Biomanufacturing for the 21st Century

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for the 21st Century
Designing a Concept Facility
Based on Single-Use Systems
Andrew Sinclair and Miriam Monge

       n its early days,                       (stainless steel), we sought to             The study recommends
       biomanufacturing was driven             identify the benefits of disposable      application of single-use disposable
       by science and technology               technologies, thereby stimulating        systems within the industry as part of
       with little regard to costs.            industry discussion.                     the drive for operational excellence.
       Now the focus is on
maximizing returns on investment               PROJECT HISTORY                          STUDY DESIGN
in expensive facilities. Commercially          Stedim commissioned Biopharm             AND PROCESS SELECTION
available single-use disposable                Services (www.biopharmservices.          Our objective was to design a
technologies have the potential to             com) to evaluate the impact of           commercially relevant production
improve manufacturing operations.              available single-use technology on       facility around the use of single-use
Reference is made to a typical                 the design of a multiproduct             disposable technologies and to
monoclonal antibody (MAb)                      mammalian cell culture facility. The     compare it with a conventional
process, relating benefits in terms of         facility design would look afresh at     stainless-steel equipped operation.
capital and cost of goods.                     layout, taking into account possible     The facility would manufacture
   The need to challenge the                   integration of single-use technology.    mammalian-based therapeutic
current orthodoxy was discussed at             The costs of the concept facility        proteins and be capable of handling
a June 2004 conference in Geneva               would be compared with an                multiple products. Material
(1). There was a strong emphasis on            equivalent traditional facility.         manufactured would be used for a
changing the mindset in the biotech            Biopharm Services worked in              phase 3 clinical trial, building up
industry, moving the focus to                  partnership with the architects          supplies for product launch and
process optimization and                       Clean Design (www.clean-                 small-scale production. The facility
operational excellence. Ways to       This is the third         design would simplify operations
achieve operational excellence                 study that Biopharm Services and         while maximizing operational
include planning for capacity and              Stedim have developed together. It       flexibility and minimizing capital
reducing time to market by                     is by far the most radical study in      and operating costs.
shortening cycles — all while                  terms of the impact of single-use           Process Selection: Commercially
reducing cost of goods. Reducing               technologies on facility design and      relevant processes were selected for
time to market is affected by                  operation.                               the concept design. The facility was
shortening not only clinical                                                            to house a multiproduct, perfusion-
development time (clone-to-clinic),            Photo 1: The RAFT single-use rapid       based MAb process. The 1000-L
                                               aseptic fluid transfer system (STEDIM)
but also the time it takes to design                                                    scale process would run for 25.5
and build a manufacturing facility.                                                     days, using a standard recovery and
   The intention of our study was to                                                    purification sequence. The perfusion
develop a leading-edge design for a                                                     rate of two volumes (cell culture
concept facility that exploits fully                                                    capacity) per media volume per day
the benefits of single-use disposable                                                   would total 2000 L of media/day.
technologies. By comparing this                                                         Two typical MAb processes were
concept facility with a traditional                                                     used for the simulation, with a
facility based on reusable equipment                                                    0.3g/L cell line expression.

26   BioProcess International   OCTOBER 2004                                                                         SUPPLEMENT
                                                                                  MANUFACTURERS AND PRODUCTS
    The process starting point was       industry as a means of achieving
                                                                                  MENTIONED IN THIS ARTICLE
inoculum through to the bulk             safe, compliant, and efficient
sterile-filtered, purified product —     processes. As the industry awakens       Biopharm Services: Technical
the stage before formulation and         to the technology benefits, there is a   consultancy in the biopharmaceutical
filling. The plant capacity is           demand for further integration of        manufacturing sector;
nominally around 90 kg of bulk           disposables into processes. The goal
purified protein per year. The exact     is to develop integrated single-use      Clean Design: Architects;
capacity depends on the perfusion        solutions that offer certain process
process itself, the number of            functionalities (such as mixing,
                                                                                  IDC (Isolateur Dénominateur
products, and changeover times.          temperature control, aseptic
                                                                                  Commun): Biosafe® transfer port
                                         connection and disconnection, and        system;
THE CHALLENGES                           controlled freeze–thaw) within a
The first challenge was to reduce        closed system. Single-use                Integrated Biosystems (a Stedim
                                                                                  Company): Celsius FT100 and Cryofin
capital and minimize the project         technology innovations that
                                                                                  Controlled freeze–thaw systems;
timeline; the second was to increase     significantly affect the economics
operational flexibility while            and design of the concept facility
minimizing operating costs.              include the following products and       Pall Corporation: KleenpakTM
                                                                                  connector, biopharmaceutical filtration
   The facility design and build         systems (the “Products Mentioned”
                                                                                  and separations products;
challenges were to design, construct,    box lists these products and their
and validate the facility to reduce      manufacturers):
the project timeline, thereby              The Flexel 3D Mixing System with       Sebra: Radio frequency (RF) tubing
allowing the product to get to           Temperature Control: Solutions are
market faster. This offers the           made up using an impeller within         Stedim products:
additional benefit of maximizing the     the Flexel 3D bag and then pumped        The Flexboy® bag system (50 mL–50 L
project’s net present value (NPV),       through a single-use sterilizing         volume) and the Flexel® 3D system
                                                                                  (50–3000 L volume); 100- and 2500-L
thus using capital more effectively      disposable filter into a hold bag.
                                                                                  Palletank®; the Single-Use Rapid
and ensuring a faster return on          The Flexel 3D system with                Aseptic Fluid Transfer (RAFT) System
investment.                              integrated impeller is used within
    The project needed to                the concept facility to prepare media
    • Remain within the given            and buffer solutions.                    connection to equipment in the
investment budget constraints               An alternative method of mixing       higher classification process area.
    • Ensure high flexibility in the     developed by Stedim but not a               The RAFT technology enables
facility                                 feature of the concept facility is       segregation of the support operation
    • Ensure a smooth and swift          mixing by recirculation. This            from the process while increasing
validation period                        method offers the benefit of being       productivity, with no more waiting
    • Meet cGMP demands                  noninvasive, offers process security     for cleaning, steaming, and cooling.
according to EMEA and FDA for a          as a closed system, and is simple to       Kleenpak Single-Use Aseptic
smooth approval of the drug              set up.                                  Connectors: In collaboration with
    • Meet health, safety, and              The Single-Use Rapid Aseptic Fluid    Pall Corporation (,
environment (HSE) objectives for         Transfer (RAFT) System: This             the Kleenpak connector mounted
the 21st century                         innovative technology brings an          on Stedim bag systems is a state-of-
    The facility operation challenges    integrated solution to a recurrent       the-art single-use aseptic connector
called for                               problem in bioprocessing: how to         that eliminates the requirement for
    • Reducing operating costs           transfer sterile processing solutions    capital equipment such as laminar
    • Increasing throughput by           from one process area to another         airflow (LAF) cabinets (with their
reducing turnaround times                without contaminating progressively      related maintenance), while
    • Ensuring high flexibility in the   cleaner environments.                    increasing flexibility regarding
process                                     The RAFT system (Photo 1,             placement of connections.
    • Minimizing operational             opening page) plays a key role in the    Productivity is also increased
overheads (labor, materials, waste)      concept facility by allowing docking     because those connections can be
    • Developing an appropriate          of Flexboy or Flexel 3D bag systems      made in seconds. The Kleenpak
design of the facility to meet lean      from 50 mL to 2500 L with an             connector is used in association with
lifecycle management criteria such as    integrated single-use Beta Biosafe to    the RAFT system within the
low maintenance and economic use         the Alfa Biosafe door. These systems     concept facility for connecting
of resources.                            are stationed in the materials hall.     perfusion bags through the wall to
                                         The door is opened, and the bag          the bioreactor and connecting small
SINGLE-USE TECHNOLOGIES                  tubing with integrated Kleenpak          volumes of buffers through the wall
Single-use technologies have gained      connector is transferred through the     to downstream processing areas.
increasing acceptance by the             Biosafe port to make the aseptic
SUPPLEMENT                                                                        OCTOBER 2004   BioProcess International   27
Photo 2: The Celsius-Pak (INTEGRATED              Other facility features include       components, thus reducing or
                                                 2500-L Palletank or two stacked        removing wash up, cleaning, and
                                               1500-L Palletanks for holding            sterilization areas; reducing high-
                                               solutions within the facility and        quality utility requirements; and
                                               minimizing footprint                     reducing liquid effluent. There is,
                                                  Radio frequency tube welding and      however, an increase in solid waste.
                                               disconnection devices for removal of     Another impact on design is the
                                               samples from the bioreactor and for      removal of solutions such as media
                                               adding small feeds to the bioreactor     and buffers from processing areas.
                                                  Automated guided vehicles (AGV)       This reduces the footprint of high-
                                               for moving solution containers           classification areas, simplifies
   Flexboy manifolds with integrated           to/from the warehouse and                operational flows, and segregates
disposable filters and tubing collect          processing areas; for example, to        material preparation and handling
smaller volume solutions from the              and from buffer and media                from process operations.
purification areas. For easy storage,          preparation areas and docking               The concept facility fully exploits
movement, and space-saving, these              stations adjacent to processing areas.   the potential of single-use systems
manifolds are stored in special                                                         and challenges the current status
racking systems.                               SINGLE-USE TECHNOLOGIES:                 quo of traditional facility design.
   Celsius-Pak: In the concept facility,       IMPACT ON DESIGN
the Celsius controlled freeze–thaw             Through the application of the           THE PROCESS
system provides a single-use scalable          single-use technologies previously       Multiple products were used as the
solution for controlled freeze–thaw.           described, the facility design can       basis of the design. They were based
The Celsius-Pak stores bulk product            now be based on single use of all        on typical MAb manufacturing
coming out of viral purification to            support systems and components           processes.
be frozen in the freeze–thaw                   (disposable filters, bags, sampling         Once inoculum is grown in the
module for later shipping to final             arrangements, and so on). This           inoculum room, it is transferred to
formulation and filling. The single-           feature, together with the               the seed culture room through a
use Celsius-Paks offer the necessary           development of methods for making        transfer hatch. The seed is grown in
flexibility for manufacturing in               sterile connections, has a major         a 250-L bioreactor. The seed
multiproduct facilities (Photo 2).             impact on facility design. Facility      culture is used to inoculate the
                                               operations do not reuse materials or     perfusion bioreactor in the

Figure 1: Concept facility layout, showing functional areas

28   BioProcess International   OCTOBER 2004                                                                         SUPPLEMENT
bioreactor room once every 30
days. The 1000-L perfusion                      Table 1: Comparison of the concept facility to a traditional facility
bioreactor runs for 25.5 days at a
                                                Changes                                     Areas Affected
perfusion rate of two volumes of
media per volume of cell culture                Floor area reductions to                    Bioreactor
                                                all the main process rooms                  Harvest
capacity per day (VVD), requiring                                                           Purification suites
2000-L of media every day.
   Fresh media are supplied at                  Removal of rooms from the facility          Autoclave
                                                                                            Wash up
docking stations in the materials                                                           Dirty equipment store
hall. Product is collected into Flexel
                                                Additional step                             Palletank container wipe down
3D bag systems (one of two 2000-L
systems). The perfusate is clarified            Downgrading and simplification              Materials movement into process suites
and concentrated tenfold. Every 24                                                          Segregation of people (material handling versus
hours, 200 L of intermediate                                                                process)
product is transferred to the previral                                                      Downgrading in materials hall to controlled but
purification room where it is                                                               not classified
purified using protein A
chromatography, followed by
ultrafiltration, ion-exchange                   areas are reduced or removed                    through the wall of the materials
chromatography, and viral                       altogether. Table 1 summarizes the              hall into the process.
inactivation.                                   changes to the layout.                             Environmental Classification: The
   The postviral purification room is              By this means, the facility layout           removal of the solutions from the
located adjacent to the previral                can be considerably smaller than                processing areas reduces the sizes of
purification room and is used for gel           that of a traditional facility. Figure 1        expensive cleanrooms. In this facility
chromatography, formulation                     shows the layout developed for the              design, the cell culture and harvest
ultrafiltration, and bulk filling. The          facility together with illustrations of         areas are designated as
final bulk product is frozen using              functional and environmental                    Class D and the purification suites
the Celsius-Pak system.                         classifications. Solution holding and           as Class C. The solution preparation
                                                product collection are moved into               areas are designated as Class D,
THE FACILITY                                    the materials hall. Single-use sterile          whereas the materials handling areas
Footprint: Through the adoption of              docking and connection                          (the storage area and materials hall)
single-use technologies, the layout of          technologies are used to connect the            are handling sterile, totally enclosed
the facility is simplified and certain          solutions and process containers                solutions. Consequently, we can

Figure 2: The flow of materials in the concept facility

SUPPLEMENT                                                                                      OCTOBER 2004      BioProcess International   29
designate such areas as controlled             the point of use stations (Photo 3,    solution is mixed and then
rather than classified spaces (CNC).           Figure 3).                             transferred to a Flexel 3D bag
                                                                                      system though a disposable sterile
MATERIALS                                      SOLUTION PREPARATION                   filter.
All materials enter and leave                  The concept adopted is similar to          Once made-up solutions are held
through the warehouse, where they              buying preformulated solutions in      as sterile solutions within their
are stored before use. Figure 2                single-use bags: You prepare the       Palletank containers, they are
describes the flow of materials. They          solution and hold it in storage        transferred through the material
include single-use systems (bags,              before use.                            airlock into the warehouse, where
filters, tubing) and raw materials                Raw materials are moved from        the Flexel 3D systems can be
and intermediates (media and                   the warehouse to the dispensary,       stacked up and sterile solutions held
buffers). Small components and                 where materials are weighed out in a   in their closed bag systems until
solutions are moved from the                   dispensing booth into a Flexel 3D      required. This approach offers the
warehouse to production down the               bag system. Storage is provided in     possibility of manufacturing
materials hall, then enter the                 the dispensary area for empty Flexel   economic batch sizes that take up
production areas through material              3D bags, which are held in racks       minimum floor space. This
transfer areas. Large-volume                   once the outer packaging is            decouples solution preparation from
solutions are moved from the                   removed. Those preweighed              the process (Photo 4).
warehouse through the materials                materials are added to WFI or
hall and placed at docking stations            purified water of the required         PERSONNEL
outside the production area.                   volume in a Flexel 3D bag system       The advantages gained by using the
Connections to the process are                 with integrated impeller. The          RAFT system to pass solutions
made though the wall using the                                                        through a wall enable segregation of
RAFT aseptic fluid transfer system                                                    materials from the main process
and Kleenpak connector. That                   Photo 3: The materials hall (STEDIM)   zones, allowing significant changes
enables sterile docking and                                                           in the way the facility can be staffed
connection without compromising                                                       and operated.
system or cleanroom sterility. The                                                       People would not handle
facility will use an automated AGV                                                    materials in the process areas, and
to move the materials from the                                                        they would not be required to
warehouse into the materials hall to                                                  manage autoclave and washing

Figure 3: People and material movements

30   BioProcess International   OCTOBER 2004                                                                       SUPPLEMENT
Photo 4: Mixing in Flexel 3D system (STEDIM)

                                                                                            FIVE CUTTING EDGE,
                                                                                          UNBIASED, STAFF WRITTEN

                                                                                          FEBRUARY 2005
                                                                                          BioProcess International’s editorial staff will
                                                                                          overview the essential factors that go into making
                                                                                          facility design and construction decisions,
                                                                                          including: How can your company predict and
                                                                                          respond to capacity demands? Can design houses,
                                                                                          contractors, and construction companies all
                                                                                          work together in a regulated industry? Are there
                                                                                          lessons to be learned from others? Where should
                                                                                          you build your new facility?

                                                                                          APRIL 2005
areas. Running the solution                    2005) we will look at how these
preparation as an offline activity and         qualitative benefits translate into        BIOINDUSTRIAL
using automation creates more                  quantifiable savings in terms of           CHROMATOGRAPHY
efficient use of the materials-                capital, time to build, and cost of        As the science of liquid chromatography advances,
management staff.                              goods. We will describe the methods,       and the number of refinements and hyphenated
                                                                                          analytical techniques increases, so too does the
                                               assumptions, and results. The analysis     number of options available to biomanufacturers.
A RADICAL REDESIGN                             will take account of operational issues    BPI’s editorial staff addresses both analytical and
Available single-use technologies can          covering maintenance, operations,          preparative chromatography in order to help
                                                                                          you navigate the maze by detailing what your
be used to rethink the way we                  and validation as well as reductions in    options are, each systems history, science,
design and operate our facilities. In          capital.                                   and applications.
particular, coupling innovative
connection technologies (RAFT and              ACKNOWLEDGMENTS                            JUNE 2005
Kleenpak) with single-use bags                 The authors wish to thank Michael Walden   CULTURE MEDIA
allows facility designers to remove            of Architects Clean Design, www.           BPI’s editorial staff will provide you with a
                                                                                          detailed history of the development of cell-culture
solutions from processing areas and  ; Björn Hammarberg of    and fermentation media and chronicle the general
eliminate the requirement to recycle           Pharmadule,; Peter      types of media used in biotherapeutic production
support equipment through washing              Karlsson of Computer Graphics Sweden       along with the concerns that each seeks to
and autoclave suites. As a                     (CGS); and GSK Beckenham.
consequence, the facility layout can                                                      OCTOBER 2005
be radically redesigned by                     REFERENCES                                 VIRAL CLEARANCE
   • Simplifying material flow                    1 BioLOGIC Europe 2004, 22–24 June
                                                                                          Presented in a tutorial format, BPI’s editorial staff
                                               2004 (Geneva). Organizer: Terrapinn,
   • Decoupling the solution                                                              will present the current state of viral clearance
                                                       technologies, current regulatory perspectives,
preparation from the process
                                                                                          and viewpoints from industry leaders involved in
   • Simplifying personnel flow                                                           developing effective and safe biotherapeutics.
   • Reducing the footprint                    Andrew Sinclair is managing director,
   • Reducing/reorganizing labor               Biopharm Services, Lancer House, East      NOVEMBER 2005
   • Reducing the equipment                    Street, Chesham HP5 1DG, United            LOGISTICS
requirements.                                  Kingdom, 44-1494-793-243.                  BPI’s editorial staff details the technology options
   These features result in significant                                                   and critical issues that you need to know in order
                                               Corresponding author Miriam Monge is
                                                                                          for your company to effectively, safely, and suc-
benefits in terms of design build and          marketing director, Stedim, Z.I. des       cessfully transport product from one location to
operation of a facility by enabling            Paluds, Ave de Jouques – BP 1051           another.
   • Fast product changeover                   13781 Aubagne Cedex, France, 33-442-
                                                                                          For sponsorship details, please contact:
   • Enhanced product security                 845-611,
                                                                                          Sandra Richard Sales Representative
   • Cost-effective manufacturing                                                         Tel: 508-614-1280 •
   • Reduced labor                             Flexboy, Flexel, and Palletank are
                                                                                          Stephanie Shaffer Director Sales & Marketing
   • Reduced utilities                         trademarks of Stedim; Biosafe is a
                                                                                          Tel: 508-614-1273 •
   • Reduced capital.                          trademark of IDC, and Kleenpak is a
   In an upcoming issue of Bioprocess          trademark of Pall corporation.
International (the Facilities
supplement scheduled for February                                               


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