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Millipore Downstream Solutions

Transitioning from hardware to disposable

Alain Rachon EU Technology Manager Biopharmaceutical Markets

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Documents Outline Tangential 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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Documents TFF in MAb processing Success criteria

Yield As close as possible to 99.9% (reality >95%) Retention >99.9% 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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Documents TFF in MAb processing What are your process pains?

1. Capital investment
- Several systems for several scales

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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

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Documents 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

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1% yield increase is significant

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TFF in MAb processing

Optimum operating conditions
Process specifications
PreConcentration Diafiltration Final Concentration
2.50 1.5 to 50 g/L Avg Flux = 70-75 LMH Number of Diafiltration volumes = 8 to 10 80 70 60 50 40 0.75 30 0.50 20 10 0 0 20 40 60 80 100 120 140 160 180 0.25 0.00 50 to > 200 g/L 200 220 Avg Flux = 20-25 LMH Avg Flux = 55-60 LMH 1.50 2.25 2.00 1.75

Flux dP

120 110

Normalized Flux 25C, (l/h/m2/barTMP)

50 g/L

100 90

dP (bar)

1.25 1.00

Permeate volume (L/m)

- Temperature : room temperature - Feed Flow rate: 6 l/min/m

- Total Process Time : 4 hours - TMP= 1.75bar/25psi

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Documents TFF in MAb processing Pellicon 3 Ultrafiltration devices

- UF membrane selection is key to increase process yield - Pellicon 3 module with Ultracell 30 kD C screen is the industry standard for MAb processing
Ultracel 10 Kda P3 0.0088m initial protein content (g) retentate protein content (g) permeate protein content (g) YIELD retentate before flushing flush protein content (g) flush + retentate content (g) YIELD retentate after flushing 5.50 5.36 0.00 97.45% 0.14 5.50 100.00% Biomax 10 Kda PXL 0.005m 5.50 5.02 0.00 91.25% 0.48 5.50 100.00%

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Documents TFF in MAb processing Pellicon 3 Ultrafiltration device

Robust and Reliable Design with tighter specifications Higher operating pressures, temperature & caustic cleaning compatibility Unbeatable performances consistency Accurate scalability Better COGS by achieving higher final concentration (>200g/l in MAb), yield & retention Low extractables Low fouling & easy cleaning Integrated gasket for ease of use

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Ultra low binding composite membrane in a Thermoplastic device

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Documents TFF in MAb processing How to design a high yield TFF system?

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1. Minimize retentate & tank holdup volume

2. Include a low-point recovery port 3. Include a high-point blowdown port

4. Forseen a pipe slope towards recovery port 5. Optimize product recovery methodology

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Documents What Are Your Key Drivers for a good design of an TFF system?
Minimise hold up volume
UF holder design , Retentate loop, Sensor ...

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Agitation & recovery

Lowest point, high point blow down

Pipe & pump size & membrane area

Pipe size Flow range Min. recirc Undrainable holdup [inches] [L/min] after blowdown volume [L] [L] 1/2 3 12 1 0.03 3/4 11 36 3 0.1

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Documents What Are Your Key Drivers for a good design of an TFF system?
Process tank design
Improper design

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Optimized design

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Documents What if you could enable a full disposable fluid path for your TFF process?

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Documents What if you could enable a full disposable fluid path for your TFF process?
TMP & delta P fully control

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Flexible Multi Product Solution High process control

So It means...
Robust & Safe process No cross contamination Reduce time to market

Gamma irriated TFF flowpath

Buffer / Product transfer

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TFF disposable assembly What does it bring to you?

Product transfer Mobius assembley Feed tank Mobius assembley

Buffer transfer Mix 100, 200, 500 L

TFF Liner For Pellicon cassettes

What it does for you?

Fully adapted to your application (working volume, tubing sizes, pump of choice) Ready & easy to use No product contact with hardware pieces (holder, pump, sensors)

So It means...
High yield No contamination Low failure risk

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What could a Full Disposable TFF process bring you in your process?

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Documents TFF in MAb processing Impact of disposable technologies on SOPs

Set up System Install Membranes Concentrate Diafilter

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No system cleaning!

Clean Membranes and System

Recover Product from System

With With TFF TFF Mobius! Mobius!

Test Integrity and Permeability No water

permeability!

Clean Membranes No cleaning! and System

Equilibrate with Process Buffer Rinse No Rinsing!

Test Integrity and Permeability No water

permeability! NoStore storage!

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Documents TFF in MAb processing Full disposable solution up to filling

Set up System Install Membranes
Process development with PTG

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Concentrate Diafilter

Caustic prep Mobius Assembly & mixer!

Clean Membranes

Recover Product from System

Disposable Product Filling Opticap and Acerta

Test Integrity

Buffer prep Mobius Assembly & mixer!

Equilibrate with Process Buffer So It means... Additional gain for development and process time and money!

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Hardware vs Disposables How to choose?

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Documents Hardware or Disposable? Validation & operating cost comparison

Processing Variables
TFF Cost Contributors

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Input
2

Total Filtration Area (m ) Number of uses

Device Cleaning Validation System Cleaning Validation Clean Sol'n Cost-Mat'l Clean Sol'n Cost-Labor

2.5 3 50 2 50 2 10 2 50 50 4 50 30 65 30 65 1000

Operator labor rate ($/hr) WFI cost ($/l) WFI consumption (l/m ) Storage sol'n cost ($/l)) Store sol'n consumption (l/m2) Cleaning sol'n cost ($/l)) Cleaning sol'n consumption (l/m2) Syetem prep rate ($/hr) System prep hrs System prep sol'n consumption (L/m2) System Clean Val (hrs) Validation rate ($/hr) Device Clean Val (hrs) Validation rate ($/hr) Mat'l used for validation ($)
2

$20,000 $18,000 $16,000 $14,000 $12,000 $10,000 $8,000 $6,000 $4,000

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

$2,000
Device Cost

$0

Single Use

Multi-Use

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Hardware or Disposable? Bioreactor size impact

m

Bioreactor Size (L)

Starting volume (L)

Final volume (L)

Membrane area

Buffer volume multi use*

5 4 3 2 1

5.000 1.000 300 100

1200 300 120 50

40 10 4 1,5

20 m 4 m 1,5 m 0,5 m

5600 1120 420 140

0,5 0,1 1 5 10 20 30 40 50

numbers of use per year

Conclusion:
Current disposable technology can be used economically up to 1.000 L batch size & 5 m UF membrane area

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Conclusion Key success criteria

Systems design for different application is important increase your yield by optimized process design Challenge your investment cost Low investment cost Fast and flexible Change out of flowpath & avoid cross contamination Complete Solution Buffer / Waste / Product handling solutions High TFF performance Pellicon 3 cassettes combined with sterile ready to use TFF assembly disposable solution free up critical space

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Conclusion Millipore Downstream Solutions

Match Your Market Challenges
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 technology evaluation & adoption Next process generation

Mobius