables databank% any
changes in the databank do not automatically propagate to the SuperPro files. The
synchronization of &alues is done by selecting Tas+s " Edit #ther Resources " Consuma/les
that brings up the dialog of (igure 19.To update the &alues of a specific consumable #e.g.% 177 4
0ell 5ag'% select it by clicking on its line number and click the $!date Consuma/leKs )ro!erties
5rom 1B record button #the button in the red circle'. "f you change the same consumable in the
design case file and you )ish to update the contents of the 8ser atabase% select the
consumable and click on the 1e!osit-$!date Consuma/le into 1B Record #the button in the
blue circle'.
Fi,ure 162 $!datin, Consuma/le !ro!erties 5rom the 1B record
17 ?esource Tracking and Sizing of =(" Systems
SuperPro has the ability to calculate and display demand for resources #e.g.% materials% utilities%
and labor' as a function of time. (or instance% (igure 1: displays the demand for =(" o&er a
period of fifteen consecuti&e batches #for Mab.67c.spf'. To generate this chart% select 4ie* "
Resource Consum!tion Trac+in, Chart " (n,redient " Multi!le Batches from the main menu
bar of SuperPro and then select the ra) material of interest in the dialog that appears #=(" in this
case'. To change the number of batches% right,click on the chart and select Set Num/er o5
Batches. The red and blue lines of the graph correspond to the 4@S y,axis and represent
instantaneous and a&eraged #for 9;,h inter&als' =(" demand% respecti&ely. The green line
corresponds to the ?@S y,axis and represents cumulati&e demand #for 9;,h inter&als'.
This chart pro&ides useful information for sizing =(" systems. Specifically% the tallest red peak
#highest instantaneous demand' is useful information for sizing the pipe diameter of the circulation
loop and its pumping capacity since the loop and the pump must be able to accommodate the highest
instantaneous demand. The tallest green peak pro&ides useful information for sizing the surge tank
of the =(" system. "t corresponds to the )orking &olume of the surge tank if a 9;,h buffer capacity is
re+uired #i.e.% a 9;,h supply e&en if the still is not operational during that period'. The blue line for the
green peak inter&al #)hich is also the blue peak' pro&ides useful information for sizing the still. The
a&eraging inter&al can be adKusted by the user. The larger the a&eraging inter&al% the greater the size
of the surge tank and the smaller the size of the still. "n other )ords% there is a trade off bet)een still
size and tank size in the sizing of =(" systems. 5ased on the &alues of (igure 1:% for a 9;,h =("
capacity% )e need a tank that has a storage capacity of around 1:7%777 kg and a still that has a rate
of slightly abo&e *%777 kg<h.
Fi,ure 172 'F( consum!tion chart (Mab7_0a.spf) 5or 1: consecutive /atches
SuperPro also can calculate and display in&entory information for material resources and utilities.
Suppose the storage capacity of the =(" tank is 177%777 kg. Suppose further that the =(" still
has a rate of /%777 kg<h and it is turned on )hen the le&el in the tank drops belo) ;7B and off
)hen it reaches 177B. To &isualize the li+uid le&el in the tank and the operation of the still% do the
follo)ing.
Select 4ie* " Resource (nventor. Chart " (n,redient " Multi!le Batches. Select P=("M and then
click on the Su!!l. (n5o button to specify the size of the tank% the rate of the still% the initial
contents% and the on<off criteria #the &alues pro&ided abo&e'. Then click EQ and on the next
dialog click EQ again. That )ill bring up the graph of (igure 1;. The green line #that corresponds
to the y,axis on the ?@S' represents the =(" le&el in the tank. The blue line #that corresponds to
the y,axis on the 4@S' represents the operation of the still.
Eb&iously% there is an infinite number of combinations of tank size and still rate that constitute a
solution. The larger the still rate% the smaller the re+uired tank size. "f the still rate is e+ual to the
tallest instantaneous demand% then% no surge tank is practically re+uired.
Fi,ure 192 'F( inventor. (,reen lines) and still o!eration (/lue lines).