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

Transcription

1 Purposeful design of a next-generation single-use film for optimized performance in biomanufacturing Susan Burke, PhD Bioprocess R&D GE Healthcare, Life Sciences

2 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 AB l February

3 Challenges with bioprocess films 3

4 Why is a new bioprocessing film needed? Single-use technology has become a standard on its own 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 *V&Q = validation and qualification AB l February

5 Bioprocess films serve multiple functions Film selection for performance Material performance attributes vary across applications Mechanical properties Physical properties Biocompatibility Flex fatigue Film strength Seal strength Film elongation Puncture resistance Abrasion resistance Heat stable Gamma stable Long shelf-life Moisture barrier Freeze/thaw stable O 2 and CO 2 barrier Low protein binding USP <661> Class VI plastic Low cytotoxicity Animal origin-free Support of cell growth Low extractable profile (BPOG E&L protocol) AB l February

6 Finding the right balance of attributes Balancing is key for optimal film performance In some cases, adjusting for one attribute can negatively impact performance in another area. Example: film processing aids (e.g., antioxidants) can become extractables AB l February

7 Designing a solution 7

8 Partnering for success Innovation for the future On August 17, 2016, GE Healthcare announced a marketexclusive 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 AB l February

9 Bioprocess film strategy Single-use bioprocess portfolio Bioprocess containers for HyClone fluids Cellbag bioreactors FUTURE STATE One film for ALL BioProcess products Film supplier: Sealed Air Bag manufacturer: GE Healthcare Continued support of legacy films ReadyToProcess bags Xcellerex disposable assemblies AB l February

10 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 EP = European Pharmacopoeia AB l February

11 10- layer structure (330 µm) Designed to meet critical performance demands Fortem film Outer layer: nylon Tie layers: modified polyethylene Dual EVOH gas barrier layers Film interior: polyethylene blend Contact layer: blend of polyethylene and cyclic olefin copolymer 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). EVOH = ethylene vinyl alcohol AB l February

12 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 AB l February

13 Material selection for performance Fluid contact layer Improved extraction profile Concentration of bdtbpp found in extract (ppb) Sample Day 3 Day 7 Control (glass bottle) below LOD below LOD Control film Control film Control film 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 cm 2 /ml All measurements post-gamma sterilization BPOG protocol: no tris(2,4-di-(tert)-butyphenyl)phosphite (TBPP) or bdtbpp in extraction prof AB l February

14 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 AB l February

15 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 AB l February

16 Material selection for durability Optimized using most physically demanding applications Liquid storage 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 Large-scale Xcellerex vessel applications Strong performance through temperature range for microbial fermentation (up to 60 C) Durability with large mixer and bioreactor applications AB l February

17 Connection of materials to architecture Robustness vs flexibility: a challenge for rocking motion and transportation WAVE Bioreactor system Less flexible layers protected in neutral plane Fluid transport y o = 1 2 σ i=1 n E i h 2 2 i h i 1 h layer thickness n E i h i h i 1 σ i=1 E Young s modulus Y o neutral plane AB l February

18 Translation of film design to performance 20 MVC/ ml transfer VCD PD ba g time (d) vs cell concentration (MVC/ml) 0 3 days at 37 C + 4 days at RT 3 days time (d) 20 time (d) vs cell concentration (MVC/ml) MVC/ ml 10 5 transfer VCD PD re f 15 7 days at 4 C 3 days time (d) Cell culture medium Pre-incubation Cell culture mab-producing CHO DG44 cell line Strong cell culture performance with a sensitive CHO cell line Population doubling (%) Cell viability (%) 98 ± 3 94 ± 1 Growth performance % = CHO DG44 cell line is sensitive to bdtbpp down to 0.1 mg/l (100 ppb) Cell growth assessment PD bag PD ref 100 CHO = Chinese hamster ovary PD = population doubling bdtbpp = Bis(2,4-di-tert-butylphenyl) phosphate AB l February

19 Supply assurance 19

20 Business continuity Quality Supply Supplying you with increased confidence Assurance comes through strategic supplier selection, quality management, and business continuity up and down the supply chain Resin Film GE manufacturing 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+) 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> 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 business continuity accredidation Online regulatory support portal *CAS no.: chemical abstract service number AB l February

21 Investing for the future $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 $40M+ Recent investments in capacity, quality controls, and security 3 $25M+ 19 year $5M+ Westborough clean room expansion Safety stock for critical materials (e.g., single-use film) Long-term supply agreements w/ critical material suppliers Extractable and leachable (E&L)capabilities ISO22301 Business continuity management certification AB l February

22 Westborough expansion and upgrade 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 October 2016 Read the full announcement AB l February

23 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 AB l February

24 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. Fortem is a trademark of Sealed Air Corporation. All other third party trademarks are the property of their respective owner 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 gelifesciences.com/contact GE Healthcare Bio-Sciences AB Björkgatan Uppsala Sweden AB l February

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