transitioning from hardware to disposable
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Millipore Downstream Solutions
Transitioning from hardware to disposable
Alain Rachon
EU Technology Manager Biopharmaceutical Markets
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OutlineTangential Flow Filtration (TFF) example
Process case study (MAb concentration) Success criteria
Design critera
Process solutions
TFF procedure
Economical comparison
Conclusions
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Background :Generic MAb Process
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TFF in MAb processing
Objectives:- High product yield & concentration
- High product purity, quality and activity
- Controlled bioburden & endotoxin levels
- Robust, efficient & economical process
Challenges:- Product stability
- Product quality (formation & aggregates)- Viscosity- Product recovery
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Yield
As close as possible to 99.9%(reality >95%)
Retention
>99.9%
TFF in MAb processingSuccess criteria
Highest concentration as possible Around 180 g/l
Standard process time for TFF process Appr. 4 hours, 8 hours including set-up & CIP
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1. Capital investment- Several systems for several scales
2. Operation cost
- Setting, Cleaning, Conditioning,
3. Process flexibility- Scalable, Adaptable
4. Product & operator safety- Self contained
5. Quality & regulatory requirements- No cross contamination, Low endotoxins & bioburden level
Photo courtesy of Novartis Pharma S.A.S. Novartis
TFF in MAb processingWhat are your process pains?
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TFF in MAb processing Yield consideration & System design
1. Membrane selection
2. Tank hold up volume
3. Recovery strategy
4. Pipe diameter
5. Pipe design
6. Pump type & capacity
7. Hold up/non recovery volume
1% yield increase is significant
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Process specifications
Permeate volume (L/m)
020 40 60 80 100 120 140 160 180 200
10
20
30
40
50
60
70
80
90
100
110
120
220
N o r m a l i z e
d F l u x
2 5 C
, ( l / h / m 2 / b a r T
M P )
0.00
0.25
0.50
0.75
1.00
1.25
1.50
1.75
2.00
2.25
2.50
d P
( b ar )
0
Flux
dP1.5 to 50 g/L
Avg Flux = 70-75 LMH
50 g/L
Number of Diafil tration
vo lumes = 8 to 10
Avg Flux = 55-60 LMH
50 to > 200 g/L
Avg Flux = 20-25 LMH
- Temperature : room temperature - Total Process Time : 4 hours- Feed Flow rate: 6 l/min/m - TMP= 1.75bar/25psi
DiafiltrationFinal
ConcentrationPre-
Concentration
TFF in MAb processingOptimum operating conditions
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- UF membrane selection is key toincrease process yield
- Pellicon 3 module with Ultracell 30 kDC screen is the industry standard for MAb processing
Ultracel 10 Kda P30.0088m
Biomax 10 Kda PXL0.005m
initial protein content (g) 5.50 5.50retentate protein content (g) 5.36 5.02permeate protein content (g) 0.00 0.00
YIELD retentate before flushing 97.45% 91.25%
flush protein content (g) 0.14 0.48flush + retentate content (g) 5.50 5.50
YIELD retentate after flushing100.00% 100.00%
TFF in MAb processingPellicon 3 Ultrafiltration devices
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Robust and Reliable Design withtighter specifications
Ultra low binding compositemembrane in a Thermoplasticdevice
Higher operating pressures, temperature &caustic cleaning compatibility
Unbeatable performances consistency
Accurate scalability
Better COGS by achieving higher finalconcentration (>200g/l in MAb), yield &retention
Low extractables
Low fouling & easy cleaning
Integrated gasket for ease of use
TFF in MAb processingPellicon 3 Ultrafiltration device
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1. Minimize retentate & tankholdup volume
2. Include a low-point recovery port
3. Include a high-point blowdown port
4. Forseen a pipe slope towardsrecovery port
5. Optimize product recoverymethodology
TFF in MAb processingHow to design a high yield TFF system?
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What Are Your Key Drivers for a gooddesign of an TFF system?
Minimise hold up volumeUF holder design , Retentate loop, Sensor ...
Agitation & recoveryLowest point, high point blow down
Pipe & pump size & membrane area Pipe size[inches]F low range
[L/min]M in. recirc
vo lume[L ]
Undrainable holdupafter blowdow n
[L ]1/2 3 12 1 0.03
3/4 11
36 3 0 .1
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What Are Your Key Drivers for a gooddesign of an TFF system?
Process tank designImproper design
Optimized design
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What if you could enable a full disposable fluidpath for your TFF process?
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Gamma irriatedTFF flowpath
Buffer / Producttransfer
TMP & delta Pfully control Flexible Multi Product
Solution
High process control
So It means...Robust & Safe processNo cross contamination
Reduce time to market
What if you could enable a full disposable fluidpath for your TFF process?
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TFF disposable assemblyWhat does it bring to you?
Buffer transfer Mix 100, 200, 500 L
Product transfer Mobius assembley
TFF Liner For Pellicon cassettes
Feed tankMobius assembley
What it does for you?Fully adapted to your application
(working volume, tubing sizes, pump of choice)Ready & easy to useNo product contact with hardware pieces
(holder, pump, sensors)
So It means...High yieldNo contaminationLow failure risk
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What could a Full Disposable TFF processbring you in your process?
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Set up SystemInstall Membranes
Clean Membranesand System
Test Integrityand Permeability
Equilibrate withProcess Buffer
ConcentrateDiafilter
Recover Productfrom System
Store
Clean Membranes
and System
Test Integrityand Permeability
Rinse
With TFF Mobius!With TFF Mobius!
No cleaning!
With TFF Mobius!
No water permeability!
With TFF Mobius!
No storage!
With TFF Mobius!
No system cleaning!With TFF Mobius!
No water permeability!
With TFF Mobius!
No Rinsing!
TFF in MAb processingImpact of disposable technologies on SOPs
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Set up SystemInstall Membranes
Test Integrity
Equilibrate withProcess Buffer
ConcentrateDiafilter
Recover Productfrom System
Clean MembranesCaustic prepMobius Assembly & mixer!
Buffer prepMobius Assembly & mixer!
So It means... Additional gain for development
and process time and money!
Disposable Product FillingOpticap and Acerta
Process developmentwith PTG
TFF in MAb processingFull disposable solution up to filling
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Hardware vs Disposables
How to choose?
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Hardware or Disposable?Validation & operating cost comparison
$0
$2,000$4,000
$6,000
$8,000
$10,000
$12,000
$14,000
$16,000
$18,000
$20,000
Single Use Multi-Use
TFF Cost Contributors
Device CleaningValidationSystem CleaningValidationClean Sol'n Cost-Mat'l
Clean Sol'n Cost-Labor
Stor. Sol'n Cost -Labor
Stor. Sol'n Cost -Mat'l
WFI Cost- Mat'l
WFI Cost- Labor
Sys San. Pre-use-labor
Sys San. Pre-us -mat'l
Risk Burden
Flow Path Cost
Device Cost
Processing Variables Input
Total Filtration Area (m 2) 2.5
Number of uses 3
Operator labor rate ($/hr) 50
WFI cost ($/l) 2
WFI consumption (l/m 2) 50Storage sol'n cost ($/l)) 2
Store sol'n consumption (l/m2) 10
Cleaning sol'n cost ($/l)) 2
Cleaning sol'n consumption (l/m2) 50
Syetem prep rate ($/hr) 50
System prep hrs 4
System prep sol'n consumption (L/m2) 50
System Clean Val (hrs) 30
Validation rate ($/hr) 65
Device Clean Val (hrs) 30
Validation rate ($/hr) 65
Mat'l used for validation ($) 1000
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1400,5 m1,550100
4201,5 m412030011204 m103001.000
560020 m4012005.000
Buffer volume
multi use*
Membranearea
Finalvolume
(L)
Startingvolume
(L)
Bioreactor Size (L)
numbers of use per year
504030201051
0,1
0,5
1
2
3
4
5
m
Conclusion:
Current disposable technology can be used economically up to 1.000 Lbatch size & 5 m UF membrane area
Hardware or Disposable?Bioreactor size impact
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ConclusionKey success criteria
Systems design for different application is important
increase your yield by optimized process design
Challenge your investment cost
Low investment cost
disposable solution
free up critical space
Fast and flexible
Change out of flowpath & avoid cross contamination
Complete Solution
Buffer / Waste / Product handling solutionsHigh TFF performance
Pellicon 3 cassettes combined with sterile ready to use TFFassembly
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Match Your MarketChallenges
Increase Your Speed
Speed to development
Speed to market
Speed to transfer
Speed to validation
Speed to manufacturing
Minimize Your Risk
Of non consistency
Of contamination
Of compliance deficiency
Of product recall
Gain an Edge
Market leadership
Competitive advantage
Early technologyevaluation & adoption
Next process generation
Mobius
ConclusionMillipore Downstream Solutions
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