Use of single-use technology in Aseptic processing of vaccines: Application strategy and validation considerations

Dr. Priyabrata PattnaikTechnical ManagerBiomanufacturing Sciences Network

Vaccine…strong, robust growth in recent years

Industry growth CAGR to 2016

How likely would you adopt a completely integrated pre-assembled disposable Solution?

For Clinical development

Source: Business Intelligence Report, 2010

Disposable Technology in Vaccine Processing: Drivers• New Facility Design• Design, construction, and validation of a GMP biomanufacturing facility

– reducing capital expenditures– minimizing the project timeline – increasing operational flexibility – “minimizing operational cost”

-Wei Huang, GEN, 2005

Retrofitting Existing Operations– Ease of Use– Flexibility – Reduce Capital expenditure– Changes in process or transfer of new process into facility

• New buffer , New media, Process hold volumes increase, etc

• Growing spectrum of applications emerge– Mixing, sampling, filtration, bioreactors, transfers, containers etc– In parallel a growing spectrum of components emerge – Engineered solution are evolving from applications and components

Single use technology -Where in Vaccine Process

Fermentation/Cell Culture Cell Harvest/

Clarification

Finish FillFormulation/Compounding

MediaPreparation

Buffer PreparationSterile

Filtration

Aseptic Applications for Disposable Technologies

• Sampling– Aseptic sampling of bioreactors and other sterile vessels

• Aseptic product transfer– Transfer of fluids from vessel to vessel

• Non sterile to sterile• Sterile to sterile

– Transfer of fluids from Class B to Class A filling operations

• Sterile Filtration of fluids to and from vessels– Including redundant filtration

• Sterile additions to bioreactors or sterile vessels – Antifoam, caustic, innoculum, other small volume additives

“The product and all of its contact parts are sterilized separately and brought together under exposed conditions where, if not properly controlled, could result in contamination.”

John W. Levchuk, Ph.D CBER, FDA

Regulatory Point of view -Aseptic processing

Regulatory Requirements -Aseptic design

“The design of equipment used in aseptic processing should limit the number and complexity of aseptic interventions by personnel…. “

- Avoid manual aseptic connection

- Use pre-assembled components

- Use pre-sterilized assemblies

What are the challenges -Balancing Product and Operator

Conflicting requirements on

Design

OperatorsSafety

ProductSafety

EnvironmentSafety

P>0P<0

Closed systemSource: M. Borlet, B. Wichert, R. Soikes, Baxter

Finish & Fill – A high risk operation

Source: James Oliver, 3D risk assesment model, JVT, Autumn 2008, page 70-76.

Vaccine Formulation & Filling Highest level of product integrity and personnel protection

Weighing

Vacuum transfer

Solution make up

Tansfer with canister

port

Avoid aerosols

Low pressure transfer

Guarded Vents

Isolator for filter train

Sampling in closed system

SOP for accidental spillage

Experienced and trained staff

Filter inside/outside isolator

Pre-use integrity test

Control of exposurePPEPersonnel monitoring

P P

Capping

Crimping

100% outer washing

Inspection

Formulation Filling Lyophilization

contained venting

P>0

100% waste decontamination

Total wipe down

P>0

Decontamination

Air monitoring

contained venting

P

Class 10,000 Class 1,000

Fixed SS set-up Multiple connections increase risk….

Source: Nigel Bell, GSK, IBC’s Biopharmaceutical Manufacturing & Development Summit, San Francisco, CA, December 2009

Dr. R Schmidt & H. SchazISPE Annual Barrier Isolation Technology Washington D. C. 1-2 June 2009

Vaccine Formulation & Filling using RABS/Isolator

• Sterilizing filters for air filtration during integrity testing

• Flush bags and bags on vent/drain (operator safety)

• Gamma-irradiated single-use assembly (efficiency)

• Optimized hardware (ease of use)

Sterilizing filtration -Post-sterilisation pre- and post- use IT

Filling transfer set to Rab’s/Isolator -Fully closed system for vaccines

Secure Sterile Connection Lynx S2S

Inline sterilizing filtration

improves yield

Closed venting in 2D

bag

Closed filter Integrity test

system

Sterile holding bag

Buffers liquid for accurate filling

Dosing Loop for peristaltic

pump

Test pre-use & line Drainage Liquid

transfer in Class A

DPTE bag

Closed Sampling

La Calhene ported bag

Changing the Paradigm -Single-use Finish & Fill for vaccines

Capping

Crimping

100% vial washing

inspection

Weighing

Solution make up

Low pressure transfer

Guarded Vents

Sampling in closed system

SOP for accidental spillage

Experienced and trained staff

Filter outside isolator

Pre-use integrity test

Control of exposurePPEPersonnel monitoring

100% waste decontamination

Total wipe down

Mixer and Powder Transfer

Air filter for product blow down

Lynx S2S for sterile transfer

For filter flushing

Solvent addition

Air filter for venting during heating

Powder bagIsolator for powder transfer,

70

75

80

85

90

95

100

0 10 20 30 40 50 60 70Time (min)

Turb

idity

(NTU

)

Bottom, Run 4 Top, Run 4 Bottom, Run 5 Top, Run 5Bottom, Run 6 Top, Run 6 Bottom, Run2 Top, Run 2

>48hrs settling

400 rpm200 rpm

570 rpm

Aseptic Alum Mixing Using Mobius Disposable Mixer

Design of Single-use Systems

• Closed systems (Avoid operator and product exposure)

• Limit material handling

• Minimise cleaning and decontamination

• Optimise product recovery

• Assembly designed for operating conditions– Easy-to-use sterile-to-sterile connections– Pre-use integrity testing of filters (post sterilisation)– Tubing fixture– Tubing selection – Closed sampling– DPTE beta-bag integrity and pressure resistance to vacuum/pressure

Validation considerations

• Risk assessment and qualification

– Chemical compatibility– Extractable and leachable– Impact on vaccine safety and efficacy– Bioburden and endotoxin– Stability studies

Pace of turn around…… Rapid response to pandemics

Andrew Sinclair & Miriam MongeBioPharm International, December 2009, pp.34-38

Carbon Footprint

Nigel Bell, sterile product lead,GlaxoSmithKline, Barnard Castle, UK

BioPharm International, February 2010, pp.20-24

Forward looking…..

Nigel Bell, GSK, Barnard Castle, UKIBC’s Biopharmaceutical Manufacturing & Development Summit, San Francisco, CA, December 2009

……confirms that the benefits seen in bulk API manufacture also are realized in vaccine fill–finish facility, specifically with regard to reduced costs, reduced energy usage, and reduced labor.

Based on the outcomes of this case study, the future for disposables use in the final filling arena has significant potential to simplify process operations…….

Conclusions

• Application of Disposable Technology to Vaccine is Growing Rapidly

• Product and operator safety present conflicting facility and equipment design challenges

• There is increasing regulatory and occupational safety oversight

• Adoption of single-use technologies can help alleviate some of these concerns

Thank You