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Biodisposables

Utility and Technological Advances

Report 9215

June 2006

Authors: J. W. Terryberry and G. Thor
Research Director: Alfred Doig
Production Manager: Tracy Beaudoin

www.drugandmarket.com
One Research Drive, Suite 400A • Westborough, MA 01581
Phone: +1 (508) 616-5500 • Fax: +1 (508) 616-5544

Terryberry and G. W.About the Authors J.drugandmarket. and the phytochemistry of novel herbal medicines. Thor Jeffery Terryberry has over a dozen peer-reviewed publications in Clinical Chemistry research. MA 01581 Phone: +1 (508) 616-5500 Fax: +1 (508) 616-5544 http: / / www. . First published in the United States by: D&MD Publications One Research Drive Suite 400A Westborough. is internationally recognized for his expertise in human diagnostics. ISBN: 1-57936-360-1 Published in the U. Biodisposables: Utility and Technological Advances Copyright © 2006 D&MD Publications All rights reserved.S. No part of this document may be reproduced in any form or by any means. without written permission from the publisher. He has researched at UCSD in the field of Neuroimmunology and is the author of numerous scientific and medical publications through NeuroConsultants.A. and. Current areas of focus include orthobiologic drug development utilizing osteoinductive peptides. monoclonal antibody production and immunogenicity.com An informa publication. including recording. Gautam Thor received his PhD in Neurobiology. or by any information storage and retrieval system. electronic or mechanical.

.................. .................. ............................... 2–30 Summary.................... 3–1 Scaling Up Logistics................................. 3–27 Synthecon’s Rotary Cell Culture System................................................. ........... 3–26 Hollow Fiber Bioreactor Applications:..... 3–11 CatchMab’s Tsunami Bioreactor........ 2–12 Return of Investment (ROI) Options............. 3–29 Fluorometrix’s Cellstation ............................. 2–20 Disposables Reduce Overall Cost of Manufacture............................................................. 2–33 Chapter 3: Disposable Bioreactors............................. 3–19 Cellexus Biosystems................................................................................................................... 2–23 Conversion from Stainless Steel Equipment to Disposable Filtration............. 3–31 Integra Biosciences’ Cellroll............................................................................................................................................ ............... 3–10 Wave Biotech Bioreactor Case Histories........................................2–7 Market Implementation..............................................Biodisposables Table of Contents Chapter 1: Executive Summary................................................ 2–11 Elimination of Waste in the Biodisposable Context..................2–2 Drivers for Single-Use Disposable Systems ................................... 2–10 Disadvantages of Disposable Systems............... Bottles........... .......... ............ 3–16 Osmotek’s LifeReactor............................................................................................ 2–11 Leachables and Extractables........2–8 Industrial Advantages of Disposable Components ................................................................................. 2–18 Monoclonal Antibody Production........... 3–30 Cellon’s RollerCell.................. Stedim................................. 2–12 A 100 – 1000L Pilot Facility Costs $10 ............................................................................................................................................. 2–14 Process Comparison Models. 3–23 FiberCell System’s FiberCell Hollow Fiber Bioreactor ..................................................................................................................................3–8 Factors that Amplify the Bioreactor’s Yield.......................................................................... .......................................................................... 3–20 Disposable Bioreactor Flasks....................................... 2–16 Model Estimation of Simulations...................... AppTec.............................................. ................................................................................ 2–13 Contract Manufacturer Xcellerex Case Study – Advantages of Biodisposables............................ 3–32  ©2006 ..........3–2 Comparison and Validation of Disposable Bioreactor Systems.......... 3–22 Integra Biosciences’ CELLine Biodisposable Flask ........................... ......................................................................................3–3 Growing Cells in Bags—Wave Cellbags® Characteristics................................... 2–1 Disposable Technology and Contract Manufacturing (CMOs)..................................................................50 million............ 2–27 Disposable Filters—For Use in Chromatography.......................................................................... Fast and Flexible Product Development........................... ........2–4 Disposable Bag Technology—Pacific GMP................................................................................................. 1–1 Chapter 2: Economics of Biodisposables: Efficient..................... and Other Containers...... ..............................................................................................

................................ 4–34 Inline Filters for Disposable Bioreactors...... 4–40 Cross Flow Filtration.............................4–5 NovAseptic .... Millipore............................................................................4–2 Disposable Filters........................... 3–32 Multi Laminate Plastic Bags .......... Acerta.................................................................................................................................. 4–11 Fully Assembled..................................................................................... 4–36 Recovery of Cell Products through Chromatography........... ... Filling and Sampling—HyNetic.......... 4–14 Separation Sciences: Filtration and Chromatography.............................................................. 4–18 Enhancing the Efficiency of Disposable Filters...................... 4–27 Membrane Chromatography and Viral Clearance...................................... ......................................................................................................... ................... 4–17 Filtration Technology.................... 4–22 Pall Corporation......................................................................................................... 4–33 Affinity Chromatography and Antibody Purification........................ 4–37 Cross/Tangential Flow Filters in Cell Processing and Diafiltration..........................................................................4–1 Faster Processing......................... 4–22 Sartorius................. 4–41 Cross Flow Process Modes for Cell Processing........... .................. 4–24 Disposable Filter Capsules and Chromatography Columns........................................................................................................................................................................ Millipore.......................................................................................................................... 4–40 Sartorius BBI Systems Inc.................... 3–34 Chapter 4: Downstream Processing and Separation Sciences................. 3–34 Stedim....................................................................................................................................................................................................................................................... 4–16 Disposable Filtration Market Statistics................ ................4–4 LevTech.................................................................................................. LevTech............................................................ 4–12 Millipore’s Mobius Disposable Systems .................. 4–21 Millipore Sterile Filtration......................................Biodisposables Corning’s CellCube®.................................................................................................... 4–16 Disposable Filter Systems..........................................4–4 Millipore................................................ 4–19 Sterile Filtration—Sartorius....................................4–7 Disposable Sampling Pump ................................................. Pre-sterilized Filtration Systems................................................................................................................................... ...........4–8 Sterile Connectors and Clean Room Technology................................................. 4–41 CellFlo Applications..........4–2 Disposable Mixing.............................................................. Nova Aseptic....................... Alfa Laval Biokinetic................ 4–46 ii ©2006 ................................................................................................................................ 4–25 Membrane Adsorption Chromatography ..........4–7 Sampling Systems................. 4–45 Blood and Serum Fractionation.....................................4–4 Sartorius................................................................................................................................... ............... 4–42 Tangential Flow Filtration TFF from SciLogic. Pall Corp.................................................................................................................................................................................4–1 Cleaning Ease .................................................4–9 Steam-in-place (SIP) Connector...... 4–1 Disposable Downstream Processing ......................................................

....... etc...............................................................................................................................5–5 Kleenpak Single-Use Aseptic Connectors...... ............................................. 5–12 Sample Regulatory Requirements......... ........................................................................................... ........................................................................................ .................................................... 4–49 Chapter 5: Biodisposables—Facility Design and Future Developments............................................... Filters....................................... 5–24 iii ©2006 ................................................................ 5–18 Market Projections...5–8 Biocompatibility........................................................... 5–1 Facility Design Capabilities with Disposables.......................................................... ...................................5–9 Disposal.................................5–8 Suppliers......................................................... 4–46 Serum Fractionation.......5–5 The Single-Use Rapid Aseptic Fluid Transfer (RAFT) System.............................5–5 Celsius-Pak..................................................................................................................................................5–9 Disposable Design Optimization......................................... ...................... 5–19 Disposable Biosensors.............................. ...................................................................5–9 Production Volume.... 5–10 Regulatory Considerations for Disposable Component Validation.................. .....................Biodisposables Blood Fractionation.................................................................5–5 Flexel 3D Mixing System with Temperature Control.........................................................................................................................................................5–5 Functional and Environmental Constraints................. ............ Bioreactors................................... 5–19 Bags.................................................................................................... ................................ 5–16 Disposable Product Innovations.5–7 Optimizing Facility Design.............................. ................................................................ 5–13 Future Outlook of Disposables...................................................... 4–47 Biosep Accoustic Technology—Applikon...................................................5–1 Multi-Component Systems........................... .

................... .............10 Analysis Reported by the FDA CBER on Cost Manufacturing.6 Monoclonal Antibody Yields for System20/50EH........... 3–7 Exhibit 3.13 Input and Output Parameters of an Analysis Tool..........11 Capital Required and Cost Savings of Disposable Model.............................. .........2–20 Exhibit 2...2–23 Exhibit 2.......5 Comparison of Daily Recombinant Protein Yields (mg/L) for Three Wave Bioreactors..............Biodisposables Table of Exhibits Exhibit 2.......................................6 Cost of Goods Cap-Ex....................2–29 Exhibit 2.............................. 2–2 Exhibit 2..17 Comparison of Set-up Times and Cost of Single-use Cartridge ............................ Filter and Stainless Steel Housing................................. Disposable Bioreactors.. 2–4 Exhibit 2....................000L Plant............2 Disposable Components and Suppliers for Manufacturing of Biologics .....16 Annual (COG/g) on a Cost Category Basis for Pilot Plant.............3 Hierarchical Representation of Biomanufacturing Tasks ..........................................................000 L Plant......................................3 Cellbag Connectors and Biocompatibility Testing...................................2–21 Exhibit 2.... and Labor in a Disposable Module Plant ..............15 Comparison of Equipment and Consumables in the Model Study........................... 3–9 Exhibit 3..................................................... and Production Scale Wave Bioreactors...............2–22 Exhibit 2...2–22 Exhibit 2........................2–25 Exhibit 2.......3–11 iv ©2006 .......................................2–21 Exhibit 2..................... and Pharmaceuticals...............4 Research...........1 Strategic Outlook for Biodisposables.............4 Reasons for Implementing Biodisposables....2–14 Exhibit 2....... Pilot..................................3–10 Exhibit 3....9 COGS from 10.......................................................18 Comparison of Process Time and Cost for Traditional Column and ....2 Principle of the Wave Bioreactor................ Disposables-based (DISP) Pilot Plant........8 COGS from 1.................... and Hybrid (HYB) Pilot Plant................................ 3–8 Exhibit 3.... Materials..............2–28 Exhibit 2.........................2–32 Exhibit 3....14 Disposable Technology and Conventional Pilot Plant COG Analyses .......2–32 Exhibit 2..1 Types of Disposable Bioreactors ....... .....2–23 Exhibit 2.....................................2–27 Exhibit 2................12 Cost Analysis of Reusable Fermenters vs........................7 COGS from 100 L Plant........................... 2–1 Exhibit 2.5 Costs of a Model Monoclonal Antibody Plant.................................................. . Membrane Chromatography Capsule......... 3–4 Exhibit 3...2–25 Exhibit 2...

...............28 Composition of Flexel 3D Bags .....16 Cellexus Biosystems Optimized Cell Growing Chamber............................................................3–19 Exhibit 3...........................................25 Corning’s CellCube® System......3–22 Exhibit 3...........................13 Excellerex Disposable Bioreactors..................3–13 Exhibit 3.....................3–33 Exhibit 3................... 4–6 Exhibit 4....14 AppliFlex Disposable Cell Culture Bag System.3–21 Exhibit 3.26 Growth of Cells under Different Seeding Densities in the CellCube System...29 Xcellerex Disposable Bags and Mixing Systems.................................................................................3–29 Exhibit 3...............................................3–24 Exhibit 3......................27 Flexel 3D Bag Bioreactor Harvesting System.........Biodisposables Exhibit 3................ 4–3 Exhibit 4.................................11 Comparisons of Batch and Perfusion MAb Production with 2L Cellbag.........24 RollerCell40 Automated Bottle System..................3–37 Exhibit 3....................3–23 Exhibit 3.............. 4–7  ©2006 ................... Wave Bioreactor.............3–14 Exhibit 3.... Wave Bioreactor...20 Comparisons of CellLine...... Wave Bioreactor (System 20/50EH)...3–32 Exhibit 3.............1 Downstream Processing Applications for Disposables.... and Bioreactor.... Wave Bioreactor with Cytodex-3 Micro Carriers .....3–15 Exhibit 3..... ...............2 Disposable Fluid Paths: Final Fill and Finish .............18 Integra CELLine Disposable Bioreactor Flask.......................................3 Acerta 4 Head Filler .......................... ............................................. ...3–38 Exhibit 4.3–28 Exhibit 3....17 Bags are more Stable than Bottles............3–17 Exhibit 3......22 Rotary Perfusion RCCS-D and -4D Disposable Bioreactors...................15 LifeReactor Plant Cell Bag Culture System...............3–31 Exhibit 3............................................3–36 Exhibit 3.................................... Roller Bottle Grown.........7 Carriers Used to Cultivate Attachment-dependent Cells in the .................................23 Cellstation High-throughput Bioreactor with Disposable Culture Vessels......9 Use of Floating Perfusion Filter with Perfusion Controller in .............................................21 FiberCell Module and Flowpath Assembly with Medium Reservoir Bottle....8 Adenovirus Production and Recovery in HEK293 Cells using a ...3–25 Exhibit 3...3–12 Exhibit 3.............19 Cost and Yield for Monoclonal Production in CELLine and Other Systems.............................................12 Tsunami Multiple Wave Agitated Culture System...3–34 Exhibit 3.......10 Comparison of Batch and Perfusion Modes for MAb Production in the ....................................... ........................... ....3–20 Exhibit 3.....................3–16 Exhibit 3............................3–15 Exhibit 3.......

.......24 Purification of Biopharmaceuticals Using Amersham .18 Antibody Downstream Processing...23 Cross Flow Hollow Fiber Membrane System for Aseptic Cell Processing.................5 Pall’s Kleenpak Sterile Disposable Connector System.........28 BioSep Cell Retention System.......15 Typical Production Scale Enzyme Purification with Multiple Filtration Steps......20 Online Affinity Purification System.....7 Ready to Run SIP Connected System: Sterilization of the ......4–46 Exhibit 4.................16 Sartorius SingleSep Disposable “Multiuse” (Autoclavable) Capsules...................... ........4–23 Exhibit 4........ Biosciences CFF Columns... 5–3 vi ©2006 ...21 CUNO’s Bioassure PES Filters for Cell and Immunoglobulin Recovery..........4–36 Exhibit 4..4–27 Exhibit 4.....8 NovAseptic SIP Connected System with Welded Connectors and ....................4–47 Exhibit 4.......4–50 Exhibit 5................................... Connection Between Millipore’s Lynx ST and SS Tank Interface...19 Inline Filters for Disposable Bioreactors......................................................................11 Applications of Sterile Filtration.............4–15 Exhibit 4..................................22 CFF Process Modes Affecting Cell Yield................. Disposable Sampling ..........4 NovAseptic Sampling System with 9-Port NovaSeptum Connector.....4–26 Exhibit 4.9 Matching Downstream Processing to Disposable Product....................4–43 Exhibit 4....4–45 Exhibit 4........... ...................................... ...................12 Applications of CUNO’s LifeAssure Filters...........4–44 Exhibit 4............4–10 Exhibit 4............ ..4–17 Exhibit 4..............................4–49 Exhibit 4................10 Disposables in Separation Sciences....1 Single-use Technology Implementation Approach.....4–24 Exhibit 4.........4–41 Exhibit 4...............26 Disposable CUNO Filter Types Used In Multilevel Blood Fractionation....17 Virus Elimination from Monoclonal Antibody Preparation (Eluate from Affinity Column) Prior to Sterile Filtration and Fill: High LRV and MAb Recovery. 4–8 Exhibit 4....4–32 Exhibit 4....................................6 Millipore’s Lynx S2S “Sliding Gate” Sterile Connector.............13 Disposable Manifolded Filtration System with SupraClean Depth Filters.........4–34 Exhibit 4...... ......................................27 Comparison of Single-use and Stainless Steel BSA Purification Systems... .....14 Phases of Biomanufacturing Utilizing Disposable Filters and ............................................Biodisposables Exhibit 4...........4–10 Exhibit 4...... .........................4–22 Exhibit 4................25 SciLog’s Automated Bioprocessing System with Disposable TFF Filtration.............................................. Chromatography Units......................................... .......................4–39 Exhibit 4........................................................4–12 Exhibit 4.......... ....4–37 Exhibit 4............4–11 Exhibit 4........

.....5–10 Exhibit 5...........Biodisposables Exhibit 5..............................3 Disposable Design Optimization .................. 5–7 Exhibit 5........................2 Layout of Facility Implementing Disposables with Functional and ....... Environmental Classifications................... ......... .............4 Validation Testing Methods and Standards.....5–23 vii ©2006 ..................5–16 Exhibit 5..5 Automated Remote FlexFactory Operation.......................................................................

life saving biopharmaceticals. Single-use technologies are not only available for an increasing range of applications. cost of goods. Biodisposable manufacturers’ responses to these trends is to develop fully integrated. highlighted by the imminent establishment of drug pricing controls and tightening regulatory and quality standards. and process engineering. but they are also expanding from stand-alone devices to multi-component systems.Biodisposables Chapter 1: Executive Summary The current economic and regulatory realities. Furthermore. At the two extreme price ranges. improve operability.000 monoclonal antibody plant scales up to a 10. There is a trend toward fewer blockbuster drugs as patient populations become smaller. Biodisposables are well established in the industry. Advantages of utilizing biodisposables in pilot and commercial scale operations involve reduced downtime for cleaning. indicates the added pressures that are emerging for pharmaceutical companies to restrategize their overall approach. therapeutic product. process steps have biodisposables at numerous points in the pilot scale as they are well suited for a multi-product clinical manufacturing setting with frequent product change-overs. filters. as well as improved equipment lead time. and process utility requirements such as validation. along with single-use membranes. Several commercial scale. Biodisposables decrease capital costs.000 L plant costing $120 million. $10. With this growing trend comes a greater number of benefits and implementation considerations from pilot scale modules to complete production facilities. a 100 L. and optimize utilization of space. flexibility. Existing manufacturing plants costs linger between $10 – 50 million depending upon required output and therapeutic bioproduct. components that integrate biodisposables with stainless steel allow hybrid plant operation. and the associated histories and genetic make up become stratified as personalized medicine begins to come into its own. quality and regulatory compliance. The average time required to construct a biotech facility is about five years. and disposable bioreactors. sterilization. turnkey manufacturing–production line that combines single-use components with modular software. 1–1 ©2006 . a disposable stir-tank and mixing system. The value of the primary and secondary US biomanufacturing market in 2006 is estimated to be approximately $50 billion with a healthy growth rate almost approaching double digits due to the escalating number of biotech drugs in the pipeline and skyrocketing sales of approved high value. putting tremendous pressure on drug manufacturers to expend capital when the risk of drug failure is still high. tubing. bags. and connectors. and there is an increasing trend toward their use because they contribute to ensure the production of a safe. and labor.

Contract manufacturing organizations (CMOs) and biotech start-ups were among the earliest adopters of disposables technology. clamps. compliant. aseptic connection. including direct-flow filtration (DFF) filters. Availability of disposable technologies for increasingly larger scale processes both upstream and downstream is reshaping the way biopharmaceuticals are made and providing an efficient path to manufacturability for emerging therapies. disconnection. cleaning validation. clean. and controlled freeze–thaw) within a closed system. The availability of this array of disposables technology has catalyzed new thinking with regard to processing approach and facility design. but they are also expanding from stand-alone devices to multi-component systems.Biodisposables Chapter 5: Biodisposables—Facility Design Developments and Future Facility Design Capabilities with Disposables Single-use technologies are not only available for an increasing range of applications. filling equipment. it is now practical to move toward a totally disposable manufacturing paradigm. Given the small batches in which such therapies are processed. With this growing trend comes a greater number of benefits and implementation considerations. and steam sterilization validation. particularly in the area of patientspecific therapies. As the industry adopts to the technology benefits. lenticular depth filters. it prevents the need to disassemble. tubing. tangential-flow filtration (TFF) cassettes. and bags. Single-use technologies have gained increasing acceptance by the industry as a means of achieving safe. CMOs saw them as a way of minimizing the risks of crosscontamination. temperature control. transport. membrane chromatography capsules. The goal is to develop integrated single-use solutions that offer certain process functionalities (such as mixing. and reassemble components in a classified cleanroom environment. An expansive and growing array of disposable technologies exists for downstream processing applications. Recently there has been a strong emphasis on changing the mindset in the biotech industry by moving the focus to process optimization and operational efficiency as a way to reduce overhead. Today. aseptic connections devices. Both groups recognized the significant time and cost benefits of eliminating cleaning. adaptors. there is a demand for further integration of disposables into processes. As a closed-loop system. whereas new biopharmaceutical companies enjoyed a considerable reduction in the need for capital investment. validate. In many cases. disposable 5–1 ©2006 . the single-use model is attracting new converts. and efficient processes. as well as the reduced potential for operator error.

storage. Exhibit 5. and filling. This new flexibility enables companies to better manage their own manufacturing expenses and investments during later development stages.1 provides design consideration steps when considering the use of disposables in a single or in multiple biomanufacturing unit operations. This option provides these companies with more control over the development process and enables production to be accelerated as needed. Within conventional facilities. chromatography. mixing. The result is not only labor savings. sampling. but also oversized utility systems are specified in anticipation of future needs. Opening a package and plugging a single-use device or multi-component disposable system into a product train offers a simplification to process development staff that otherwise must develop extensive cleaning protocols. The burden of conducting necessary changeovers and associated validation studies when using stainless steel equipment reduces available production time in a multi-product facility. centrifugation. outsourcing production was the only economical option. Also. Instead. without the need for significant capital investment in hard-piped systems. 5–2 ©2006 . when greater drug supply requirements for advanced clinical trials can still carry considerable risk of product failure. Considering that validation accounts for 10–20% of the cost of a new plant. their translucency provides operators with visibility into manufacturing operations. they can be performed side by side as closed-loop systems. Disposables can also simplify transfer of the drug production processes to other manufacturing sites. Even as disposable systems seal off processes from contamination. Disposables may be substituted in numerous unit operations in a biological production process such as production (bioreactors). The FDA has been a major proponent of disposables technology. This allows for the more efficient use of facility space. or other facilities within a company. Single-use processes also allow for a high degree of modularity in that capacity can be built out gradually in phases as demand increases. such as CMOs. disposables provide the industry with practical solutions to alleviate the challenges and costs associated with cleaning operations. when a company may handle a variety of drugs each year with limited quantities required. single-use technologies have allowed biotech startups to manufacture their products in-house.Biodisposables products are supplied pre-sterilized to eliminate the need for steam-in-place (SIP) or autoclaving. connection/disconnection. especially for CMOs and biotech start-ups. but also a shift in facility design toward fewer cleanrooms and reduced environmental monitoring requirements. With single-use operations. filtration. Singleuse (disposable) manufacturing technology can be particularly useful in clinical phases of development. Previously. Users can observe flow and fluid levels as well as spot fluid discoloration and air pockets immediately. applications no longer need to be physically segregated. Retrofitting is significantly easier with disposables than with fixed equipment since disposable components are inherently modular. not only do hard-piped systems need to be factored into the initial facility design. product transfer.