bio solve process cost model workshop
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© BioPharm Services Ltd CONFIDENTIAL
Tools and Techniques for Evaluating the best fit of Single Use Technologies
Single-use technology in biopharmaceutical manufacturing
Campus Grüental, Wädenswil.
Tuesday 8th June 2010
Andrew Sinclair, President Biopharm Services Ltd, a.sinclair@biopharmservices.com
Miriam Monge, VP Global Key Accounts, Biopharm Software Solutions
m.monge@biopharmservices.com
www.biopharmservices.com
© BioPharm Services Ltd CONFIDENTIAL
Agenda
State of the Industry
Why use cost models?
Building a good biotech process model
Understanding cost: example: disposables
Cost modelling workshop: mAbcase study
Summary of results
DiscussionStainless Steel
Disposables
© BioPharm Services Ltd CONFIDENTIAL
Acknowledgements
Ms. Claire Hill, Biopharm ServicesMr. Bruce Williams, MSD biologics/ Avecia Dr. Richard Turner, MedImmuneDr. Brendan Fish, GSKMr Kit Erlebach, MSD biologics
© BioPharm Services Ltd CONFIDENTIAL
BioPharm Services
Our focus is on helping our clients achieve operational excellence with the ultimate goal of delivering more cost effective medicines to patients
The recognized leading international bioprocess consultancy
Biopharm Engineering & Consultancy Services
b i o p h a r ms e r v i c e s
© BioPharm Services Ltd CONFIDENTIAL
Cost Trends
Productivity in development is reducingAs spend per drug increasesProductivity is decreasingNow overall cost of bring a successful biologic to market is between $0.8bn to $1.2bn
Manufacturing costs are increasing proportionately20 years ago about 3% of sales price for chemical candidateBiologics range between 10% to 20%1
Healthcare providers are putting pressure on the industry to reduce prices by looking at the cost benefit balance2
1. In a recent GE Healthcare webinar they quoted a figure of 14%2 . The Evidence Gap British Balance Benefit vs. Cost of Latest Drugs, December 3, 2008, New York Times
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Implications for Manufacturing
Manufacturing cost is single variable costDevelopment costs are fixed and include losses around failed drugs
14%
21%
19%9%
37%
Price Breakdown
Manufacturing R&D Sales & G&A Profit share Pre tax profit
1. Source GE Healthcare webinar
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Why use models?
Get the big picture – what are the variables?
Make predictions – what will happen if…
Evaluate alternatives – which one is best?
Communication – a simple picture or chart is better than a thousand words
Make better business decisions
How much will it cost to make 75kg of product?
Is it cheaper to use disposable bags or stainless steel vessels
Which plant changes will have the biggest impact on cost?
What is the cost/benefit for installing new technology?
If production falls from 100kg/yr to 50kg/yr, what will happen to the cost of goods per gram?
To answer questions such as…
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Cost model considerations
For manufacturing projects the key
parameters to consider are
How much has to be spent upfront on capital
How long before the facility is operational
Proportion of fixed and variable costs
The life time of the operation
Cost of money
© BioPharm Services Ltd CONFIDENTIAL
Cost of Goods – Cost of Production
Includes just manufacturing costsFacilityMaterialsConsumablesLabour
Does not includeSales, General & AdminR&DInterest & Taxes
Why is it used?Provides insight into cost driversAllowing analysis of process and technologies
SnapshotCosts over a defined (short term) period No overall lifecycle costsFailure
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Fixed vs. variable costs
Fixed: Capital, some materials & labour
Variable: Materials, consumables & some labour
Also referred to as direct/indirect costs in cost accounting.
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Cost model components
“Fixed” costs
Size of facility (how much capital was initially invested)
Base facility running costs (insurance, electricity, etc.)
Administration (receptionist, etc)
Air filters
Variable costs
Materials
Consumables
Labour
Utilities/waste
Productivity
Batches per year
Batch size
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Driving Down Cost of Goods Product Priorities
Process Development
Higher titres
Better match the process to the facility
Chromatography matrices
Filtration rates/membranes
Design
Good Facility design
Appropriate process equipment
Appropriate infrastructure (neither too` small nor too large)
Latest manufacturing technologies
Platform Technologies
Continuous processing
Integrated operations
Integrated disposables
Manufacturing
Appropriate process equipment
Optimum working practices
Incr
ease
d b
enefits
$100s millions
$100s millions
$10s millions
$10s millions
© BioPharm Services Ltd CONFIDENTIAL
Building a good biotech Process model
Understand the manufacturing processResource requirements
Timing
Understand the cost structureFixed/variable – not always obvious
Beware of hidden costs
Activity-based costing (ABC) can help with this
Understand where to make assumptionsImpossible to model all variables
Can introduce more error by false confidence
© BioPharm Services Ltd CONFIDENTIAL
BioSolve: Configurable CoGs Model
Rapid process configurationRapid option evaluation
TechnologiesProcesses
Scalable mass balanceStandard formatConsumables estimates
Scalable equipment listBased on standard costs, sizesBasis for capital cost estimate
Insight into utilities, environmentPW & WFIWaste streams
Capacity and capital estimates
Process Sequence Conc (g/L) Vol (L) Mass (g) Yield (%) Time (h)
1 N-2 Seed 0.0 50 0 0% 58.0
2 N-1 Seed 0.0 500 0 0% 59.0
3 Production 5.0 5,000 25,000 0% 210.0
4 Centrifugation 5.0 4,250 21,250 85% 9.0
5 Depth Filtration 4.3 4,250 18,063 85% 9.2
6 UF/DF #1 40.4 425 17,159 95% 12.4
7 Protein A 3.1 4,926 15,443 90% 12.9
8 Virus Inactivation 3.0 5,025 15,135 98% 2.5
9 Capture IEX 7.8 1,847 14,378 95% 11.4
10 Flow Through IEX 7.4 1,847 13,659 95% 6.2
11 Viral Filtration 7.2 1,847 13,386 98% 9.3
12 UF/DF #2 35.5 369 13,118 98% 12.4
13 Sterile Filtration 34.8 369 12,856 98% 9.1
Process Definition
Product Titre 5.00 g/L
Capacity Utilisation 80%
Production Bioreactor Volume 5000 L
MAb Typical
Single-Use Systems
Bioreactors (up to 2000L) No
Media Preparation (up to 2000L) Yes
Buffer Preparation (up to 2000L) No
© BioPharm Services Ltd CONFIDENTIAL
Process Cost Model Features Scalable
Mass balance calculationsStep timesEquipment/consumable sizingLabour requirementsUtility requirements
OutputsCalculationInterfaceProcess
Process Description
Dashboard
Scenarios
Production Customisation
LabourBill of
Materials
Consumables & Materials
Cost of Goods
Equipment Capital
Sensitivity
Technology Options
Solution prep methodologyDisposable systemsMode of operation (fed-batch vs. perfusion, packed bed vs. EBA, etc)
Cost Database
EquipmentConsumables
MaterialsLabour
Waste treatment
© BioPharm Services Ltd CONFIDENTIAL
Applications
Process development Rapid, multiple scenario analysis in process development • Impact of different titers• Expression systems (E. coli versus mammalian)• Crystallisation vs. Protein A
Technology assessment Analyse the impact of a specific technology within a process for example• Disposable bags vs. stainless• Membrane chromatography• Perfusion vs. fed batch
Manufacturing First past analysis• Facility fit• Manufacturing scenarios• Process improvement screening
© BioPharm Services Ltd CONFIDENTIAL
BioSolve Output (Water)How Does it Compare
40%
50%
60%
70%
80%
90%
100%
0 10,000 20,000 30,000 40,000 50,000 60,000
Bioreactor Harvest Volume L
Stainless Steel % Water Used for CIP
Actual
BioSolve
Power (Actual)
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Capital Estimate Comparison
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Case Study Assumptions
For client confidentiality, the process was based on a generic MAb production data*
3 x 2,000L; 2g/L, 80% utilisation
One purification train
Mode of solution make-upMedia: per batchBuffer: per batch
Basis of costs (i.e. materials, consumables, equipment etc.)
Vendors, suppliers, benchmarking information from over 10 biotech operations
* Morrow, K. J. Industrial-Scale Antibody Production Strategies. Genet. Eng News, 22(17),
8-71, 2002
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BioSolve Disposable Options
Using MAb TypicalSet up SS facility base case
Disposable options generic*Bags impactMixing system optionsBioreactors
SensitivityHold bag costsBioreactor pricing Consumables Hardware
Analysing Individual Operations
Membrane absorber*
*Based on average vendor pricing
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Performance
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Impact of Single Use vs. Reusable
Water
Key indicator of the impact of disposables
Plastics
Key indicator of the solid waste stream
Capital infrastructure
Labour
Materials
© BioPharm Services Ltd CONFIDENTIAL
Stainless Steel Option
• Capital $ 60.6M
• CoG 174.5 $/g
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Hold bags option
• Capital $ 43.3M
• CoG 144.3 $/g
So what is happening?
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Metrics
Stainless Option Plastic (kg)
Plastic Waste 66.2
Process (m3) Cleaning (m3)
Water 11.5 73.1
Usage Media Prep Media Hold Buffer Prep Buffer Hold Product Hold
Vessels 4 4 12 12 11
Bags 0 0 0 0 0
Hold Bag Option Plastic (kg)
Plastic Waste 167.6
Process (m3) Cleaning (m3)
Water 11.5 24.8
Usage Media Prep Media Hold Buffer Prep Buffer Hold Product Hold
Vessels 0 12 0 0
Bags 0 4 0 13 11
© BioPharm Services Ltd CONFIDENTIAL
Impact on CIP – Cleaning ListsUnit
OpEquip Type Description
Volume
(L)
Flowrate
(L/hr)
Flowrate
(L/min)
Time
(hr)
Labour
(hr)PW 0.2M NaOH
0.04M
Phosphoric
Acid
PW WFI
1 Bioreactor Bioreactor 20 0 37 2 4.0 183 183 183 183 183
2 Bioreactor Bioreactor 200 0 79 3 6.0 395 395 395 395 395
3 Bioreactor Bioreactor 2,000 0 170 4 8.0 851 851 851 851 851
4 Centrifuge Disk Stack Centrifuge 0 400 20 2 4.0 100 100 100 100 100
5 Filter HousingDepth Filter 0 440 22 3 6.0 110 110 110 110 110
6 UF Skid UF Filter 0 638 32 4 8.0 160 160 0 160 160
11 Filter HousingViral Filter 0 120 6 3 6.0 30 30 30 30 30
12 UF Skid UF Filter 0 182 9 4 8.0 46 46 0 46 46
3 Vessel Product Hold 2,000 0 170 1 2.0 851 851 851 851 851
4 Vessel Product Hold 2,000 0 170 1 2.0 851 851 851 851 851
5 Vessel Product Hold 2,000 0 170 1 2.0 851 851 851 851 851
6 Vessel Product Hold 200 0 79 1 2.0 395 395 395 395 395
7 Vessel Product Hold 750 0 123 1 2.0 614 614 614 614 614
8 Vessel Product Hold 1,000 0 135 1 2.0 676 676 676 676 676
9 Vessel Product Hold 500 0 107 1 2.0 536 536 536 536 536
10 Vessel Product Hold 500 0 107 1 2.0 536 536 536 536 536
11 Vessel Product Hold 500 0 107 1 2.0 536 536 536 536 536
12 Vessel Product Hold 100 0 63 1 2.0 314 314 314 314 314
13 Vessel Product Hold 100 0 63 1 2.0 314 314 314 314 314
1 Vessel Media Prep / Hold 200 0 79 1 2.0 395 395 395 395 395
1 Vessel Media Prep / Hold 200 0 79 1 2.0 395 395 395 395 395
3 Vessel Media Prep / Hold 50 0 50 1 2.0 249 249 249 249 249
3 Vessel Media Prep / Hold 50 0 50 1 2.0 249 249 249 249 249
3 Vessel Media Prep / Hold 50 0 50 1 2.0 249 249 249 249 249
3 Vessel Media Prep / Hold 50 0 50 1 2.0 249 249 249 249 249
3 Vessel Media Prep / Hold 2,000 0 170 1 2.0 851 851 851 851 851
3 Vessel Media Prep / Hold 2,000 0 170 1 2.0 851 851 851 851 851
6 Vessel Buffer Prep / Hold 200 0 79 0.2 0.4 0 0 0 0 395
6 Vessel Buffer Prep / Hold 200 0 79 0.2 0.4 0 0 0 0 395
6 Vessel Buffer Prep / Hold 1,000 0 135 0.2 0.4 0 0 0 0 676
6 Vessel Buffer Prep / Hold 1,000 0 135 0.2 0.4 0 0 0 0 676
7 Vessel Buffer Prep / Hold 150 0 72 0.2 0.4 0 0 0 0 359
7 Vessel Buffer Prep / Hold 150 0 72 0.2 0.4 0 0 0 0 359
7 Vessel Buffer Prep / Hold 1,000 0 135 0.2 0.4 0 0 0 0 676
7 Vessel Buffer Prep / Hold 1,000 0 135 0.2 0.4 0 0 0 0 676
7 Vessel Buffer Prep / Hold 3,000 0 195 0.2 0.4 0 0 0 0 974
7 Vessel Buffer Prep / Hold 3,000 0 195 0.2 0.4 0 0 0 0 974
8 Vessel Buffer Prep / Hold 25 0 40 0.2 0.4 0 0 0 0 198
8 Vessel Buffer Prep / Hold 25 0 40 0.2 0.4 0 0 0 0 198
8 Vessel Buffer Prep / Hold 25 0 40 0.2 0.4 0 0 0 0 198
8 Vessel Buffer Prep / Hold 25 0 40 0.2 0.4 0 0 0 0 198
9 Vessel Buffer Prep / Hold 500 0 107 0.2 0.4 0 0 0 0 536
9 Vessel Buffer Prep / Hold 500 0 107 0.2 0.4 0 0 0 0 536
9 Vessel Buffer Prep / Hold 500 0 107 0.2 0.4 0 0 0 0 536
9 Vessel Buffer Prep / Hold 500 0 107 0.2 0.4 0 0 0 0 536
9 Vessel Buffer Prep / Hold 500 0 107 0.2 0.4 0 0 0 0 536
9 Vessel Buffer Prep / Hold 500 0 107 0.2 0.4 0 0 0 0 536
9 Vessel Buffer Prep / Hold 1,500 0 155 0.2 0.4 0 0 0 0 773
9 Vessel Buffer Prep / Hold 1,500 0 155 0.2 0.4 0 0 0 0 773
10 Vessel Buffer Prep / Hold 200 0 79 0.2 0.4 0 0 0 0 395
10 Vessel Buffer Prep / Hold 200 0 79 0.2 0.4 0 0 0 0 395
10 Vessel Buffer Prep / Hold 200 0 79 0.2 0.4 0 0 0 0 395
10 Vessel Buffer Prep / Hold 200 0 79 0.2 0.4 0 0 0 0 395
10 Vessel Buffer Prep / Hold 200 0 79 0.2 0.4 0 0 0 0 395
10 Vessel Buffer Prep / Hold 200 0 79 0.2 0.4 0 0 0 0 395
10 Vessel Buffer Prep / Hold 500 0 107 0.2 0.4 0 0 0 0 536
10 Vessel Buffer Prep / Hold 500 0 107 0.2 0.4 0 0 0 0 536
11 Vessel Buffer Prep / Hold 25 0 40 0.2 0.4 0 0 0 0 198
11 Vessel Buffer Prep / Hold 25 0 40 0.2 0.4 0 0 0 0 198
12 Vessel Buffer Prep / Hold 50 0 50 0.2 0.4 0 0 0 0 249
12 Vessel Buffer Prep / Hold 50 0 50 0.2 0.4 0 0 0 0 249
12 Vessel Buffer Prep / Hold 500 0 107 0.2 0.4 0 0 0 0 536
12 Vessel Buffer Prep / Hold 500 0 107 0.2 0.4 0 0 0 0 536
Unit
OpEquip Type Description
Volume
(L)
Flowrate
(L/hr)
Flowrate
(L/min)
Time
(hr)
Labour
(hr)PW 0.2M NaOH
0.04M
Phosphoric
Acid
PW WFI
1 Bioreactor Bioreactor 20 0 37 2 4.0 183 183 183 183 183
2 Bioreactor Bioreactor 200 0 79 3 6.0 395 395 395 395 395
3 Bioreactor Bioreactor 2,000 0 170 4 8.0 851 851 851 851 851
4 Centrifuge Disk Stack Centrifuge 0 400 20 2 4.0 100 100 100 100 100
5 Filter HousingDepth Filter 0 440 22 3 6.0 110 110 110 110 110
6 UF Skid UF Filter 0 638 32 4 8.0 160 160 0 160 160
11 Filter HousingViral Filter 0 120 6 3 6.0 30 30 30 30 30
12 UF Skid UF Filter 0 182 9 4 8.0 46 46 0 46 46
1 Vessel Media Prep / Hold 200 0 79 1 2.0 395 395 395 395 395
3 Vessel Media Prep / Hold 50 0 50 1 2.0 249 249 249 249 249
3 Vessel Media Prep / Hold 50 0 50 1 2.0 249 249 249 249 249
3 Vessel Media Prep / Hold 2,000 0 170 1 2.0 851 851 851 851 851
6 Vessel Buffer Prep / Hold 200 0 79 0.2 0.4 0 0 0 0 395
6 Vessel Buffer Prep / Hold 1,000 0 135 0.2 0.4 0 0 0 0 676
7 Vessel Buffer Prep / Hold 150 0 72 0.2 0.4 0 0 0 0 359
7 Vessel Buffer Prep / Hold 1,000 0 135 0.2 0.4 0 0 0 0 676
7 Vessel Buffer Prep / Hold 3,000 0 195 0.2 0.4 0 0 0 0 974
8 Vessel Buffer Prep / Hold 25 0 40 0.2 0.4 0 0 0 0 198
8 Vessel Buffer Prep / Hold 25 0 40 0.2 0.4 0 0 0 0 198
9 Vessel Buffer Prep / Hold 500 0 107 0.2 0.4 0 0 0 0 536
9 Vessel Buffer Prep / Hold 500 0 107 0.2 0.4 0 0 0 0 536
9 Vessel Buffer Prep / Hold 500 0 107 0.2 0.4 0 0 0 0 536
9 Vessel Buffer Prep / Hold 1,500 0 155 0.2 0.4 0 0 0 0 773
10 Vessel Buffer Prep / Hold 200 0 79 0.2 0.4 0 0 0 0 395
10 Vessel Buffer Prep / Hold 200 0 79 0.2 0.4 0 0 0 0 395
10 Vessel Buffer Prep / Hold 200 0 79 0.2 0.4 0 0 0 0 395
10 Vessel Buffer Prep / Hold 500 0 107 0.2 0.4 0 0 0 0 536
11 Vessel Buffer Prep / Hold 25 0 40 0.2 0.4 0 0 0 0 198
12 Vessel Buffer Prep / Hold 50 0 50 0.2 0.4 0 0 0 0 249
12 Vessel Buffer Prep / Hold 500 0 107 0.2 0.4 0 0 0 0 536
Stainless cleaning list
Hold bag cleaning listA significant reduction in cleaning
operations
© BioPharm Services Ltd CONFIDENTIAL
Impact of Disposables on Water
At this point stainless steel starts to take over from disposables based on vessel size
Using multiple bags instead of larger vesselsMaximises water saving
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Why
SS majority of water used for cleaning
At 1000L 90% used for CIP
Disposables significantly reduce water load
A 10 fold reduction at 1,000L scale3 fold at 10,000L scale (best case) which may not be practical
© BioPharm Services Ltd CONFIDENTIAL
Scenario Analysis – Rapid Evaluation of OptionsScenario Definition Base Hold Bio Liner Mixer Membrane
Single-Use Systems
Bioreactors (up to 2000L) No No Yes No No No
Media Preparation (up to 2000L) No No No No No No
Buffer Preparation (up to 2000L) No No No Yes Yes No
Type of Buffer Prep System Liner Liner Liner Liner Bag System Liner
Media and Buffer Hold (up to 3000L) No Yes No No No No
Intermediate Product Hold (up to 2000L) No Yes No No No No
Use Stainless Steel above Threshold No No No No No No
Threshold Volume 2000 2000 2000 2000 2000 2000
Membrane Adsorber for Flowthrough No No No No No Yes
Size of MA Capsule 10 10 10 10 10 10
Batches per year 90 90 94 90 90 90
Throughput (kg or doses per year) 185 185 193 185 185 185
Total capital (US$ M) 60.6 43.3 46.2 56.0 57.1 56.7
0.0% -28.6% -23.7% -7.6% -5.7% -6.4%
Cost per gram (US$) 174.46 144.28 153.80 168.02 172.61 168.97
0.0% -17.3% -11.8% -3.7% -1.1% -3.1%
Capital Charge 68.53 48.93 50.07 63.35 64.62 64.12
0.0% -28.6% -26.9% -7.6% -5.7% -6.4%
Materials 26.47 25.55 26.31 26.47 26.47 26.32
0.0% -3.5% -0.6% 0.0% 0.0% -0.5%
Consumables 20.55 28.59 27.06 20.89 23.89 21.12
0.0% 39.1% 31.7% 1.7% 16.3% 2.8%
Labour 40.24 28.43 36.33 40.06 40.06 39.85
0.0% -29.4% -9.7% -0.5% -0.5% -1.0%
Others 18.67 12.78 14.04 17.26 17.57 17.55
0.0% -31.6% -24.8% -7.5% -5.9% -6.0%
© BioPharm Services Ltd CONFIDENTIAL
Pricing
© BioPharm Services Ltd CONFIDENTIAL
Hold Bag Pricing
Price $/g ∆ CoG
25% 141.52 -1.9%
50% 142.44 -1.3%
75% 143.36 -0.6%
100% 144.28 0.0%
125% 145.20 0.6%
150% 146.12 1.3%
175% 147.04 1.9%
200% 147.96 2.6%
225% 148.88 3.2%
250% 149.80 3.8%
Hold Bag Pricing
© BioPharm Services Ltd CONFIDENTIAL
Bioreactor Bag Pricing
Price $/g ∆ CoG
25% 148.92 -3.2%
50% 150.55 -2.1%
75% 152.17 -1.1%
100% 153.80 0.0%
125% 155.43 1.1%
150% 157.06 2.1%
175% 158.69 3.2%
200% 160.32 4.2%
225% 161.94 5.3%
250% 163.57 6.4%
Bioreactor Bag Pricing
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Bioreactor Hardware Pricing
Price $/g ∆ CoG
25% 138.22 -10.1%
50% 143.42 -6.8%
75% 148.61 -3.4%
100% 153.80 0.0%
125% 158.99 3.4%
150% 164.19 6.8%
175% 169.38 10.1%
200% 174.57 13.5%
225% 179.77 16.9%
250% 184.96 20.3%
Bioreactor System Pricing
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Conclusions
© BioPharm Services Ltd CONFIDENTIAL
Conclusions
To drive out cost in biologics manufacturing
Many challenges remain
The earlier in development the better
Carefully evaluate the technologies
It is important to understand the costs:
Remove opinion its not always obvious
Provide insight – understand the drivers
Reduce risk
Cost Modelling
Provides insight
Helps make informed decisions
Single Use Systems
We have demonstrated that they have a significant role
This is a function of price, scale and process
Process cost modelling is important to support targeted cost effective applications
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