1. PDA Connecting People, Science and RegulationSM
Disposable Biopharmaceutical Processes
Advances & Benefits
March 15-19, 2010, Orlando, FL
Maik W. Jornitz & Thomas Paust, Sartorius Stedim Biotech

2. PDA Connecting People, Science and RegulationSM
Agenda
Benefits of Disposability
Existing & Emerging Single-use Technology
Example Cases
Conclusion

3. PDA Connecting People, Science and RegulationSM
Benefits of Disposability

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Benefit – Risk Reduction
Risks (drug efficacy, approval)
CAPEX Motivation

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Media
Media Filtration
Media Bags
Upstream
Bio
Reactors
Harvesting
Contaminant
Removal
Fermentation/Cell
Culture
Concentration
Target
Purification
Purification
Viral
Removal
Sterile
Filtration
Form/Fill
Buffer Prep/Filtration
$ k $ M $ M $ k $ k
Possible Investment Costs
$ k - M
Possible Validation Costs
Potential Costs for a Process per m²: $ 60 - 100
Source: S.J. Tarnowski, PhD, ImClone, San Diego, 2001
Benefit - Capital Investment Reduction

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Benefit – Set-up Time Reduction
Example: Cell Culture Media Hold

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Benefit – Cleaning/Protection of the End-user
Increasing Potency of Drug Products
Fraction of
Daily Dose Permitted
Topical products 1/10th-1/100th
Oral products 1/100th-1/1000th
Injections, 1/1000th-1/10,000th
ophthalmics
Research, 1/10,000th-1/100,000th
investigational
products
Source: PDA Technical Report #29
Source: FDA CDER, Florida office, 2009

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Benefit – Environmental Impact ?
Source: Sinclair; Leveen, et.al.; The Environmental Impact of Disposable Technologies, The Biopharm International Guide, 11.2008

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Single-use Limitations
Volume [L]
Phases
104
103
102
101
100
10-1
Development Pilot Phase III/ProductionClinical Material (Phase I – II)Screening
Trends:
Higher Expression Rates
Increasing Titers &
Personalized Medicine
Reduction in
Process Volume10-2
hybrid
system
s
m
ulti-use
system
s
single-use
system
s

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Existing Technology – Benefits vs. Shortcomings
Benefits
☺ Reduced CAPEX
☺ Reduced cleaning
☺ Minimal set-up
☺ Reduced down-time, i.e.
increased equipment utilization
☺ Reduced foot-print needs
☺ Increased flexibility/multi-
purpose use
☺ End-user protection
Shortcomings
Extractable/Leachable
Scalability (in instances)
Mechanical strength
Sensor stability
Performance comparability
“The great unknown”
Source: Aspen Brook Consulting, 2009

11. PDA Connecting People, Science and RegulationSM
Existing & Emerging Single-use Technologies

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Source: ATMI
Existing – Single-use Process Components
Source: Pall
Source: GE Healthcare
Source: Xcellerex
Source: Millipore
Source: Sartorius Stedim
Source: ThermoFisher
Source: Cuno
Source: NewAge Industries

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Emerging – Single-use Unit Operations
Source: Sartorius Stedim
Source: Millipore
Next Integration of SU
Unit Operations
to a Process ?!

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Single-use Technology Positions (comparison of SU technologies)
Low Level of Experience High
High
Level
of
Use
Low
Filter
Capsules
Polymeric
Tubing
RFID
Unit
Ops.
SU
Bags
SU
Mixing
Chroma-
tography
Bio-
reactor
Connector
SU
Valves
SU
Pumps
SU
Sensors
SU
Filling
Technology & Experience Trend
SU
TFF
Source: Aspen Brook Consulting, 2009

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Validation/Qualification Requirements
γ Sterilization Validation
Extractables Analysis
Actual Product Contact &
Duration
RP-HPLC, GC-MS, FTIR
USP Class VI
Chemical Compatibility
Physical Testing
Burst Test
Leak Test,
Seal Strength
Film Thickness
Endotoxin Testing
Permeation Analysis
Long-term Shelf Life
Unspecific Adsorption
Particle Release
1- Polyethylene Terephthalate (PET)
2- Polyamide (PA)
3- Ethylene Vinyl Alcohol (EVOH)
4- Ultra Low Density Polyethylene (ULDPE)

16. PDA Connecting People, Science and RegulationSM
Example Cases

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Single-use vs. Multi-use (water consumption w/o steam needs)
Source: BioPharm Services
60 % of the costs
of a re-usable system
Major cost component:
Water,
also a common
major bottleneck

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Cleaning/Set-up Delay Impact (actual case)
Biotech facility produces max 4 batches, often only 3
Each batch has an estimated market value of $ 30 Mio
It turned out the bottlenecks are holding tanks:
Cleaning/Set-up/Sterilization Time > 8 hours
additional rinse WFI availability limitations
A disposable holding and/or mixing system
would be set-up in minutes
This improvement would mean:
min 1 batch more/week $ 1.5 Bio additional revenue

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Single-use vs. Multi-use (time to implementation)
Source: Stephen Brown, Vialis, PDA/EMEA Meeting 2009
The time to implement a single-use fermentation system is greatly reduce
in comparison to a multi-use system:
2 - 3 years
4 - 7 months
Main reasons for the 5 fold reduction:
• Qualification of the equipment
• Cleaning validation
• Qualification of set-up

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Costs of Polishing: Resin or Membrane ?
Anion exchanger polishing step (flow through) for the removal of
DNA, HCP, Protein A and endotoxins
Source: Gottschalk, PhD

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Cost Evaluation Tools
End-user Information
- Type of Process
(e.g. mAb)
- Brief Process Description
(e.g. Block schematic)
- Basic Process Data
(# Batches, Titre, ...)
- other Informations
Output for end-user
- Process Flow Diagram
- Equipment List
- Standard Layout Studies
- Total Investment Cost
- Capital investment
- Operational costs
(disposables vs. re-usable)Vendor input
- Equipment Data
- Pricing Informations
- Process Know-how
- Process Pattern
- Other information

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Possible Process Schematic
Source: Xcellerex
Benefits in this Scenario:
• Lower HVAC ceiling area
• Reduced energy costs
• Contained system design
• Lower risk by human intervention
• High production flexibility

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Possible...?
Production Micro-Sites using single-use technology to produce,
for example, a vaccine at the point-of-use
Source: GE Healthcare
Source: Sartorius Stedim

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Conclusion
Some disposable technology has been used successfully for
decades
Some components and validation requirements still pose the
„great unknown“
New technologies are developed to fill existing process gaps –
a 90% disposable process might be possible
Disposability creates major advantages, by reducing costs,
increasing production utilization and protect end-users

25. PDA Connecting People, Science and RegulationSM
A pessimist sees the difficulty in every opportunity;
an optimist sees the opportunity in every difficulty.
Sir Winston Churchill
Maik.Jornitz@Sartorius-Stedim.com
Thomas.Paust@Sartorius-Stedim.com
Thank you