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D I S P O S A B L E S FACILITY DESIGN
Biomanufacturing
for the 21st Century
Designing a Concept Facility
Based on Single-Use Systems
Andrew Sinclair and Miriam Monge
I
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 design.co.uk). 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 www.biopharmservices.com
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 www.clean-design.co.uk
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; www.idcbio.com
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 www.integratedbio.com
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 www.pall.com
and validate the facility to reduce manufacturers):
the project timeline, thereby The Flexel 3D Mixing System with Sebra: Radio frequency (RF) tubing
welders; www.sebra.com
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 (www.pall.com),
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
BIOSYSTEMS INC., IBI, A STEDIM COMPANY)
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)
SupplementSeries
2005
FIVE CUTTING EDGE,
UNBIASED, STAFF WRITTEN
SUPPLEMENTS
FEBRUARY 2005
BIOFACILITIES
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 clean-design.co.uk; Björn Hammarberg of and fermentation media and chronicle the general
eliminate the requirement to recycle Pharmadule, www.pharmadule.com; 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
address.
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
www.lifescienceworld.com. 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, m-monge@stedim.fr.
Sandra Richard Sales Representative
• Cost-effective manufacturing Tel: 508-614-1280 • srichard@bioprocessintl.com
• Reduced labor Flexboy, Flexel, and Palletank are
Stephanie Shaffer Director Sales & Marketing
• Reduced utilities trademarks of Stedim; Biosafe is a
Tel: 508-614-1273 • sshaffer@bioprocessintl.com
• 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 www.bioprocessintl.com
SUPPLEMENT
