development of next-generation single-use films for...

Development of next-generation single-use films for optimal performance in biomanufacturing

Susan Burke, PhDBioprocess R&DGE Healthcare, Life Sciences

Confidential. Not to be copied, distributed, or reproduced without prior approval.

Overview

• Importance of voice of customer in film innovation

• Plastic films used in bioprocess applications

• Key film attributes for optimal performance

• Philosophy of purposeful film designPerformance, simplification, security of supply

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Communication + Collaboration = Solution

Partnering for success

End users communicate needs and observations

End users + single-use system manufacturer + film supplier share knowledge and technical expertise

Collaboration results in purposely designed bioprocess film



Typical structure of bioprocess filmPerformance requires several layers of polymers

• Materials of construction must be consistent, biocompatible, and chemically inert, with low extractable levels and security of supply

• Resin selection and film architecture defined based on critical to quality attributes

Fluid contact layer: inert, barrier to moisture

Outer layer: strength and abuse resistance

Barrier layer: optimal gas barrier propertiestie layer

tie layer

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FILM SELECTION FOR PERFORMANCE

Mechanical properties

Flex fatigue

Film strength

Seal strength

Film elongation

Puncture resistance

Abrasion resistance

Physical properties

Heat stable

Gamma stable

Long shelf-life

Moisture barrier

Freeze/thaw stable

O2 and CO2 barrier

Low protein binding

Biocompatibility

USP <661>

Class VI plastic

Low cytotoxicity

Animal origin-free

Support of cell growth

Low extractable profile (BPOG E&L protocol)

Material performance attributes vary across applications

Bioprocess films serve multiple functions

E&L = extractables and leachables



Finding the right balance of attributes

In some cases, adjusting for one attribute can negatively impact performance in another area.

Example: film processing aids (e.g., antioxidants) can become extractables.

Balancing is key for optimal film performance



Performance, simplification, security of supply

Platform film purposely designed to achieve critical to quality parameters for all applications • Single-use containers and cell culture chambers

Breadth and depth of knowledge of raw materials in combination with scientific and engineering proficiency

Transparent, collaborative, and knowledgeable partnership

Simplification Performance

Security of supply



Partnering for success

Innovation for the future

• On August 17, 2016, GE Healthcare announced a market-exclusive commercial supply agreement with Sealed Air Corp., leader in polyolefin films for parenteral solutions for > 30 years.

• This collaboration targets the development and supply of a new film suitable for use across GE’s full single-use BioProcess™ portfolio.



A strategic partner to meet critical end user needsSUPPLY CHAIN: INCREASED CONFIDENCE AND CONTROL

Manufacturing and supply chain• Film manufactured in accordance with ISO 15378.• Manufactured to GMP standards in line with FDA CFR21.• Strong raw material and film characterization capabilities.

Business continuity• Long-term supply contract. Termination rights addressed. • Agreements in place for last time buy and safety stocks.• Agreements in place with all raw material suppliers.

Communication• Disclosure of raw materials down to CAS number*.• Identification of resin suppliers and sub-suppliers.

*CAS no.: chemical abstract service number



Bioprocess film strategyGE’s SINGLE-USE BIOPROCESS PORTFOLIO

FUTURE STATEOne film for ALL

BioProcess™ products

Film supplier: Sealed Air

Bag manufacturer: GE Healthcare

Bioprocess containers for HyClone™ fluids

Cellbag™ bioreactors

ReadyToProcess™ bags

Xcellerex™ disposableassemblies

Continued support of legacy films



Co-extruded film manufactured in Class 8 cleanroom Supplied as double ply; contact layer only exposed to Class 5 air (Sealed Air Corp. film design patent).

Contact layer: blend of polyethylene and cyclic olefin copolymerClean, inert surface (no slip or anti-block agents)

10

-la

yer

stru

ctu

re (3

30

µm

)

Designed to meet all performance demandsNew film from GE Healthcare

Dual EVOH gas barrier layers Excellent barrier properties (both wet and dry conditions)

Outer layer: nylon

Tie layers: modified polyethylene

Film interior: polyethylene blend Durable and flexible over wide temperature range

EVOH = ethylene vinyl alcohol

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Improved strength and durability

Tensile Properties MethodTensile Strength at break, long (psi)

ASTM D882

Tensile Strength at break, trans (psi)

Elongation at break, long (%)

Elongation at break, trans (%)

Young’s modulus, long (psi)

Young’s modulus, trans (psi)

Optimized tensile strength and flexural properties

Crucial for rocking bioreactors and bulk liquid transport

Enhanced gas barrier properties

Essential for long-term storage and product stability to avoid:

(1) Oxidative degradation of sensitive chemistries

(2) Concentration of formulation components due to loss of moisture

Increased robustness

Key for integrity assurance and support for large volumes of liquid

PHYSICAL PROPERTIES

Transmission rates Method

H2O vapor (g/100in2/day) ASTM F1249

O2 – dry conditions (cc/m2/day) ASTM D3985

O2 – wet conditions (cc/m2/day) internal



Robustness vs flexibility: a challenge for rocking motion and transportation

𝑦𝑜 =1

2×σ𝑖=1𝑛 𝐸𝑖 × ℎ𝑖

2 − ℎ𝑖−12

σ𝑖=1𝑛 𝐸𝑖 × ℎ𝑖 − ℎ𝑖−1

h – layer thicknessE – Young’s modulusYo – neutral plane

FILM ARCHITECTURAL DESIGN

Less flexible layers protected in neutral plane

Fluid transport

WAVE Bioreactor™ system

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Concentration of bDtBPP found in extract (ppb)

Sample Day 3 Day 7

Control (glass bottle, no film) below LOD below LOD

Control film 1 6000–6500 6000–6500

Control film 2 800–1000 800–1000

Control film 3 25–35 25–35

New film from GE below LOD below LOD

Optimized antioxidant package

Extraction study using full BioPhorum Operations Group (BPOG) protocol in progress.

For esample. antioxidant: Bis(2,4-di-tert-butylphenyl) phosphate (bDtBPP) analysisLimit of detection (LOD) and limit of qualification (LOQ): 2 ppb and 5 ppbExtraction solvent: water

Extraction temperature: 50°CSurface area to volume ratio: 0.37 cm2/mLAll measurements post-gamma sterilization



Confirmation by cell culture

Cell culture medium

3 days at 37°C+ 4 days at RT

7 days at 4°C

time (d)

0 1 2 3 4 5 6 7

MV

C/

ml

0

5

10

15

20

time (d) vs cell concentration (MVC/ml)

transfer VCD

time (d)

0 1 2 3 4 5 6 7

MV

C/

ml

0

5

10

15

20

time (d) vs cell concentration (MVC/ml)

transfer VCD

PDbag

PDref

3 days

3 days

G𝐫𝐨𝐰𝐭𝐡 𝐩𝐞𝐫𝐟𝐨r𝐦𝐚𝐧𝐜𝐞 % =𝑷𝑫𝑏𝑎𝑔

𝑷𝑫𝑟𝑒𝑓× 𝟏𝟎𝟎

Pre-incubation Cell growth assessmentCell culture

mAb-producing CHO DG44 cell line

15

Population doubling (%) Cell viability (%)

98 ± 3 94 ± 1

Strong cell culture performance with a sensitive CHO cell line

CHO DG44 cell line is sensitive to bDtBPP down to 0.1 mg/L (100 ppb)

CHO = Chinese hamster ovaryPD = population doublingbDtBPP = Bis(2,4-di-tert-butylphenyl) phosphate



Optimize for performance in the most physically demanding applications

• Strong performance through temperature range for microbial fermentation (up to 60°C)

• Durability with large mixer and bioreactor applications

Large-scale Xcellerex™ vessel applications

• Low extraction for minimal impact on fluid properties

• Remain integral through freeze/thaw down to -80°C

• No deformation or integrity loss when exposed to static and dynamic stresses

Liquid storage applications

FUNCTIONAL PROPERTIES



Purposeful film design for bioprocess applications

• Design to achieve critical to quality attributes across all applications.

• Incorporate latest industry needs (e.g., extractables information, supply chain transparency, etc.).

• Technology that can serve as cornerstone for future product development.

• Supported by strong foundation of material science knowledge and understanding of bioprocess application.

New GE Film

• Evaluation kits with 3 lots of film available Q4, 2016.

• Launch of single-use products Q2–Q4, 2017.



GE, the GE Monogram, Bioclear, BioProcess, Cellbag, HyClone, ReadyToProcess, Xcellerex, and WAVE bioreactor are trademarks of General Electric Company. All other third party trademarks are the property of their respective owners.

© 2016 General Electric Company.

All goods and services are sold subject to the terms and conditions of sale of the company within GE Healthcare which supplies them. A copy of these terms and conditions is available on request. Contact your local GE Healthcare representative for the most current information.

For local office contact information, visit www.gelifesciences.com/contact

www.gelifesciences.com

GE Healthcare Bio-Sciences ABBjörkgatan 30751 84 UppsalaSweden

October, 2016 29237694AA Printed in USA

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