Purposeful design of a next-generation single-use film for optimized performance in biomanufacturing

Susan Burke, PhDBioprocess R&DGE Healthcare, Life Sciences

Overview

• Complex demands on bioprocess films

• First principles approach to new film design

• Translation of film design to performance and process

simplification

• Technology built on robust supply chain

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Challenges with bioprocess films

3

Why is a new bioprocessing film needed?

Simplicity: reduce V&Q requirements with single film platform

Material science: meet critical attributes for sensitive

applications

Performance: optimize for a wide range of applications

Security of supply: mitigate risks through supply and quality

control, from resin to assembly manufacturing

Single-use technology has become a standard on its own

*V&Q = validation and qualification

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Bioprocess films serve multiple functions

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

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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

629237694AB l February 2017

Designing a solution

7

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.

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Bioprocess film strategy

Single-use bioprocess portfolio

FUTURE STATE

One film for ALL

BioProcess™ products

Film supplier:

Sealed Air

Bag manufacturer:

GE Healthcare

Bioprocess

containers for

HyClone™ fluids

Cellbag™ bioreactors

ReadyToProcess™

bags

Xcellerex™

disposable

assembliesContinued support of legacy films

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First principles approach to film design

Material selections

• Define performance needs and specifications

• Establish resin selection criteria (e.g., animal origin

free, EP compliance)

• Leverage knowledge of bioprocess needs

• optimized antioxidant package

• Thorough analysis of raw materials• physical and mechanical properties

• extraction profile

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EP = European Pharmacopoeia

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 copolymer10

-la

ye

r str

uctu

re (

33

0 µ

m)

Designed to meet critical performance demandsFortem™ film

Dual EVOH gas barrier layers

Outer layer: nylon

Tie layers: modified polyethylene

Film interior: polyethylene blend

EVOH = ethylene vinyl alcohol

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Material selection for performance

Fluid contact layer

Blend of polyethylene and cyclic olefin copolymer (COC)

• COC is compliant with EP 3.1.3, EP 3.1.5, JP 7.02, UPS Class VI

• COC acts as macromolecular slip agent, eliminating need for

traditional small molecule additives

• The blend provides a tight matrix to limit migration of extractables

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Material selection for performance

Fluid contact layer

Concentration of bDtBPP found in extract (ppb)

Sample Day 3 Day 7

Control (glass bottle) 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

Fortem™ below LOD below LOD

Bis(2,4-di-tert-butylphenyl) phosphate (bDtBPP) analysis

Limit of detection (LOD) and limit of qualification (LOQ): 2 ppb & 5 ppb

Extraction solvent: water

Extraction temperature: 50°C

Surface area to volume ratio: 0.37 cm2/mL

All measurements post-gamma sterilization

Improved extraction profile

BPOG protocol: no tris(2,4-di-(tert)-butyphenyl)phosphite (TBPP) or bDtBPP in extraction profile

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Material selection for versatility

Gas barrier

• Gas barrier provided by internal EVOH layers

• Two different type of EVOH (alcohol substitution)

incorporated into structure– Provides barrier to gases in both wet and dry conditions

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Material selection for durability

• Specific nylon chosen for outer layer to provide strength

even in humid conditions

• Interior layers composed of polyethylene blend for

robustness and flexibility over wide temperature range

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Material selection for durability

• 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

Optimized using most physically demanding applications

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Connection of materials to architecture

𝑦𝑜 =1

2×σ𝑖=1𝑛 𝐸𝑖 × ℎ𝑖

2 − ℎ𝑖−12

σ𝑖=1𝑛 𝐸𝑖 × ℎ𝑖 − ℎ𝑖−1

h – layer thickness

E – Young’s modulus

Yo – neutral plane

Less flexible

layers protected

in neutral plane

Fluid transport

WAVE Bioreactor™ system

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Robustness vs flexibility: a challenge for rocking motion and transportation

Translation of film design to performance

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

PDba

g

PDre

f

3 days

3 days

G𝐫𝐨𝐰𝐭𝐡 𝐩𝐞𝐫𝐟𝐨r𝐦𝐚𝐧𝐜𝐞 % =𝑷𝑫𝑏𝑎𝑔

𝑷𝑫𝑟𝑒𝑓× 𝟏𝟎𝟎

Pre-incubation Cell growth assessmentCell culture

mAb-producing

CHO DG44 cell line

1

8

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 ovary

PD = population doubling

bDtBPP = Bis(2,4-di-tert-butylphenyl)

phosphate

Population doubling (%) Cell viability (%)

98 ± 3 94 ± 1

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Supply assurance

19

Supplying you with increased confidence

20

Resin Film GE manufacturing

Su

pp

ly Strategic, long-term relationships

(+10 years)

Resin supply risk assessment

ISO 15378; aligned with FDA CFR21

Class 8 cleanroom (co-extruded film)

Class 5 air (exposure to contact layer)

ISO 7 bag manufacturing

3x clean-room expansion ($7M+)

Qualit

y 100% of raw material lots are tested

Benchmarking against CofA and

historical data

In-process extrusion and die controls

In-process film control

Incoming material testing, in-process

controls, and finished assembly testing

USP <788>

Bu

sin

ess

co

ntin

uity 2 year change notification

2 year right-to-buy option

Disclosure of raw materials down to

CAS number*

1 year safety stock for all raw resins

1 year safety stock for finished film

Redundant manufacturing lines

Backup site options

Cumulative 4 yr supply consistency

ISO 22301 business continuity accredidation

Online regulatory support portal

*CAS no.: chemical abstract service number

Assurance comes through strategic supplier selection, quality management, and business

continuity up and down the supply chain

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Investing for the future

21

Recent investments in capacity,

quality controls, and security

$40M+

Westborough clean room expansion3×

$25M+ Safety stock for critical materials (e.g., single-use film)

$5M+ Extractable and leachable (E&L)capabilities

ISO22301 Business continuity management certification

Long-term supply agreements w/ critical material suppliers19 year

$7M+ expansion in Westborough: automation and quality system upgrades

$5M+ E&L testing lab, equipment, and methods to create enhanced data packages

BPOG and BPSA: active collaboration with industry associations ensures alignment

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Westborough expansion and upgrade

22

3× cleanroom expansion

Automated manufacturing

• Drive quality improvements and efficiency

• Automation equipment, in-process

sensors, and data collection on critical

process parameters improve consistency

Business continuity accreditation –

ISO 22301

• October 2016

Read the full announcement

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Purposeful film design for bioprocess applications

• Supported by strong foundation of material science and application

knowledge.

• Design achieves critical to quality attributes across applications.

• Meets industry needs (e.g., extractables data, supply chain

transparency).

• Cornerstone technology for future advances in biomanufacturing

applications.

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gelifesciences.com

GE, the GE Monogram, Imagination at work, Bioclear, BioProcess, Cellbag, HyClone, ReadyToProcess, Xcellerex, and WAVE Bioreactor are trademarks of General Electric

Company.

Cellbag bioreactors with integrated optical sensors are sold under a sublicense from Sartorius Stedim Biotech under US patent numbers 6,673,532, 7,041,493, and/or its foreign

equivalents, and please visit www. pall.com/patents.

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