Development of next-generation single-use films for optimal performance in biomanufacturing Susan Burke, PhD Bioprocess R&D GE Healthcare, Life Sciences
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 design Performance, simplification, security of supply
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 Communication + Collaboration = Solution
Typical structure of bioprocess film Performance 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 tie layer tie layer Outer layer: strength and abuse resistance Barrier layer: optimal gas barrier properties Fluid contact layer: inert, barrier to moisture 4
FILM SELECTION FOR PERFORMANCE Bioprocess films serve multiple functions 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) E&L = extractables and leachables
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.
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 Simplification Performance Breadth and depth of knowledge of raw materials in combination with scientific and engineering proficiency Security of supply Transparent, collaborative, and knowledgeable partnership
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.
A strategic partner to meet critical end user needs SUPPLY 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 strategy GE s 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
10- layer structure (330 µm) Designed to meet all performance demands New film from GE Healthcare Outer layer: nylon Tie layers: modified polyethylene Dual EVOH gas barrier layers Excellent barrier properties (both wet and dry conditions) Film interior: polyethylene blend Durable and flexible over wide temperature range Contact layer: blend of polyethylene and cyclic olefin copolymer Clean, inert surface (no slip or anti-block agents) 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 11
Improved strength and durability PHYSICAL PROPERTIES 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 Tensile Properties Tensile Strength at break, long (psi) Tensile Strength at break, trans (psi) Elongation at break, long (%) Elongation at break, trans (%) Young s modulus, long (psi) Young s modulus, trans (psi) Transmission rates H 2 O vapor (g/100in 2 /day) O 2 dry conditions (cc/m 2 /day) O 2 wet conditions (cc/m 2 /day) Method ASTM D882 Method ASTM F1249 ASTM D3985 internal
Robustness vs flexibility: a challenge for rocking motion and transportation FILM ARCHITECTURAL DESIGN 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 13
Optimized antioxidant package 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 For esample. antioxidant: Bis(2,4-di-tert-butylphenyl) phosphate (bdtbpp) analysis Limit of detection (LOD) and limit of qualification (LOQ): 2 ppb and 5 ppb Extraction solvent: water Extraction temperature: 50 C Surface area to volume ratio: 0.37 cm 2 /ml All measurements post-gamma sterilization Extraction study using full BioPhorum Operations Group (BPOG) protocol in progress.
Confirmation by cell culture 20 MVC/ ml 15 10 PD bag time (d) vs cell concentration (MVC/ml) 5 transfer VCD 3 days at 37 C + 4 days at RT 3 days 0 0 1 2 3 4 5 6 7 time (d) 20 time (d) vs cell concentration (MVC/ml) MVC/ ml 10 PD ref 15 5 transfer VCD 7 days at 4 C 3 days 0 0 1 2 3 4 5 6 7 time (d) Cell culture medium Pre-incubation Cell culture Cell growth assessment mab-producing CHO DG44 cell line Strong cell culture performance with a sensitive CHO cell line Growth performance % = PD bag PD ref 100 Population doubling (%) Cell viability (%) 98 ± 3 94 ± 1 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 15
Optimize for performance in the most physically demanding applications FUNCTIONAL PROPERTIES 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
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 AB Björkgatan 30 751 84 Uppsala Sweden October, 2016 29237694AA Printed in USA 18