This document summarizes a presentation about the benefits and existing/emerging technologies of disposable biopharmaceutical processes. Some key benefits discussed include reduced capital investment and validation costs, faster set-up times, improved product safety, and reduced environmental impact compared to traditional stainless steel systems. Existing single-use technologies mentioned include bags, tubing, connectors and unit operations like mixing and chromatography. Emerging technologies integrate more single-use unit operations into entire disposable processes. Examples demonstrate savings from reduced water usage and faster implementation times versus traditional systems. The conclusion discusses how some disposable technologies have been used for decades but validation remains challenging, and that new technologies aim to enable fully disposable bioprocesses.

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Disposable Biopharmaceutical Processes
Advances & Benefits
March 15-19, 2010, Orlando, FL
Maik W. Jornitz & Thomas Paust, Sartorius Stedim Biotech

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Agenda
Benefits of Disposability
Existing & Emerging Single-use Technology
Example Cases
Conclusion

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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)

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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