bio solve process cost model workshop

© 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, [email protected]

Miriam Monge, VP Global Key Accounts, Biopharm Software Solutions

[email protected]

www.biopharmservices.com

mailto:[email protected]

mailto:[email protected]

http://www.biopharmservices.com/


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


Acknowledgements

Ms. Claire Hill, Biopharm ServicesMr. Bruce Williams, MSD biologics/ Avecia Dr. Richard Turner, MedImmuneDr. Brendan Fish, GSKMr Kit Erlebach, MSD biologics


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


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


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


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…


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 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


Fixed vs. variable costs

Fixed: Capital, some materials & labour

Variable: Materials, consumables & some labour

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

https://www.teamcrb.com/07160.SO/Equipment Cut Sheets/Sartorius Stedim/Stedim_Anim_041220_largemp2.mpg


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


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


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


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


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


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

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)


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-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


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


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

So what is happening?


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 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


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



6 Vessel Product 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 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


































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



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























Stainless cleaning list

Hold bag cleaning listA significant reduction in cleaning

operations


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


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


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%


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%

Hold 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 Bag Pricing


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


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