single use technologies in downstream processing …...single use technologies in biomanufacturing...

Single Use technologies in Downstream processing and Fill-Finish

Niels Guldager

Senior consultant, Process and Technology

[email protected]

Single use technologies in Biomanufacturing processesISPE DACH Conference, Marseille, May 26-26th, 2011

Single Use Technologies in Biomanufacturing Processes, ISPE DACH/France – May 26-27, Marseille, FranceNiels Guldager, Senior Consultant Bioprocess and Technology, [email protected]

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Presentation outline

Single Use Technologies in Downstream Processing and Fill-Finish

• Purpose: Overview presentation - highlight technical/process/plant floor aspects

• Background and perspective

• SU in Downstream processes

• SU in Fill-Finish

• Case: Compounding

Disclaimer:

Overview only partial, - not comprehensive

Examples selected for illustrative purpose

360° survey always recommended

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NNE Pharmaplan: Our history

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Close to 1,700 colleagues at more than 25locations in 12 countries around the world.

NNE Pharmaplan: Where we are


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Industry trends

• One example: 900 Medicines and Vaccines against Cancer in testing

• 200+ are Monoclonal Antibody-based (mAb)

• Towards personalized medicine

• More specialized therapies

• More specific (smaller) patient populations

• Orphan drugs

• Biosimilars

• - other factors…

• Smaller campaigns

• Multiproduct facilities

• More frequent product changeovers PhRMA 2011 Report

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Generalized Biomanufacturing Bulk process flow

Bulk Filtration Freezer

• Basis: MAb production process

Isolate product Bulk formulationVirus clearance, orthogonal methods

Remove impurities, reduce volume, change buffers

Day Days

Physical-chemical processes

Virus inactivation

Virus filtration

Generate biomass Remove biomass

Weeks Day

Biological processes Physical-chemical

Generate product

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Centrifugation

• CARR Unifuge

• Disc bowl operation – discharge etc. – integrated with pump/skid

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Depth filtration

• Cell removal

• Elimination of cleaning housing, aerosols generation

• Significant solid waste contribution

• Membrane can also have secondary purification effect (HCP, DNA…)

3M Purification PALL Sartorius Stedim Merck Millipore

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Column chromatography

• GE Healthcare – also including disposable fluid path• Prepacked• Campaign use (not one-time use)

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Membrane chromatography

• Flow through polishing (HCP, DNA, Viruses)

• Membrane bound ligands for improved mass transfer area

• No packing, large throughput, buffer and time savings

Sartorius-Stedim PALL Merck Millipore Natrix

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UF/DF TFF

• Buffer exchange, volume reduction

• Shear

• Pressures

• Flowrates, tube diameters

JM SeparationsMilliporeSciLog

Novasep

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Virus reduction filtration

• Timing

• Pressure monitoring

• Flushes

• Integrity testing

Sartorius-Stedim Millipore

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Freeze-thaw

• Controlled rate – cryopreservation prevention

• Bag protection

Sartorius-Stedim Celsius Bag freeze-thaw system

Advanced Scientific Sartorius-Stedim

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Generalized Biomanufacturing Bulk process flow

Bulk Filtration Freezer

• Basis: MAb production process


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Generalized Biomanufacturing Fill-finish flow


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SU in Fill-Finish: Potentially a good match

• Volumes and flow rates in general relatively low• Heat and mass transfer demands in general moderate• Concern more: Repeatability, accuracy, physical stress

• Container/closure, filters already characterized, leachables/extractrables not ”new”• Risk high – everything critical• Durations relatively short• Protein concentrations high

Bosch PreVas single use filling assembly

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Compounding - mixing

HycloneATMI ATMI Xcellerex

• Mixing technology – vibrating, paddle, agitator, levitating impeller

• Circular or rectangular

• Several designs to avoid/reduce particle generation

• Ability to move impeller really slow

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Compounding - mixing

Merck Millipore Sartorius-Stedim Hynetics

• Large range of volumes

• Mobile or stationary

• Visual process

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Powder transfer

• Transfer and rinse from pre-weighed bag

• Very controlled operation

• Very low dust generation to surroundings

Hyclone

ATMI


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Example: Compounding large scale

CHALLENGE

• Washing and sterilizing tanks

• Physically moving stainless steel tanks around

• Many tanks in clean, dirty, operation states – housekeeping effort

• Maintenance

Example mobile tank (IAI Biopharma)


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Example: Compounding large scale

SINGLE USE TECHNOLOGY ALTERNATIVE

• Single use mixing systems – bag plus powder bags

• Floor scale

POTENTIAL IMPROVEMENTS

• Fast setup

• Improved ergonomics

• Faster compounding operation

Sartorius-Stedim


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Single use filling

Now available from all well known filling machine suppliers

• Eliminate washing, sterilization• Fast setup

Bosch

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From Compounding to Filling

• Single use sterile filtration manifold - connect through wall

Millipore

Bosch

Recommended reference:

[1] Miriam Monge, Andrew Sinclair: End-to-End Deployment of Single-Use Technology in Aseptic Filling of Vaccines at GSK, BioPharm International, Feb 1, 2010, Vol 23, Issue 2

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Single use filling flow path

• Enabling formulation-to-filling single use flow path

From Groninger

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Filling

• Layout – integration with facility

From Groninger

Flexicon


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• Novel pre-washed, pre-sterilized container technologies

• To reduce need for support functions and simpliy operations


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Reducing support operations

Pre-filled syringes – NEST technology

• Nest arrives with syringes pre-sterilized, gamma-irradiated

• Outside surface sterilized before entry to filling machine (VHP, E-beam…)

• System also potentially useful for introducing assemblies etc.

• Reducing need for wash and sterilization tunnel

Bausch and Strobel Becton Dickinson


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Reducing support operations

Pre-sterilized, closed vial system

• Vial and stopper integrated, closed system

• Filling by penetration of seal

• Re-seal by laser beam

• Stopper in place through entire operation

• Eliminating cleaning and sterilization

Aseptic Technologies, Crystal system


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Sequence optimization

Lyophilization cap system

• Perhaps more optimal sequence – cap in place before lyophilization

• Cap clicks in place by place tray pressure

• Simplifies operations after freeze drying

Lyoseal, Biocorp, biocorp.fr


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Presentation message

• Large potential for single use technology

• Industry trends support introduction of single use technology in fill-finish

• Risk management central for successful introduction

PDA Technical report on SU, due 2011


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Thank you for your attention!

• Now with single use technology chapter!!!

ISPE Biopharm development and manufacturing baseline guide

ISPE Baseline Guide Bioproces…Due 2011

• -

• -

• -

• Regulatory

• Qualification

• Process

• Support systems

• Facility

• Scale-up, tech transfer

• Single Use technology

Biopharm processdevelopment and manufacturing

single use technologies in downstream processing …...single use technologies in biomanufacturing...

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