disposable technology - a technobusiness perspective€¦ · antibodies will gradually increase...

Disposable Technology - a technobusiness perspective A Business Briefing being held on 10th March 2011With Mrs Miriam Monge, VP Marketing Biopharm Services, Chairs: Prof Gary Lye and Prof Eli Keshavarz-Moore, UCL

The Senior Executive Vision Programme runs Business and Technical briefings throughout the year and a 3 day core-course on 18-20th May 2011 www.ucl.ac.uk/biochemeng/industry/vision

UCL The Executive Suite Roberts Building Torrington Place, London WC1E 7JE

Programme:3:30 Registration & coffee 4:00 Lecture

5:00 Q&A5:30 Close followed by Drinks

For further information contact Dr Karen Smith, Director of Bioprocess Leadership on +44 (0)20 7679 4411 or email her [email protected]

© BioPharm Services Ltd

Disposable Technology - a Techno-business Perspective

Senior Executive Vision Programme 10th March 2011

Miriam Monge, VP Marketing & bioprocess applications, Biopharm Services Ltd

E-mail: [email protected]

www.biopharmservices.com

mailto:[email protected]

http://www.biopharmservices.com/

© BioPharm Services Ltd 2 CONFIDENTIAL

Agenda

Disposable technologies: historical origins & growth Biomanufacturing challenges & trends Industry requirements & disposables business drivers Disposables: an industry in transition

Maturing technology Myths & misconceptions Case studies and analysis

Perspectives Strategic & Operation Regulatory & Validation Suppliers Society

What’s next? Future Potential


Acknowledgements

Andrew Sinclair Monge, BioPharm Services

Claire Hill, BioPharm Services

Andrew Brown, Biopharm Services

Gráinne McDonagh, BioPharm Services

Johannes Roebers, Elan

Parrish Galliher, Xcellerex

Lindsey Leveen1, Genentech

Stacey Cox, Genentech

Tobias Vilby, CMC

1. For more information on green issues see Lindsay’s blog http://www.greenexplored.com/


BioPharm Services

Delivering Operational Excellence

Our focus is on helping our clients achieve the goal of delivering cost effective medicines to

patients through better understanding of process, product and manufacturing

The recognized leading international bioprocess consultancy

Biopharm Services

Biopharm Software

Biopharm Consultancy


Disposable technologies, historical origins & growth

Flasks & Lab Equipment

Single-use filters (mid-1970s)

Media and Hold bags (mid-1990s)

Wave Bioreactors (late 1990s)

Single-Use Bioreactors (2006)

Sigma-Aldrich

Pall

GE Healthcare

ThermoScientific Hyclone, Invotrogen Life Technologies

ThermoScientific Hyclone


Biomanufacturing Challenges Lessons from the Last 20 years

Capital intensive

Long build times In excess of 5 years

Facilities generally

don’t make what

they designed to do

Product forecasts are inaccurate beyond 3 years

-75

-50

-25

0

25

50

2014 2015 2016 2017 2018 2019 2020

Cu

mu

lati

ve C

ash

Flo

w (

US$

M)

Year

Investment decision start (2014) year -5

Long range forecast typically accurate 3 years (2017) year -5

By the time beneficial production starts, capacity may not be requires and the facility needs to make an alternative


First Understand Manufacturing Trends

Trends Success rates & yields increased Personalised medicine –targeting therapies (smaller patient groups1

Titre improvements continue & will reduce the volume of bioreactor capacity. Titres and Yields of Licensed Antibodies will gradually increase over time2

There will be more Antibodies with smaller market penetration/sales and lower Product Mass (50-500kg) requirements1.

Required to reduce costs (by 10 fold?)

Implications Plant size will decrease Need for more flexible facilities

Integrated, Modular Decouple process

Disposable technologies will have greater application for commercial supply However

Cost is an issues Maturity and supply chain security

Develop cost effective processes. Focus on process cost optimisation and sustainability in PD

The best process Reduce risk

1. Personalised Medicine Fitting the Treatment to the Patient Dr Horst Kramer, Roche 2010

2. 2. Roebers, ISPE Barcelona December 2009


Requirements

Build faster

Plan better

Reduce capital intensity

Design for easy reconfiguration

Reducing uncertainty at the time of investment Reducing risk Where disposables fit into this picture?


Business Drivers – Influencing Disposables

Purpose Pilot versus launch

In market supply

Scale of the operation

Project Type New build

Retrofit

Flexibility in Operation Single vs. multi product

Rapid change over

Frequency of change over

Risk management

Certainty of requirements

When and what capacity is required

When will requirements be known

Delay capital spend

Utilization target and range

Cost

Upfront costs

Operating costs

Lifecycle costs

Environment

Facility Factors Business Factors


So What are Disposable Technologies?


Disposables are still Evolving – Bioreactors


The Drivers as we see them Now

Cost of Goods

Processing Time

Utilities & Waste

Validation costs

Other Factors

Ad

va

nta

ge

s

Capital

Materials

Labour

Reduced non-productive time

Setup time

Campaign & product turnaround time

Cleaning water

Steam

Electricity

Waste water

Cleaning validation

Increased Flexibility

Fewer failures (closed operation & simple set-up)

Adopting lean principles

Dis

ad

va

nta

ge

s

Consumables

Ergonomics Plastics waste

Waste treatment

Leachables & Extractables studies

Supply chain security

Lack of robust disposable sensors

Scalability & large scales of operation


Misconceptions

Disposable technologies

They create waste?

They cost money?

They require more people?


Impact on the Environment

Disposable

Typical stainless

Based on the November 2008 BioPharm International paper

“The environmental impact of disposable technologies – Can disposables reduce your facility’s environmental footprint?” (Sinclair, Leveen,

Monge, Lim and Cox)

http://biopharminternational.findpharma.com/biopharm/Disposables+Articles/The-Environmental-Impact-of-Disposable-

Technologie/ArticleStandard/Article/detail/566014

http://biopharminternational.findpharma.com/biopharm/Disposables+Articles/The-Environmental-Impact-of-Disposable-Technologie/ArticleStandard/Article/detail/566014












Carbon Footprint (pounds/batch)

DISP SS delta

SIP - 338.5 (338.5)

CIP 19.3 688.4 (669.1)

Transporting Plastic 148.5 - 148.5

Pumping Water and Wastew ater 2.4 18.2 (15.8)

Steel Fabrication Amortized Per Batch 2,970.7 7,723.8 (4,753.1)

Polymerizing Plastic Per Batch 505.8 - 505.8

Extruding Plastic 316.1 - 316.1

WFI Still 7,308.7 29,828.8 (22,520.1)

Cleanroom Energy 83.6 129.2 (45.5)

Incinerating Plastic 6,029.3 - 6,029.3

Workers Driving CO2 Footprint 72,232.4 81,465.1 (9,232.7)

Total CO2 LBs Per Batch 89,616.7 120,191.9 (30,575.2)

Total CO2 LBs Per Batch Without Workers Driving 17,384.3 38,726.8 (21,342.5)

SourceAvg USA Mix of Coal, Gas and Other


Disposables Plastic Waste1

BPSA2

Waste stream volumes are relatively small compared to say hospitals (is this true?) Difficult to justify recycling from the economic standpoint

Waste treatment options Look at hospital options

Remember Carbon footprint is reduced Overall waste streams are reduced specifically water load

Plastics used are complex mixtures & not easily separated

1. First presented by A Sinclair at IBC Bioproduction conference in Barcelona 2009 2. http://www.bpsalliance.org/ BioProcess Systems Alliance part of SPI the plastic industry trade association

http://www.bpsalliance.org/


Comparing Hospital Output to Biotech

Hospitals

7,300 beds/1 million of population1

417kg plastic waste/bed/year2

For a population of 70 million this equals 213,300 te/year (population of the UK)

Biotech MAbs

About 10 te/year worldwide

At maximum disposables integration we generate 0.19kg/g of product

Equivalent to 1,900 te/year

BPSA assertion is valid

1. Source OECD average for Western World 2. State of California, www.ciwmb.ca.gov/bizWaste/FactSheets/Hospital.htm#Appendix%20A


Not All Disposables Save Money Comparing Technologies

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%


Savings Change with Scale

Varying scale Basis 3 bioreactors

Changing titre

Changing volume

Large scale 3 x 15,000L

8 g/L

Savings still seen, < 6%

At small scale 3 x 500L & 1g/L

Saving > 20%

1

3

5

7

5%

10%

15%

20%

25%

30%

35%

40%

500 1,000 2,000 3,000 5,000 7,000 9,000 10,000 12,000

Titre

Cosr

Sav

ings

Volume L

35%-40%30%-35%25%-30%20%-25%15%-20%10%-15%

Increasing scale

Increasing titre g/L absolute savings

Relative savings stainless vs. disposable

g/L


Current Trends

Disposable suppliers Extending the range Increasing Scale

Designers Modular design approaches

Users Adoption for commercial setting

1982

1,0

00L

Faci

lity

1994 2009


Case Study – Elan1

What is Iomlán?A facility for process development and production of drug substance for

monoclonal antibody therapeutic products

Iomlán

2008

Biopharmaceutical

Manufacturing Plant

2006

Construction cost* €143 M €352 M

Site size 20 acres 30 acres

Gross floor area 16,890 m2 35,382 m2

Drug substance output 455 or 910 kg 782 kg

Production capacity

bioreactor

12,000

or 24,000 litres

30,000 litres

Other functions

Commercial Production

Clinical Production

Process Development Labs

Quality Control Labs

Warehousing

Yes

Yes

Yes

Yes

Yes

Yes

No

No

Yes

Yes

Total Installed Cost (TIC) includes all construction costs, equipment, fees and contingencies. Iomlán is based

on 2008 estimates, BMP based on 2006 estimates.

1 Disposables and Lean Manufacturing Concepts Emmet Cronin, élan biologics (USA), Disposables and Containment Technology in Biomanufacturing: Managing Risk, Reducing Cost ISPE Strasbourg Conference, 28 - 29 September 2009


Elan Comparing Stainless with Hybrid Single Use


Case Study – GSK Single Use Fill Finish Implementation1

Basis H1N1 Response Fast track project retrofit to increase capacity

Not possible for stainless

Disposable fluid path

Intrusions into Grade A filling line reduced from 2hrs to 0

Simpler operation reduced operator error and process risk

Eliminated SIP and CIP

Campaign fill time reduced from 26 hrs to 12 hrs

Significant site reduction in energy usage coupled with a 40% increase in capacity

1End-to-End Deployment of Single-Use Technology in Aseptic Filling of Vaccines at GSK, BioPharm International Volume 23, Issue 2 2010. www.biopharminternational.findpharma.com

http://www.biopharminternational.findpharma.com/

http://www.biopharminternational.findpharma.com/


Case Study – Xcellerex FlexFactory1

50% reduction in capital cost

70% reduction in time to build and start GMP mfg.

25% reduced operating costs

70% reduction in water consumption

70% reduction in waste water generation

20% reduction in utility consumption

Flexible, modular, transferable

1982

1,0

00L

Faci

lity

1994 2009

1Turnkey Modular Single Use Multiproduct Biomanufacturing Facilities, ISPE Annual Meeting, Advances in Vaccine Manufacturing and Development, Parrish M. Galliher


Perspectives

Cost Pricing variation between suppliers The end-user may appreciate a new disposable technology but it has to be cost effective

Quality and reliability. By moving to disposables, the end user is effectively outsourcing a major part of manufacturing and quality management. the user must work very closely with the supplier to ensure that robust quality throughout the manufacturing process is maintained.

Supply chain. Supply chain risk is a common source of complaints related to dual sourcing and consistency of supply.

Ergonomics. "When working with disposables, there is a much greater dependence on the operators themselves. Suppliers need to design disposable systems that are as intuitive as possible

User Viewpoints on Disposables Implementation What end users think about single-use systems. Jun 1, 2009 By: Andrew Sinclair, Miriam Monge BioPharm International Volume 22, Issue 6

http://biopharminternational.findpharma.com/biopharm/author/authorInfo.jsp?id=39820

http://biopharminternational.findpharma.com/biopharm/author/authorInfo.jsp?id=36347


Suppliers Perspective

Strong move towards standardization/modularization Circuit approach reducing the number of different contact materials to facilitate validation Recognize the importance of speed and flexibility in process design

Are moving to answer perceptions such as the true environmental impact of disposables

New entrants are offering customization of small orders that the large players do not wish to tackle


Key issues for suppliers

Level of technology maturity

Very little true liaison between suppliers

In situ integrity testing of critical components such as disposable bioreactors requested by end-users

Lack of clear industry standards with which the disposables should comply


End-Users Need to Manage Lifecycle Risk

Operations Identify requirements Operability Define cost goals Define & understand risks Compromise

Op

era

tion

s

En

gin

ee

ring

Pro

cu

rem

en

t

Engineering Identify best technology that’s fit for purpose Design for whole lifecycle Ensure designs support procurement Deliver the project to cost, time, quality

Procurement Understand supply chain risk Develop procurement strategy Integrate capital and operational procurement approach Ensure design minimises supplier dependencies


What's Next

Return to the Beginning Build faster Plan better Reduce capital intensity Design for easy reconfiguration

Plant size will decrease Need for more flexible facilities

Integrated, Modular Decouple process

How? Is it better to modularise? How do we measure risk? What role continuous processing?


Measuring Risk Assessing Time Value of Money

NPV (Net Present Value) is today's value of future costs and benefits

ROI (Return on Investment) is a measure of

financial gain (or loss) of a project in relation to

its cost:

(Financial Gain or Loss – Project Cost) / (Project Cost) X 100

Breakeven Point is the year when the facility begins to make a profit.


Scale up or Scale out? – Economic Benefit

One large stainless bioreactor or multiple small disposable bioreactors?

NPV (Net present value) & ROI (Return on Investment) Analysis

Spending profiles capital project

Stainless steel 4 years (10%, 40%, 40%, 10%)

Disposable 3 years (23%, 57%, 20%)

Production up to 2020

Sale price constant per dose

Batch size depends on turnaround time and number of bioreactors


Scenarios

1 X 6000L DSP Batch

Scenario 1 6000L SS

3 X 2000L DSP Batches

Scenario 2 6 X 1000L Single Use




1 X 6000L DSP Batch




CoG and Capital Investment – Guidance

Highest capital investment is for stainless steel option Highest cost per gram is

for 6 x 1000L options (see large number of batches)

Lowest CoG option is 3 x 2000L disposable bioreactors pooled into 1 DSP batch

Results from Biopharm Services, BioSolve Process cost model running a MAb model using data from Morrow, K. J. Industrial-Scale Antibody Production Strategies. Genet. Eng News, 22(17), 8-71, 2002


NPV & ROI

Highest NPV & ROI and earliest Breakeven point are for 3 x 2000L disposable bioreactor with all bioreactors pooled for downstream.

NPV and ROI is higher for all disposable options due in part to shorter spending profile for disposable facilities (so production starts earlier)


Breakeven Graph Cumulative Cash flow

Breakeven Point


Role of Continuous – Potential

Focus is on downstream

Maximise potential linking to small scale high titre upstream

Fit with disposable technology

Continuous 12,000L harvest every 2 days, continuous process sized on 200L/hr

Maximum tube size is less than 9.5 mm

Link to continuous in line dilution of buffers reduces size and frequency of solution prep operations

Batch harvest whole batch 12,000L over 6 hours at 2000L/hr

Tube size in the range of 25 to 49 mm

Continuous facility is physically much smaller and continuous in operation, we expect

Less labour

High asset utilisation

10th smaller scale

More Flexible? What's the turndown on the line? How easy is a product changeover?


Process

Viral Filtration

Affinity Chromatography Hydroxyapatite Chromatography

Downstream Processing (Purification)

Virus Inactivation

Ion Exchange

Ultrafiltration SkidBuffer Preparation

Ultrafiltration Skid

Final filtration

Upstream based on ATF

Concentrate buffer feeds

Minimal headcount


Some Preliminary Results

Each product should be ~200 kg/yr The products are produced in identical processes MAb Typical

No more than 10,000L is pooled to make up a batch (5 x 2,000L SUBs per batch) Changeover is set to 7 days

Continuous Flow rate through the SMCCs can’t go above ~1,000 cm/hr and the no. of columns can’t go above 6

Maximum no. of 1,000L SUBs is 4 times as long as only columns and one DSP train are used

Changeover is set to 14 days Control systems have to be reconfigured and validated

Perfusion Culture Protein A SMCC IEX SMCC MA Flow Through

Media Flow (vvd) 2 No. of columns 3 No. of columns 5 Capsule size (in) 30

Growth Phase (days) 3 Column volume (L) 6.3 Column volume (L) 1 Capsule volume (mL) 540

Perfusion Factor 40 Capacity (g/L) 50 Capacity (g/L) 60 Capacity (g/L) 10,000

Max Flux (LMH) 5 Max no. of reuses 50 Max no. of reuses 50 Max no. of reuses 1

Max flowrate (cm/hr) 796 Max flowrate (cm/hr) 378


Preliminary Results

Significant savings are seen

Reduced CoG Footprint Reduced capital

Key assumptions Compared fed batch to perfusion with 5:1 titre difference Assumed longer changeover time

More work required

Description Batch Continuous Delta

SUB size (L) 2,000 1,000

No. of SUBs 8 4

No. of SUBs per batch 2 4

Titre (g/L) 5 1

Total throughput (kg/yr) 1,028 1,012 -2%

Changeover time (days) 7 14

Two products

Total installed capital (US$ M) 56.9 26.4 -49%

CoG per gram (US$) 65.05 48.72 -22%

Footprint (m2) 3,388 1,981 -43%

Five products

Total installed capital (US$ M) 66.7 37.2 -44%

CoG per gram (US$) 48.68 37.34 -23%

Footprint (m2) 3,568 2,444 -32%


What next?

There are demonstrated benefits using disposables Options worth considering

Modularisation Scale out approaches

Continuous

But we are still learning the best approaches

Not likely to be one solution

Always keep in mind the business case

Suppliers have much more work to do

Users role is to define and think about the implications

Decoupling process from building what are the real opportunities

Think OpEx, lean


Models Provide Insight Supporting Decision Making

CoG Models provides insight into process options Example comparing expression systems Can compare different process routes Evaluate technologies

Screen out non viable options Provide visibility Quickly identify drivers

Provided methods Transparent Proven

Support the drive to cost effective manufacturing


Is the Future Disposable?

Thank you for your attention!

Any Questions?

E-mail: [email protected]

disposable technology - a technobusiness perspective€¦ · antibodies will gradually increase...

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