Transitioning From Hardware to Disposable

8/13/2019 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


50 to > 200 g/L


- 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



Cli k H & U d


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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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