Bio Solve Process Cost Model Workshop

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
Disposables

State of the Industry
Why use cost models?
Building a good biotech
process model
Understanding cost: example:
disposables
Cost modelling workshop: mAb
case study
Summary of results
Stainless Steel
Discussion


Acknowledgements

Ms. Claire Hill, Biopharm Services
Mr. Bruce Williams, MSD biologics/ Avecia
Dr. Richard Turner, MedImmune
Dr. Brendan Fish, GSK
Mr Kit Erlebach, MSD biologics


BioPharm Services
The recognized leading international bioprocess consultancy

Our focus is on helping our clients achieve operational excellence with
the ultimate goal of delivering more cost effective medicines to patients

b i o p h a r m
s e r v i c e s

Biopharm Engineering
& Consultancy Services


Cost Trends
Productivity in development is reducing
As spend per drug increases
Productivity is decreasing
Now overall cost of bring a successful biologic to
market is between $0.8bn to $1.2bn
Manufacturing costs are increasing proportionately
20 years ago about 3% of sales price for chemical
candidate
Biologics 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

Implications for Manufacturing
Price Breakdown
Manufacturing R&D Sales & G&A Profit share Pre tax profit

14%
37%

21%

9% 19%

Manufacturing cost is single variable cost
Development costs are fixed and include losses around failed drugs
1. Source GE Healthcare webinar


Why use models? To answer questions such as…

Get the big picture – what are How much will it cost to make
the variables? 75kg of product?
Make predictions – what will Is it cheaper to use disposable
happen if… bags or stainless steel vessels
Evaluate alternatives – which one Which plant changes will have
is best? the biggest impact on cost?
Communication – a simple picture What is the cost/benefit for
or chart is better than a thousand installing new technology?
words If production falls from 100kg/yr
Make better business decisions to 50kg/yr, what will happen to
the cost of goods per gram?


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


Cost of Goods – Cost of Production

Includes just manufacturing costs
Facility
Materials
Consumables
Labour
Does not include
Sales, General & Admin
R&D
Interest & Taxes
Why is it used?
Provides insight into cost drivers
Allowing analysis of process and technologies
Snapshot
Costs over a defined (short term) period
No overall lifecycle costs
Failure


Fixed vs. variable costs

Fixed: Capital, some materials Variable: Materials, consumables
& labour & some labour

Also referred to as direct/indirect costs in cost accounting.


Cost model components
“Fixed” costs Variable costs
Size of facility (how Materials
much capital was Consumables
initially invested) Labour
Base facility running Utilities/waste
costs (insurance,
electricity, etc.) Productivity
Administration Batches per year
(receptionist, etc) Batch size
Air filters


Driving Down Cost of Goods
Product Priorities
Process Development $100s millions
Higher titres
Better match the process to the facility
Chromatography matrices
Filtration rates/membranes

Increased benefits
Design
Good Facility design $100s millions
Appropriate process equipment
Appropriate infrastructure (neither too` small nor too large)
Latest manufacturing technologies
Platform Technologies
Continuous processing
Integrated operations $10s millions
Integrated disposables
Manufacturing
Appropriate process equipment
Optimum working practices $10s millions

Building a good biotech Process
model
Understand the manufacturing process
Resource requirements
Timing
Understand the cost structure
Fixed/variable – not always obvious
Beware of hidden costs
Activity-based costing (ABC) can help with this
Understand where to make assumptions
Impossible to model all variables
Can introduce more error by false confidence


BioSolve: Configurable CoGs Model
Process Definition MAb Typical
Rapid process configuration Product Titre
Capacity Utilisation
5.00 g/L
80%
Rapid option evaluation Production Bioreactor Volume 5000 L

Technologies Single-Use Systems
Processes Bioreactors (up to 2000L) No

Scalable mass balance
Media Preparation (up to 2000L) Yes
Buffer Preparation (up to 2000L) No
Standard format
Process Sequence Conc (g/L) Vol (L) Mass (g) Yield (%) Time (h)
Consumables estimates 1 N-2 Seed 0.0 50 0 0% 58.0

Scalable equipment list
2 N-1 Seed 0.0 500 0 0% 59.0
3 Production 5.0 5,000 25,000 0% 210.0

Based on standard costs, sizes
4 Centrifugation 5.0 4,250 21,250 85% 9.0
5 Depth Filtration 4.3 4,250 18,063 85% 9.2

Basis for capital cost estimate
6 UF/DF #1 40.4 425 17,159 95% 12.4
7 Protein A 3.1 4,926 15,443 90% 12.9

Insight into utilities, environment
8 Virus Inactivation 3.0 5,025 15,135 98% 2.5
9 Capture IEX 7.8 1,847 14,378 95% 11.4

PW & WFI
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

Waste streams 12
13
UF/DF #2
Sterile Filtration
35.5
34.8
369
369
13,118
12,856
98%
98%
12.4
9.1

Capacity and capital estimates


Process Cost Model Features Scalable

Mass balance calculations
Step times
Process Interface Calculation Outputs Equipment/consumable
sizing
Labour requirements
Production Customisation Utility requirements
Dashboard
Bill of Technology Options
Labour
Materials
Process
Description
Scenarios Solution prep methodology
Consumables Disposable systems
Cost of Goods
& Materials
Sensitivity Mode of operation (fed-
batch vs. perfusion, packed
Equipment Capital bed vs. EBA, etc)

Cost Database
Equipment
Consumables
Materials
Labour
Waste treatment

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


BioSolve Output (Water)
How Does it Compare

Stainless Steel % Water Used for CIP
100%

90%

80%

70% Actual
60% BioSolve

50% Power (Actual)

40%
0 10,000 20,000 30,000 40,000 50,000 60,000
Bioreactor Harvest Volume L


Capital Estimate Comparison


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-up
Media: per batch
Buffer: 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


BioSolve Disposable Options
Using MAb Typical
Set up SS facility base case
Disposable options generic*
Bags impact
Mixing system options
Bioreactors
Sensitivity
Hold bag costs
Bioreactor pricing
 Consumables
 Hardware
Analysing Individual
Operations
Membrane absorber*
*Based on average vendor pricing

Performance


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


Stainless Steel Option

• Capital $ 60.6M
• CoG 174.5 $/g


Hold bags option

• Capital $ 43.3M
• CoG 144.3 $/g

© BioPharm Services Ltd So what is happening? CONFIDENTIAL

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


Impact on CIP – Cleaning Lists
0.04M
Unit Volume Flowrate Flowrate Time Labour
Equip Type Description PW 0.2M NaOH Phosphoric PW WFI
Op (L) (L/hr) (L/min) (hr) (hr)
Acid
1 Bioreactor Bioreactor 20 0 37 2 4.0 183 183 183 183 183
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 0.04M
Unit Volume Flowrate Flowrate Time Labour
3 Vessel Product Hold 2,000 0 170 1 2.0 851 851 851 851 851 Equip Type Description PW 0.2M NaOH Phosphoric PW WFI
4 Vessel Product Hold 2,000 0 170 1 2.0 851 851 851 851 851
Op (L) (L/hr) (L/min) (hr) (hr)
Acid
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 2 Bioreactor Bioreactor 200 0 79 3 6.0 395 395 395 395 395
8 Vessel Product Hold 1,000 0 135 1 2.0 676 676 676 676 676 3 Bioreactor Bioreactor 2,000 0 170 4 8.0 851 851 851 851 851
9 Vessel Product Hold 500 0 107 1 2.0 536 536 536 536 536 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
12 Vessel Product Hold 100 0 63 1 2.0 314 314 314 314 314 6 UF Skid UF Filter 0 638 32 4 8.0 160 160 0 160 160
13 Vessel Product Hold 100 0 63 1 2.0 314 314 314 314 314 11 Filter HousingViral Filter 0 120 6 3 6.0 30 30 30 30 30
1 Vessel Media Prep / Hold 200 0 79 1 2.0 395 395 395 395 395
12 UF Skid UF Filter 0 182 9 4 8.0 46 46 0 46 46
3 Vessel Media Prep / Hold 50 0 50 1 2.0 249 249 249 249 249 1 Vessel Media Prep / Hold 200 0 79 1 2.0 395 395 395 395 395
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
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 200 0 79 0.2 0.4 0 0 0 0 395 7 Vessel Buffer Prep / Hold 150 0 72 0.2 0.4 0 0 0 0 359
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 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 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
7 Vessel Buffer Prep / Hold 3,000 0 195 0.2 0.4 0 0 0 0 974 9 Vessel Buffer Prep / Hold 500 0 107 0.2 0.4 0 0 0 0 536
7 Vessel Buffer Prep / Hold 3,000 0 195 0.2 0.4 0 0 0 0 974 9 Vessel Buffer Prep / Hold 500 0 107 0.2 0.4 0 0 0 0 536

Hold bag cleaning list

A significant reduction in cleaning

operations

Stainless cleaning list

Impact of Disposables on Water

At this point stainless steel starts to Using multiple bags
take over from disposables based on instead of larger vessels
vessel size Maximises water saving

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 scale
3 fold at 10,000L
scale (best case)
which may not be
practical


Scenario Analysis – Rapid
Evaluation of Options
Scenario 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%

Pricing


Hold Bag Pricing
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%


Bioreactor Bag Pricing
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 Hardware Pricing
Bioreactor System 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%


Conclusions


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


Bio Solve Process Cost Model Workshop

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