Introducing the XDR-10 Benchtop Bioreactor from...

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1.866.Xcellerex • [email protected]

The biggest idea in

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SEE REVERSE FOR DETAILS

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The XDR-10 single-use bioreactor is the latest addition to Xcellerex’s industry leading line of GMP cell-

culture systems. The XDR-10 shares the same robust design and vessel geometries as its larger siblings,

providing seamless linear scale-up from 10L to 2000L. The XDR-10 also features industrial grade in-

strumentation and controls to deliver consistent process control across the entire product family. And of

course, the XDR-10 also comes with the support of the hands-on cell-culture experts at Xcellerex to get

your process up and running fast.

37211111184_714870.pgs 10.21.2011 07:32 ADVANSTAR_PDF/X-1a blackyellowmagentacyan

BioPharmwww.biopharminternational.com

Supplement to:

INTERNATIONAL

Single-Use

Technologies and Facilities

November 2011

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K. A. Ajit-Simh President, Shiba Associates

Fredric G. Bader Vice President, Process Sciences, Centocor, Inc.

Rory Budihandojo Manager, Computer Validation Boehringer-Ingelheim

Edward G. Calamai Managing Partner Pharmaceutical Manufacturing and Compliance Associates, LLC

John Carpenter Professor, School of Pharmacy, University of Colorado Health Sciences Center

Suggy S. Chrai President and CEO The Chrai Associates

Janet Rose Rea Vice President, Regulatory Affairs and Quality Poniard Pharmaceuticals

John Curling President, John Curling Consulting AB

Rebecca Devine Biotechnology Consultant

Leonard J. Goren Global Leader, Human Identity Division, GE Healthcare

Uwe Gottschalk Vice President, Purification Technologies, Sartorius Stedim Biotech GmbH

Rajesh K. Gupta Laboratory Chief, Division of Product Quality Office of Vaccines Research and Review, CBER, FDA

Chris Holloway Group Director of Regulatory Affairs ERA Consulting Group

Ajaz S. Hussain VP, Biological Systems, R&D Philip Morris International

Jean F. Huxsoll Senior Director, QA Compliance Bayer Healthcare Pharmaceuticals

Barbara K. Immel President, Immel Resources, LLC

Denny Kraichely Principal Research Scientist Centocor R&D, Inc.

Stephan O. Krause Principal Scientist, Analytical Biochemistry, MedImmune, Inc.

Steven S. Kuwahara Principal Consultant GXP BioTechnology LLC

Eric S. Langer President and Managing Partner BioPlan Associates, Inc.

Howard L. Levine President BioProcess Technology Consultants

Herb Lutz Senior Consulting Engineer Millipore Corporation

Hans-Peter Meyer VP, Innovation for Future Technologies, Lonza, Ltd.

K. John Morrow President, Newport Biotech

Barbara Potts Director of QC Biology, Genentech

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Tim Schofield Director, North American Regulatory Affairs, GlaxoSmithKline

Paula Shadle Principal Consultant, Shadle Consulting

Alexander F. Sito President, BioValidation

Gail Sofer Consultant, Sofeware Associates

S. Joseph Tarnowski Senior Vice President, Biologics Manufacturing & Process Development Bristol-Myers Squibb

William R. Tolbert President, WR Tolbert & Associates

Michiel E. Ultee Vice President of Process Sciences, Laureate Pharma

Thomas J. Vanden Boom Vice President, Global Biologics R&D, Hospira, Inc.

Krish Venkat Principal, AnVen Research

Steven Walfish President, Statistical Outsourcing Services

Gary Walsh Associate Professor Department of Chemical and Environmental Sciences and Materials and Surface Science InstituteUniversity of Limerick, Ireland

Lloyd WolfinbargerPresident and Managing PartnerBioScience Consultants, LLC

November 2011 Single-Use Technol. and Facilities 2011 3

Guide to

Single-Use Technologies and Facilities

CONTENTS

Foreword

A Brief History of Single-Use Manufacturing 5Jerold Martin

Bioreactors

Emerging Bioprocessing Methods 8Sarfaraz K. Niazi

single Use

The Evolution from Fixed

to Single-Use Systems 15Gary M. Dennis, Charles Weidner, and Saeid Zerafati

Vaccine prodUction and Facilities

Approaches for Flexible Manufacturing

Facilities in Vaccine Production 22Kim L. Nelson

enVironmental impact

An Environmental Life-Cycle

Assessment Comparing Single-Use

and Conventional Process Technology 30Matthew Pietrzykowski, William Flanagan,

Vincent Pizzi, Andrew Brown, Andrew Sinclair, and Miriam Monge

Cover images are courtesy of Arkema, GE, and Therapeutic Proteins.

4 Single-Use Technol. and Facilities 2011 November 2011


FOREWORD SINGLE USE

A Brief History of Single-Use Manufacturing

Single-use manufacturing may

seem like a new trend, but it has

actually been around for almost 30

years, beginning in the early 1980s when

filter manufacturers began to make small

process-scale plastic filter capsules

to replace “junior” size stainless-filter

housing assemblies. Small laboratory

syringe filters were already being sup-

plied presterilized by gamma radiation,

but originally, disposable filter capsules

for pharmaceutical production were only

available in nonsterile format for auto-

claving by the user. Higher area filter

capsules for even larger volumes did not

become available until the late 1980s to

early 1990s, eventually including the

large scale 10 -inch modular capsule fil-

ter assemblies available today. Around

the same time, the smaller production-

scale filter capsules presterilized by

gamma irradiation began to be offered.

On a parallel track,

the mid-1980s also

brought develop-

ments in disposable

biocontainers. Bio-

processers began to

use plastic film bags originally developed

for large volume parenterals or food storage

for serum and culture media containment as

well as for buffers. Similar to the large-scale

filter capsule developments, the late 1980s

and early 1990s brought the introduction of

large-scale single-use processing with 2D

bags in volumes from 50 to 1600 L and by

mid to late 1990s, 3D bags for process vol-

umes up to 3000 L, along with the first gen-

eration of totes to contain them.

As larger-scale capsules and bio-

containers became more available,

bioprocessers began to request that

suppliers assemble early systems with

pre-connected tubing, and by the mid-

1990s, bag suppliers had begun offering

single-use systems with filter capsules

that were pre-attached to biocontainers,

and filter manufacturers began offering

filter capsules with tubing and bags pre-

connected. Gamma-irradiated systems

followed shortly thereafter, and by the

mid 2000s, they were being validated

as sterile systems. In addition, more ad-

vanced totes and biocontainer designs

offered reduced leakage risks.

continued on next page

Jerold Martin

Jerold Martin is senior VP of

global scientific affairs for Pall

Life Sciences, and chairman of

Bio-Process Systems Alliance,

www.bpsaalliance.org

Jerold Martin


SINGLE USE FOREWORD

Single-use manufacturing was further

facilitated in the early 2000s by the in-

troduction of large-scale tube welders

and sterile connectors that enabled the

connection of two sterilized f luid path-

ways/systems while maintaining the ste-

rility of both. Availability of larger bio-

containers by the early 2000s brought

with them the innovative development of

the disposable rocking-bag bioreactor,

and by the late 2000s, stirred tankliner

bioreactors and mixers came to market,

with the larger filter capsule formats

enabling the development of membrane

chromatography units for trace-contam-

inant polishing.

The mid-late 2000s also brought the

industry disposable depth-filtration cap-

sule systems and a new generation of dis-

posable sensors. During that time, the

Bio-Process Systems Alliance (BPSA)

was established. BPSA has been instru-

mental in promoting best practices for

implementation of single-use technolo-

gies. The most recent developments in

the 2010s have been sterile disconnec-

tors and single-use tangential-f low filtra-

tion systems.

Today, the term “single-use technol-

ogy” encompasses a broad range of

primarily plastic disposable technolo-

gies that are suitable for a wide variety

of scales and applications, from upscale

bioprocessing to final formulation and

filling. They can be found in manufac-

turing processes for licensed drug and

vaccine products around the world.

This primer explores these various

uses with articles on moving from a fixed

system to a single-use system, working

with f lexible manufacturing facilities,

determining carbon footprints, and

more.

Acknowledgment: The author wishes

to acknowledge Paul Priebe of Sartorius-

Stedim Biotech for his input. BP

Single-use technology

applications can be found

in manufacturing processes

for licensed drug and

vaccine products around

the world.


SINGLE USE BIOREACTORS

Bioprocessing Methods

Single-use technology for bioreac-

tors has come a long way during

the past 25 years, yet some of

its capabilities remain to be exploited.

Equipment manufacturers have adopted

the technology as if it were an evolution-

ary step, but it is, in fact, revolutionary.

Current offerings in single-use technolo-

gies often are not presented this way,

however.

Single-use bioreactors currently fol-

low one of two general formats. In one

of these, the single-use components are

used as linings for stainless-steel tanks.

In a second model, a f lexible bag is af-

fixed to a rocker system that helps aerate

and mix components inside the bag (1–3).

Both of these models limit the value of

single use systems, however.

Equipment manufacturers conduct

extensive exercises to chart the future

of bioprocessing methods, but the real

judge of what is needed is the consumer.

The development of large-scale bioreac-

tors for the manufacture of commercial

quantities of monoclonal antibodies and

vaccines at an affordable cost and with

a short development time would fill an

unmet need. Therapeutic Proteins is

looking at ways to meet this demand by

incorporating a comprehensive biopro-

cessing unit capable of upstream and

downstream processing inside a single

bag without any moving parts. The com-

pany has filed or received dozens of US

and worldwide patents for these inven-

tions. In this way, the company hopes to

spur the further evolution of single-use

technologies.

In this new unit, mixing is achieved

by gentle pressing on the bag to create

a wave. Figure 1 shows a bioreactor with

a f lapper that pushes down on the bag

to create a wave motion inside the bag.

The bag itself lies f lat and does not move.

The Navier–Stokes equations describe

the motion of f luid substances, such as

liquids and gases (4). These equations

state that changes in the momentum

(i.e., force) of f luid particles depend only

on the external pressure and internal

viscous forces (which are similar to fric-

tion) acting on the f luid. The equations

also describe the balance of forces acting

New technology is designed to improve production efficiency by taking advantage of

the properties of single-use bags.

Sarfaraz K. Niazi

Sarfaraz K. Niazi, PhD, is executive chairman of

Therapeutic Proteins, 3440 S. Dearborn St., Chicago, IL

60616, [email protected].


BIOREACTORS SINGLE USEA

LL F

IGU

RE

S A

RE

CO

UR

TE

SY

OF

TH

E A

UT

HO

R

at any given region of the f luid. A force

applied to any portion of a f luid would

thus be transferred to the rest of the f lu-

id (4). A f lexible bag never needs to be

shaken or rocked. All that is needed is to

apply a minimal force, a pressure on any

part of the bag, to start the motion of liq-

uid. Rocking and shaking technologies

generally fail to account for the physical

constraints on the amount of stress that

can be applied to the bag. Bags used in

the rocking model cannot hold more than

500 -L of media because the bag would

break when rocked at a larger size.

Air-septum mixing is another efficient

method employed by the new system.

Figure 2 shows a model of an air septum

that pushes air from the bottom of the

bioreactor to create mixing throughout

the bag. The bag design incorporates

three layers of polyethylene. The middle

polyethylene layer has fine holes and

is joined to the bottom layer at various

points to create an upper chamber and

a lower chamber. Gas is passed through

the bottom chamber to create a sparging

system that extends to the entire base

of the bag. This system allows extensive

mixing, thus removing the need for mov-

ing parts in the bioreactor.

Aeration is provided either by a ce-

ramic sparging rod or by a perforated

septum. (see Figures 2 and 3). Aeration

levels of 6 vvm are easily reached, thus

allowing every type of cell and organism

to grow in f lexible bags. The KLa values

are comparable with or higher than those

achieved in stainless-steel bioreactors.

Until now, it was not possible to manufac-

ture bacterial products in f lexible bags.

The new invention, combining a sparging

system with a proprietary exhaust sys-

tem, broadens the uses of this technol-

ogy. The GE WAVE system uses surface

aeration, which limits it to cell-culture

work. Other products use traditional

mixing systems that add substantial cost

to the design and almost inevitably limit

the size of the bioreactor.

The size of the new bioreactor is less

limited because the bag remains station-

ary, which eliminates stress on the seam.

Because the mixing and aeration systems

in the new invention are part of the bag,

a f lexible bag can take any size, from a

few liters to thousands of liters. The f lap-

pers are arranged along the longer edge

of the f lexible bag, and, in the case of the

air-septum design, mixing and aeration

are fully integrated. In addition, because

the bag is not pressurized or bloated,

the volume of nutrient medium can be as

much as 70–80% of the bag volume. This

feature further reduces the cost of manu-

facturing.

Batch size is varied by a gravity-driven

system that mixes the contents of mul-

tiple bags to meet the 21 CFR definition

Figure 1: A 400-L bioreactor for bacte-

rial fermentation used by Therapeutic

Proteins to manufacture filgrastim.



of a batch without the need for transfer-

ring the nutrient media to a larger con-

tainer. This design eliminates the need

for validating multiple batch sizes. This

invention, though not unique to the new

bioreactor, confirms the idea that it is not

necessary to validate large bioreactors.

Instead, manufacturers can save costs

by validating a single size and making

a daisy chain of bioreactors to produce

large batches. The gravity system (see

Figure 4) reduces stress on the biologi-

cal culture and requires no equipment

other than a moving platform. The col-

lection bag has no moving parts for mix-

ing, which is achieved through a venturi

effect as the media enters the bag.

Perfusion of culture is made possible

by installing a ceramic filter. An air-

scrubbing method prevents the filter

from clogging. (see Figure 4). The nutri-

ent media is drawn through filters that

are continuously scrubbed by a constant

stream of fine air bubbles. This filter can

be used in many other stages of biopro-

cessing that require the concentration of

nutrient media, thus making cross-f low

filtration redundant. No equipment cur-

rently available can perform the function

of this filter. It can be positioned inside

the bag and used indefinitely.

Secreted proteins can be harvested by

binding them to a resin in the bioreactor,

thus eliminating the need for cell separa-

tion and cross-f low filtration. The resin

is added to the bag after the completion

of the upstream cycle in the upper cham-

ber of the air-septum bioreactor (see

Figure 3). Once the binding is complete,

the nutrient medium and cell culture are

drained out. The protein–resin complex

can be eluted or packed into columns for

further purification. This method works

on the principle that it is unnecessary to

A single-use bioreactor that

takes advantage of gravity can

reduce stress on the biological

culture and requires no equip-

ment other than a moving

platform.

2

3

6

7

8

10

9

14

5

Figure 2: A stationary bioreactor, including (1) a flexible 2D bag, (2) gas intake, (3)

gas sterilizing filter, (4) sparging rod, (5) exhaust, (6) media inlet, (7) flapper, (8)

heating and cooling element, (9) support frame, and (10) support base.

GE HealthcareLife Sciences

GE, imagination at work and GE monogram are trademarks of General Electric Company. ReadyToProcess, WAVEPOD and UNICORN are trademarka of GE Healthcare companies.

© 2011 General Electric Company – All rights reserved. GE Healthcare Bio-Sciences AB, Björkgatan 30, 751 84 Uppsala, Sweden

GE03-11. First published May 2011.

Control & ConfidenceReadyToProcess™ delivers reliable, reproducible results in cell culture.

• New embedded optical pH sensor enhances cell culture control

• New WAVEPOD™ II with quick and accurate regulation of process parameters

• New data logging capabilities with UNICORN™ DAQ software.

Find out more about our plug & play options, upstream and

downstream, at www.gelifesciences.com/readytoprocess



remove the cells and reduce the volume

of nutrient media if the purpose is to sep-

arate a protein. The binding resin can be

a specific resin, such as protein A, that

can be reused hundreds of times, or a

mixture of inexpensive resins, including

hydrophobic and ion-exchange resins.

The nutrient media’s properties can be

adjusted to maximize the binding.

This invention is intended to reduce

the time and cost of drug manufacturing.

Two major steps, both requiring expen-

sive equipment and substantial time to

achieve the same goal, are eliminated. It

is anticipated that in the manufacturing

of monoclonal antibodies, this new unit

saves a process time of approximately

50 h for a 2000 -L batch. In addition, the

limited handling of proteins can improve

the final yield substantially, sometimes

as much as 20–30% (5).

Proteins can be purified in the bag by

using it as a chromatography column. Al-

though the idea of using a f lexible bag as

a chromatography column appears alien,

nothing prevents a process from being

developed by taking into account the

geometry and the physical state of resin

suspension in the bag. The elution may

include a step elution, a gradient elution,

or a programmed elution. An example is

washing the bound resin to remove cells,

and then equilibrating the protein–resin

conjugate in a buffer to elute the target

drug. A buffer that would break down the

binding can be used to collect a highly

1

2

3

11

4

5

6

127

8

13

15

16

17

1819

14 20

10

9

Figure 3: A separative bioreactor, including (1) liquid inlet–outlet, (2) exhaust, (3)

media sample, (4) flexible 2D bag, (5) polyethylene perforated septum, (6) heating–

cooling element, (7) gas sterilizing filter, (8) gas flow valve, (9) source of gas, (10)

drain, (11) drain control valve, (12) lower chamber, (13) upper chamber, (14) nutrient

media or chromatography media, (15) support stand, (16) support base, (17) sep-

tum tufting point, (18) buffer inlet, and (19) mixing plenum.


BIOREACTORS SINGLE USE

purified solution of the target protein.

Even if this process of purification does

not achieve the quality that traditional

methods do, the possibility of eliminat-

ing a few steps in downstream process-

ing would have a great effect on the cost

of purification because no equipment

needs to be installed for large volumes to

be fed through the purification column.

An AKTA Pilot liquid-chromatography

system (GE Healthcare) might do the job

of an AKTA Processor (GE Healthcare),

for example.

Other uses of the new bioreactors in-

clude media and buffer preparation and

sterile transfer to final containers. The

unit also may be used as a pressure ves-

sel in pharmaceutical manufacturing.

The air-septum bioreactor is suited to

performing many functions. As a com-

plete system with no moving parts and

the ability to be pressurized, this inven-

tion fulfills the bioprocessing industry’s

needs for manufacturing recombinant

proteins, monoclonal antibodies, and

vaccines.

Other uses of the perfusion filter in-

clude concentration of slurries, reduc-

tion of volume of a bacterial nutrient me-

dia, water purification, and sterile liquid

transfers. The filter can be made in sev-

eral shapes and combinations to fulfill

the need for a particular f low rate from a

specific mixture. Using air to scrub a fil-

ter and keep the pores open enables new

filtration methods. This filter system re-

quires a solid base to keep the filter from

collapsing. The base can be layered with

fine membranes, such as a 0.22-µm filter,

to separate bacteria and sterilize a solu-

tion. The filter system can be sterilized

in situ and placed inside a bag for an un-

limited time of operation.

The new technology described above is

designed to take advantage of the proper-

ties of a f lexible bag. By incorporating a

bioreactor inside the bag, the technology

offers a transportable system that does

not require extensive validation when

manufacturing sites are changed. Be-

cause users can link the units together to

produce batches of practically any size,

12

3 4 5

6

Figure 4: A gravity-driven mixing system, including (1) vertical moving stand, (2)

bioreactors, (3) drain tube, (4) support base, (5) transitory vessel, (6) and venture

mixing vent.



the technology could expand the adop-

tion of single-use systems for the com-

mercial production of biological drugs.

A significant advantage of the new tech-

nology developed is its low capital and op-

erational costs. The flexible bags are placed

on a heating or cooling platform (see Figure

1). The system monitors the nutrient media

for dissolved oxygen, pH, and glucose lev-

els either by remote sensors or by direct

sampling. Although other methods, such as

fluorescence-based monitoring, are avail-

able, Therapeutic Proteins believes that, in

the long-term, the wired sensors inside the

bags are the most appropriate tools.

The systems described above are rou-

tinely used at Therapeutic Proteins’s

cGMP compliant facility to manufacture

large-scale cytokine and monoclonal-an-

tibody production batches. Although the

technology requires substantial modifi-

cation and validation of the process, the

systems operate smoothly once these ef-

forts have been completed because they

contain few components.

RefeRenceS 1. S. Niazi, Disposable Bioprocessing

Systems (CRC Press, Boca Raton, FL,

2011).

2. Xcellerex, “XDR Single-Use

Bioreactors,” (Marlborough, MA),

www.xcellerex.com/platform-xdr-

single-use-bioreactors.htm, accessed

Oct. 4, 2011.

3. GE Healthcare, “WAVE Bioreactor

Systems,” (Chalfont St Giles, UK),

www.gelifesciences.com/aptrix/

upp01077.nsf/Content/wave_

bioreactor_home, accessed

Oct. 4, 2011.

4. R. Temam, Navier-Stokes Equations:

Theory and Numerical Analysis (AMS

Chelsea Publishing, Providence, RI,

2000).

5. J. Liderfelt, G. Rodrigo, and A. Forss,

“The Manugfacture of mABS—A

Comparison of Performance and

Process Time between Traditional

and Ready-to-Use Disposable

Systems,” in Single-Use Technology

in Biopharmaceutical Manufacture, R.

Eibl and D. Eibl, Eds. (John Wiley and

Sons, Hoboken, NJ, 2011). BP

Figure 5: Air-scrubbed filtration system for nutrient media perfusion, cell removal

and volume reduction.


Disposable CompoNeNts SINGLE USE

The Evolution from Fixed to Single-use Systems

For many years, “blockbuster” drugs

have made fixed systems the most

pragmatic choice for manufactur-

ing high volumes to meet high demand.

Fixed systems rely heavily on stainless

steel for piping, valves, tanks, and fit-

tings because the parts needed are rigid

and fixed in nature. Steel components

can be manufactured with a variety of

surface finishes, are sterilizable using

most sanitizing medium, and can with-

stand high temperature.

Production runs in fixed

systems tend to be long

with infrequent change-

over. For the above rea-

sons, and because of

the risk-adverse culture

that is synonymous with drug manufac-

turing and engineering, stainless steel

has been the predominant material in

biopharmaceutical manufacturing.

This thinking began to evolve with the

advent of single-use systems (SUS), most

commonly referred to as “disposables.”

A new mindset and technical platform

was introduced to meet the changing

industry needs presented by “personal-

ized” large-molecule drugs. Initial SUS

processes were deployed by manufac-

An overview of applications for disposable components

and important property considerations.

Gary M. Dennis, Charles Weidner, and Saeid Zerafati

Gary M. Dennis is market manager

for high-purity � uropolymer resins,

Charles Weidner is a business devel-

opment manager, and Saeid Zerafati

is a senior research engineer, all

at Arkeme Inc., 900 First Avenue,

King of Prussia, PA 19406. tel.,

610.205.7535 gary.dennis@

arkeme.com

Ima

ge c

ou

rte

sy o

f th

e a

uth

ors


SINGLE USE Disposable CompoNeNts

turers in response to the need for the

low-volume production of vaccines in

high concentration (Merck) and to meet

hormone medication commercialization

(Amgen) in a relatively short period of

time (1). Fixed stainless-steel systems

require extensive downtime because the

process needs to be revalidated and ster-

ilized after each use. Disposable process

technology, on the other hand, utilizes

fewer parts and eliminates the costly

need to revalidate; the system can be

used once before the prevalidated com-

ponents are replaced for a fast change-

over to a new vaccine or drug.

Factors favoring the fundamental shift

to SUS are:

• Reduced R&D costs compared with

using a high volume fixed system as

part of the research line.

• Decreased time to market for a spe-

cific medicine, which can be tailored

for smaller volume use.

• Rapid setup and regional deployment

to meet drug needs worldwide.

• Ability to manufacture many prod-

ucts in the same facility with no risk

of cross-contamination.

• Minimal expansion cost through

drug development and scale up.

• Lower utility costs in cleaning and

system revalidation.

Compared with stainless-

steel systems, disposable

process technology utilizes

fewer parts and eliminates

the costly need to

revalidate.

Chemical name Brand name examples Applications

Polytetrafluoroethylene Teflon Filters, tubing

Polyvinylidene fluoride Kynar, Kynar Flex Filters, fittings, tubing, bags

Polycarbonate Lexan Fittings

Polypropylene Moplen, Profax Filters, housing, piping

Polyethylene Dowlex, Engage Bags

Polyamide Nylon, Rilsan 11& 12 Films, filters

Polyvinylchloride Lacovil Pipes, films, tubes

Silicone Tubings, fitting

Poly ether block amide Pebax Tubing

Ethylene vinyl acetate copolymers

Evatane, Elvax Bags

Compounds (blends of multiple polymers)

C-Flex, Santoprene Tubing, fittings

Table I: Chemical, brand name, and application of common plastics.



Plastic comPonents and

single-use system ReseaRch

Many questions were raised over ini-

tial plastic designs. These issues were

exacerbated by the general lack of

polymer knowledge after years of metal

use.

The list of candidate plastics for

single-use pharmaceutical processing

includes those currently used in indus-

try designs (see Table I). One of the

strengths of these plastic components is

the diversity of properties and designs

presented. However, this also represents

one of the main challenges as biopharm

engineers struggled with how to incor-

porate a number of material components

into a system and industry designed to

minimize risk.

Membrane and filtration

The longest running polymer compo-

nents used in biopharmaceutical applica-

tions are filter membranes and cartridg-

es. These components have been used in

fixed systems for many years. Membrane

filtering applications have primarily used

polytetraf luoroethylene (PTFE), polyvi-

nyldene f luoride (PVDF), polypropylene

(PP), and polyethersulfone (PES) (2).

PVDF has been the resin of choice for

over 20 years in protein synthesis and

separation for biopharm applications.

The large surface to volume ratios re-

quired in filter membranes exceeds that

of other common components including

tubing and containers. Therefore, this

f luoropolymer resin has been long vet-

ted and provides biopharmaceutical pro-

cess engineers with a track record and

history of successful performance in in-

dustry processes.

Piping

Polymer materials, especially PP and

PVDF, have experienced success sup-

planting stainless steel in some fixed

industry piping designs as the materials

could be used in various water service

criteria, including United States Phar-

macopeia (USP) purified water for both

plastic resins. Additionally, PVDF piping

lends itself to use in ultra high purity

water, laboratory reagent grade water

Injection molded type I bars

Stress at yield (psi)

Strain at yield (%)

Stress at break (psi)

Flexural modulus

(psi)

Kynar RX Homopolymer 7210 5.9 4600 199000

Kynar RX Homopolymer Gamma Irradiated

7440 5.5 4400 207000

Kynar RX Copolymer 3570 10.6 4300 57800

Kynar RX Copolymer Gamma Irradiated

3670 9.6 4700 60400

Table II: Properties of PVDF fluoropolymer (Kynar) before and after gamma sterilization

at 50 kgy.



Type 1, as well as Semiconductor UHPW

ASTM Type 1 service criteria. One ad-

vantage of polymer components to stain-

less steel is the latter’s capacity to rust

or rouge in high-purity water causing

system contamination. Chemical pas-

sivation is frequently required to remove

free ions from the surface and restore

the oxide film that gives stainless steel

its corrosion resistance (4).

Tubing and fittings

Tubing is the most highly utilized compo-

nent within a disposable system because

large f luid transfer is required with the

single-use system design. Multiple ma-

terials have been used ranging from sili-

cone, EVA, TPE compounds, low density

PE, PTFE, and PVDF copolymers.

Molded fittings are required to attach

or weld to other process componetry in-

cluding bags and containers. Therefore,

welding and processability becomes

an important design criteria. The most

common industry fitting materials are

PE, PP, polycarbonate (PC), silicone,

and PVDF.

Bags

Film bags and containers pose possibly

the most significant challenge as they

are needed in numerous disposables

functions starting with reaction vessels

and progressing to transfer, storage and

media preparation. Long dwell times are

the norm, which makes purity concerns

paramount despite being only one of a

host of factors that affect their maximum

utilization. These bags must be strong and

tough, possess barrier properties and have

the ability to melt bond effectively in multi-

layer structures. Purity, melt processabili-

ty and bonding, as well as the contact layers

ability to be sterilized while providing a sig-

niflcant barrier or permeation properties

is a tall task. Common bag layers include

EVA, PE, and PVDF.

FluoRoPolymeRs

move to the FoReFRont

As previously stated, one of the original

concerns with plastics was the many va-

rieties to meet multiple design charac-

teristics. Biopharm engineers desired a

more universal option. In other words,

a polymer alternative to stainless steel.

The industry hit on the idea of a more

defined and singular “contact layer” to

meet the diversity required in SUS. This

search for a common contact material

instinctively led its way to PVDF f luo-

ropolymers (e.g., Kynar) for many rea-

sons, as noted below (5).

Processability

PVDF is completely melt processable on

conventional equipment allowing for its

ability to be found in the complete range

of component forms required. This melt

processability attribute extends itself to

not only rigid parts (pipe, fllter housings

and membranes, pumps) which use PVDF

homopolymers, but also to parts favoring

added fiexibility (tubing, flttings, and

fllm). Copolymer PVDF resin helps at-

These bags must be

strong and tough, possess

barrier properties and have

the ability to melt bond

effectively in multilayer

structures.



tain the more flexible part designs while

maintaining the purity and processability

aspects. Most importantly, the ease of

melt processability allows for welding by

various industry methods (6).

High purity

No processing aids or additives are re-

quired in PVDF fluoropolymer resin man-

ufacturing, allowing for its compliance

with USP Classification VI. There are no

animal derivatives in Kynar resins.

Cholesterol binding

Fluoropolymers have low surface ten-

sion properties and as such do not have

the propensity to attach to organic mat-

ter such as proteins and lipids. This pro-

motes increased manufacturing efficien-

cies as proteins do not stick to the bags

or vessel walls.

Sterilizable

PVDF is unique among polymer materi-

als as it is compatible to the various ster-

ilization methods including gamma, au-

toclave (steam), and chemical (EtO) (7).

Gamma radiation is commonly used in

disposables practices. Common indus-

try gamma sterilization levels are 25 -30

KGy. Table II contains data that shows

no change in properties even after doses

twice the industry level (50 KGy).

Multilayer adhesion technology

The ability to make multilayer film (bags)

and tube structures was a final obstacle to

overcome. As PVDF f luoropolymers have

the advantage of low surface tension, this

same property can make it more difficult

to adhere to complementing resins when

appropriate. This can often be the case

in bag manufacturing. Multilayer bag

structures and technology utilizing

PVDF f luoropolymers as the contact

layer are now readily available due

to the development of new extrusion

designs. Such designs allow plastics

with additional barrier properties, such

as EVOH, and lower cost softer resins,

such as PE and copolyamides, to be

incorportated in outside layers.

Chemical resistance

The appropriate selection of polymers

can offer long term advantages to met-

als in areas where cleaning agents are

used. Plastic materials are available that

fully resist a broad range of chemicals

and rusting or rouge is never a concern.

PVDF can handle steam, chlorinated

disinfectants, oxidants and acidic chemi-

cals at varied concentrations. PVDF be-

longs to the f luoropolymer family of res-

ins which contains the carbon-f luorine

bond which is one of the strongest bonds

in chemistry. The high energy that is

required to break this bond creates its

unique chemical resistance across a

broad range of pH values. PVDF compo-

nents are commonly used in applications

where bleach, chlorine dioxide, chlori-

nated water, brominated water, ozone,

peroxide, peracetic acid, HCl, and alco-

hols are used in cleaning and bacterial

control processes.

Stainless steel continues to lead

the way for mass-production

drugs, but disposables equip-

ment has moved into the

biotechnology–pharmaceutical

mainstream.



conclusion

Stainless steel continues to lead the way

for mass-production drugs and fixed-

system approaches. Disposables equip-

ment has moved into the biotechnology–

pharmaceutical mainstream. Only 3% of

biopharmaceutical manufacturers use

no disposables today, according to the

Third Annual Report on Biopharma-

ceutical Manufacturing Capacity and

Production, issued in June 2005 by Bio-

Plan. Additionally, the Biopharm Miram

Murge Study estimated capitol costs

reduction of 40% by single use systems.

This trend is expected to continue as the

industry evolves into a more pragmatic

approach to regionalized and smaller-

dose drugs. The need for lighter and

more efficient components and systems

will become increasingly important as

quick changeover and low costs move to

the forefront. The PVDF f luoropolymer

alternative has continued to gain accep-

tance as a single f luid contact surface

as it offers biopharm engineers the ad-

vantage of reduced risk and a universal

polymer-system approach.

ReFeRences

1. A. S. Brown, Chem. Process.

(February, 2006).

2. D. R. Keer, Ultrapure Water (July/

August 1993) 40–44.

3. R. Greene, Chem. Eng. Progress (July

2002) 15–17.

4. L. Shnayder, Pharm. Eng. (November/

December 2001) 66-72.

5. W. J. Hartzel, Innov. Pharm. Technol.

(22) 2008.

6. T. Sixsmith and B. Paul, Chem.

Process. (September 1995) 86-89.

7. H. Gruen, M. Burkhart, and G.

O’Brien, Ultrapure Water (October

2001) pp. 31-38. BP

Upcoming special issues of BioPharm International will focus on

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To contribute, contact the senior managing editor Angie Drakulich

at [email protected].

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SINGLE USE VacciNe ProductioN

Approaches for Flexible Manufacturing Facilities in Vaccine Production

According to the US Centers for Dis-

ease Control and Prevention’s (CDC)

vaccine price list, US vaccine manu-

facturers receive a wholesale price of between

$9 and $109 per dose for pediatric and adult vac-

cines (1). For influenza vaccines, the wholesale

price paid to manufacturers ranges from $5 to

$9 per dose (2). Doses that reach the market

early in the season command a higher than

average price, and prices decline throughout

the season. Any excess inventory is destroyed

at the end of the influenza season. Small batch

sizes, the high cost of labor involved in egg or

cell culture based production, and the cost of

filling results in a profit margin that is quite low

relative to that of the rest of the biopharmaceu-

tical industry. Such low profit margins affect

manufacturers’ willingness to invest capital in a

commodity business such as influenza or other

vaccines. This consideration is particularly true

when providing vaccines to developing coun-

tries, where the price for vaccines per dose are

a fraction of those in the US. Table I provides

average reimbursement prices paid by UNICEF

in 2010 and vaccine prices in high income coun-

tries are represented by the CDC vaccine price

list for 2011 (1, 3).

The pressure to reduce facility-investment

costs and the cost of goods manufactured is a

primary driver in the paradigm shift occurring

in the industry’s approach to facility design. The

objective is to be more competitive, reduce risk,

and provide higher value for investments. Pro-

duction facilities must be flexible, cost effective,

and provide more rapid construction and start-

up. In addition, for pandemic influenza vaccines,

a surge capacity is crucial to produce the maxi-

mum number of vaccine doses in the shortest

time. Cell-culture influenza vaccine processes

being developed offer many advantages in scal-

ability, but traditional manufacturing facilities

may not be available or adaptable to produce

such vaccines thus presenting a bottleneck to

their commercialization.

Applicable to both clinical and full-scale manu-

facturing, single-use systems have become a

mainstay of flexible and adaptable process and

facility design. Although disposables provide

opportunities, they also introduce challenges

for biopharmaceutical manufacturing. This ar-

ticle discusses facility and process-design issues

that should be examined when considering or

implementing single-use technology.

The eFFeCT oF The

Room enviRonmenT

To evaluate the potential risk of contamina-

tion or adulteration involved in a production

process, one must first examine the potential

sources, which include carryover between

batches, cross-contamination between prod-

With careful analysis to mitigate risk, disposable technology and process closure

can enable adaptable designs and reduced costs.Kim L. Nelson

Kim l. Nelson, PhD., is a senior associate and director

of strategic consulting at CRB Consulting Engineers,

tel: 215.435.0390, [email protected].

SINGLE-USE TECHNOLOGY

Single-use, reusable or hybrid. The right solution for each process step.

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www.sartorius-stedim.com/single-useturning science into solutions



AL

L F

IGU

RE

S A

RE

CO

UR

TE

SY

OF

TH

E A

UT

HO

R

ucts, and the introduction of contaminants

from the environment, raw materials, or from

inadequate cleaning.

In the US, FDA recognizes the cleanroom

standards of the International Organization for

Standardization, speciflcally ISO 14644-1 (4).

European standards go further in distinguish-

ing between static conditions at rest and dy-

namic conditions in operation (5). Controlled

nonclassifled (CNC) is a classiflcation often

used in noncritical areas in GMP manufactur-

ing facilities. CNC areas are designed to pro-

vide a consistently controlled environment, but

are not monitored to the same levels as ISO or

Grade classifled areas. The International Soci-

ety of Pharmaceutical Engineering (ISPE) has

“Sterile”

filters

renders the

system

closed

Asceptic

connections

maintain the

system closed

Closed

systems

Closed

systems

OPENe.g. fraction collecting

RENDERED CLOSEDe.g. Buffer & Media prep

CLOSEDe.g. Cell culture or

Fermentation

CLOSEDe.g. Chrom columnfraction collecting

TO CONTROL BIOBURDEN A CLASSIFIED ENVIRONMENT

OR LOCAL HOOD ISREQUIRED

PROCEDURES & GOWNINGREQUIRED

Classified space required

Unclassified(CNC) space



Figure 1: Distinction of open, closed and rendered closed processes in classified and

controlled nonclassified (CNC) spaces.

DiseaseAverage vaccine cost per dose

Low-income countries (2) High-income companies (1)

Measles mono $0.24 Measles, mumps, and rubella $15.50

Diphtheria, tetanus, and pertussis (DTP)

whole cell $0.25 DTP $10.55

TuberculosisBacillus

Calmette-Guérin $0.07 none N/A

Hepatitis Bmono and in combo

with DTP $0.27 in combo $9.00

Hemophilus influenza Type B

in combo with DTP $3.20 in combo $21.38

Polio oral polio vaccine $0.10 inactivated poliovirus vaccine in combo $8.25

Influenza N/A N/A flu vaccines (various) $10.82

Table I: Cost for single and combination vaccines in low- and high-income countries.


VacciNe ProductioN SINGLE USE

similarly deflned CNC as a nonclassifled room

environment where closed processes and their

immediate support systems may be located.

CNC spaces are cleanable, have access control,

and are served with flltered HVAC air, but do

not have the ridged procedural controls and per-

sonal gowning requirements of classifled areas.

Room classiflcations and the heavy burden

they carry were considered in a recent article

prepared by biopharmaceutical industry rep-

resentatives that examined environmental

controls in the context of current manufactur-

ing technology (6). The authors discussed the

rational for breaking the cleanroom paradigm

and lowering room classiflcations using risk-

based approaches to reduce capital and operat-

ing costs.

SySTem CloSuRe—An enAbling

TeChnology

Closed processes or systems use process equip-

ment that does not expose the product to the

immediate room environment and therefore

prevent entry of contaminants (7). In the case

of biocontainment, the system must also pre-

vent escape of organisms or products. Closure

is usually achieved through aseptic connections

or by using flltration in the system as a means

FAULT TREE ANALYSISCLOSURE SYSTEM

Fault treeanalysis diagram

Question (1)

No furtheraction required



Redesign the

closure system

Upgrade the

room environment

Add/Modify

downstream step

Yes

Yes

Yes

No

No

No

Question

1

Question

2

Question

3

Is the system closure consistent withthe user or process requirements

Question (2)

Does the connection effectively isolatethe process from the environment

Question (3)

Are there downstream controlsthat effectively mitigate the risk

Mitigate usingdownstream

stepUpgrade thesurroundingenvironment

Redesign theclosure system

Figure 2: Fault-tree analysis for system closure.



of rendering it closed. Additions to or withdraw-

als from the system must be done in a manner

that ensures the integrity of system closure. It is

important to note that it is the manufacturer’s re-

sponsibility to both deflne system closure, and

to prove closure for each process step. Impor-

tantly, the loss of a closed state due to routine

or infrequent activities (e.g., maintenance and

cleaning) does not negate the need for the use

of closure as a key aspect of the facility’s design.

In such cases, validated procedures for reinsti-

tuting the closed state should be part of the stan-

dard operating procedures for manufacturing.

Newberger and Melton discuss brief exposure

in the context of API production facility design,

and it is an important concept that should also

be incorporated into risk-based approaches to

system closure (7).

It can be difflcult or impractical to fully close

some processes, for example inoculum prepara-

tion, where robotics or isolators are impractical

because of high cost or operator resistance re-

spectively. In such situations, open processing

is acceptable, providing that it is protected by a

suitable, monitored room environment.

In closed-system processing, the room envi-

ronment becomes secondary to the integrity of

the closed systems and any connections made

to introduce, remove, sample, or analyze the

contents. In an open operation, which is not

subsequently flltered, the cleanroom environ-

ment is relied upon to reduce the probability of

contamination from room air. If the process is

rendered closed (e.g., by flltration into a closed

tank or bag), the room environment does not af-

fect the integrity of the system. With a closed

process that is never exposed to the room, the

environment does not affect the system at all.

CloSuRe AnAlySiS

Closure analysis is a systematic evaluation of the

risk in each process step, based on the process

control level required and the closure level used

for particular connections. At it simplest, clo-

sure analysis examines critical unit operations

and each connection into or out of the closed-

Figure 3: FutureFacility concept for vaccine-manufacturing facility.


VacciNe ProductioN SINGLE USE

system boundary. Closure analysis generally

consists of the following steps:

• Identify the system boundary and all pene-

trations of the unit operation’s closed-system

boundary.

• Evaluate each particular unit operation ac-

cording to its bioburden control speciflca-

tion (e.g., controlled bioburden, low biobur-

den, and aseptic).

• Evaluate each connection according to

agreed closure deflnitions (e.g., open, brief-

ly exposed, cleaned, closed, or unexposed).

• Calculate a risk ranking based on the prod-

uct of the bioburden control ranking and the

closure ranking for the particular connec-

tions being evaluated.

• Evaluate connections with unacceptable

risk ranking using a closure fault tree (see

Figurefi2). Modify the closure system, or up-

grade the environment for points having un-

acceptable risk, or ensure that downstream

steps mitigate the risk acceptably (e.g., by

flltration).

All of the connections’ risk rankings can be

tabulated to give a snapshot of the system, and

a frequency histogram can show the number

of connections considered to be higher risk;

the objective is then to evaluate ways to move

these to lower risk rankings. Connections that

are inconsistent with bioburden control; identi-

fled for redesign, increased environmental or

downstream controls; or connections that are

not clearly deflned in documentation will all re-

quire further attention.

FuTuRe FACiliTy ConCepTS

By leveraging closed systems and maximizing

the use of single-use systems, it is possible to de-

sign a facility that allows work areas to be com-

bined and room classiflcations to be lowered.

Such a facility offers many beneflts; in studies

done by CRB for a number of biophamaceutical

clients where the FutureFacility concepts were

utilized and the corresponding facility costs,

utility costs, and cost of goods were examined,

advantages included:

• Reduced manufacturing area (by 15–30%).

• Reduced HVAC (resulting in reductions in

room classiflcations, gowning, cleanroom

areas, air changes per hour, fan power de-

Process/clinicaldevelopment



Future facilityproject Facility licensing

Facility licensing

Improved timeto market

Additional timefor process development

and business planning

Strategy A

Strategy B

Traditional project Facility licensing

Figure 4: Schedule showing how shorter project times compared with those of a tradi-

tional stainless-steel facility can allow for improved time to market; or for added time

for process development, clinical result generation, and business planning before com-

mitting to major capital investments.



mand, number of air handling units, and

maintenance).

• Reduced utilities (single-use systems can

reduce clean steam and water-for -injection

requirements by up to 80–90%, chilled water

and steam demands are reduced by up to

60%, and wastewater is also reduced.

• Reduced construction and start-up schedule

(by 30–50%).

• Possible reduced cost of goods.

In the FutureFacility concept (see Figure

3) for a vaccine manufacturing plant, a con-

tained zone is provided for the virus work,

while the nonviral support functions, as well

as the post inactivation steps are combined

into a single room. Such an approach re-

duces the circulation areas of corridors and

airlocks, maximizes the efflciency of labor,

and offers the maximum in fiexibility for

changing processes. Each unit operation is

connected to utility plates in the ceiling and

can be readily relocated to accommodate

various processes. Even the containment

area can be demounted and removed, should

biocontainment no longer be necessary, for

example if a monoclonal antibody operation

is inserted into the facility. Inoculum prepa-

ration operations in the FutureFacility uti-

lize isolators with integrated incubators

and directly adjacent seed bioreactors. Cell

buildup for the viral process is outside of the

containment zone, and transfer into the pro-

duction bioreactors at the flnal stage.

The design and construction schedule for

this sort of facility is signiflcantly shorter

than a traditional stainless steel facility.

Time spent on design and construction is

reduced because of lower system and build-

ing complexity and reduced piping require-

ments, and procurement of single-use sys-

tems avoids the long lead times associated

with stainless steel equipment. Time saved

on design and construction can be used to

improve time-to-market, or if the project

initiation is delayed, it can be used to allow

additional process development time, or to

have more certainty in clinical results before

committing to major capital investments in a

facility (see Figure 4).

ConCluSion

Process closure provides superior product

protection and permits lower room classifl-

cations. A risk-based approach must be used

to review the state of process system closure

and to identify all connection points, evaluat-

ing their suitability with regard to the process

and quality requirements. Manufacturing fa-

cilities that use these closed-system process-

es in combination with single-use technolo-

gies offer process fiexibility; adaptable and

expandable design; shortened construction,

start-up, and validation schedules; as well as

decreased utility costs, all of which have the

potential to reduce the cost of vaccines.

ReFeRenCeS

1. CDC, “Vaccine Price List,” www.cdc.gov,

accessed Oct. 14, 2011.

2. UNICEF, “Vaccine Price Data 2001-

2010,” www.unicef.org, accessed Oct.

14, 2011

3. President’s Council of Advisors on

Science and Technology, “Report to the

President on Reengineering the Influenza

Vaccine Production Enterprise to Meet the

Challenges of Pandemic Influenza” (Aug.

2010).

4. ISO 14644-1, Cleanrooms and

Associated Controlled Environments –

Part 1: Classification of Air Cleanlines

Cleanroom Standards (ISO, 1999).

5. European Commission, EudraLex Vol.

4: Good manufacturing practice (GMP)

Guidelines, Annex 1: Manufacture of

Sterile Medicinal Products (2003).

6. S. Chalk et al., BioPharm Intl. 24 (8)

44–65 (2011).

7. Newberger et al., Pharm. Eng. 28 (6), 1–7

(2008). BP

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SINGLE USE ENVIRONMENTAL IMPACT

An Environmental Life-Cycle Assessment Comparing Single-Use

and Conventional Process Technology

Many biopharmaceutical com-

panies have replaced or are

planning to replace traditional

multi-use process equipment (fixed-in-

place stainless-steel fermenters, tanks,

downstream processing equipment, and

associated piping) with single-use sys-

tems to improve f lexibility, productivity,

and cost (1–3). The use of disposable

components reduces or eliminates the

need for extensive cleaning and steam

sterilization between batches. However,

single-use process technologies can also

have negative environmental impacts be-

cause they involve the use and disposal of

consumable materials.

Several previous studies have looked

at environmental impacts of single use

biopharmaceutical manufacturing tech-

nologies (4–7). To further understand

the balance of environmental impacts,

GE Healthcare in collaboration with GE’s

Ecoassessment Center of Excellence has

completed an extensive study of the life-

cycle environmental impacts of the full

process train required to produce mono-

clonal antibodies (mAbs). The study

compares the use of single-use versus

traditional durable process technologies

at 100 -L, 500 -L, and 2000 -L scales. The

scales were chosen to ref lect the clinical

phase, the scale-up phase, and the final

production phase. Process data were

derived in collaboration with BioPharm

Services, developer of BioSolve, an in-

dustry-standard bioprocess model that

can be used to build any process includ-

ing those for manufacture of mAbs, vac-

The authors compare the environmental impact of monoclonal antibody production using fixed-

in-place processing and single-use systems.

Matthew Pietrzykowski, William Flanagan, Vincent Pizzi, Andrew Brown,

Andrew Sinclair, and Miriam Monge

Matthew Pietrzykowski is a research chemist, and William

Flanagan* is the leader, both at at the Ecoassessment Center of

Excellence, GE Global Research, Niskayuna, NY. Vincent Pizzi is a

global product marketing leader at GE Healthcare, Westborough,

MA. Andrew Brown is a bioprocess engineer, Andrew Sinclair is

managing director, and Miriam Monge is vice-president, all at

Biopharm Services Ltd., Chesham, UK. *[email protected]


ENVIRONMENTAL IMPACT SINGLE USE

cines, and bacterial-based products.

This comprehensive environmental

study of single-use process technology is

the first to offer a comprehensive exami-

nation of environmental impacts across

the full process train using life cycle as-

sessment (LCA). LCA is an international-

ly recognized discipline that can be used

to examine products and processes from

an environmental perspective across

the full lifecycle of a product or process,

from raw-material extraction and refin-

ing through manufacturing, use, and

end-of-life disposal or recycling. The

methods involve analyzing material and

energy f lows from cradle-to-grave to cal-

culate potential environmental impacts.

This study was performed in accordance

with the International Standards Organi-

zation ISO 14040 and ISO 14044 (8, 9).

The details and quality of the study were

evaluated by a third-party critical re-

view panel as per ISO 14044 because the

study involved comparative assertions.

The critical review panel consisted of an

independent LCA expert and two domain

experts from the biopharmaceutical

manufacturing industry (10).

The results reported here focus on glob-

al warming potential (i.e., greenhouse gas

emissions), cumulative energy demand

(i.e., embodied energy), and water usage.

The study also examined a range of addi-

tional environmental impact categories,

such as ozone depletion, acidi�cation,

eutrophication, resource depletion, par-

ticulate matter formation, photochemical

oxidant formation, as well as others. A

companion article describing the results

of the more comprehensive set of environ-

AL

L F

IGU

RE

S A

RE

CO

UR

TE

SY

OF

TH

E A

UT

HO

RS

N-2 Seed

KEY

N-1 Seed

Cell growthmedia prep

Cell growthmedia sterilization

Blending/storage

Blending/storage

Blending/storage

NFFpleated

Sterile/filtration

Sterile/filtration

Diafiltration/concentrationProduct

fill

Support CIP/SIP system(not shown)

Adjustment/holding

pHadjustment

Virusinactivation

Vent filter

Cell culture

Air filtration

Clarification

Clarification

Pool mixing

Removal

Storage

Storage

Polishing

Capture

Virus filtration

1 N-2 Seed 2 N-1 Seed 3 Bioreactor 4 Depth filtration clarification 5 Bioburden reduction I 6 Protein A 7 Virus inactivation 8 Bioburden reduction II 9 No tank bioburden reduction 10 Capture IEX 11 Flow through IEX 12 Viral filtration 13 UF/DF 14 Sterile filtration IISupport CIP/SIP System

Figure 1: Process diagram of full process train for the production of monoclonal anti-

bodies (mAbs). For this study, the process train was categorized into 14 unit opera-

tions and a 15th category, “Support CIP/SIP System,” that included the clean-in-place/

steam-in-place infrastructure and common support activities, such as process water

and HVAC requirements. IEX is ion-exchange chromatography, UF/DF is ultrafiltration/

diafiltration.



mental impact categories is in preparation

and will be published separately.

Methodology

Goal definition

The goal of this study was to compare the

potential environmental impacts associ-

ated with the production of mAbs using

either single-use or traditional durable

process technologies. The full process

trains were evaluated at 100 -L, 500 -L,

and 2000 -L scales. Calculations were

based on a 10 -batch campaign assuming

6 g/L titres. The study did not account

for any potential difference in product

yield resulting from choice of process

technology. Any such issues are product-

or process-specific and beyond the scope

of this study.

The results of this LCA will be used to

communicate potential environmental

impacts to interested stakeholders and

to identify key areas for potential im-

provement in terms of supply chain, prod-

uct design, manufacturing, or end-of-life

as appropriate.

Scope

The scope of this study included both

upstream and downstream processes in-

volved in the production of mAbs. Figure

1 shows a process schematic of the full

process train categorized into fourteen

unit operations. A 15 th category included

the clean-in-place/steam-in-place (CIP/

SIP) infrastructure and common sup-

port activities, such as process water and

HVAC requirements (collectively termed

“Support CIP/SIP System”).

The potential for a smaller production

facility enabled by the choice of single-

use technology was not specifically

included in the scope of this study. How-

ever, the f loor space used per HVAC class

for each technology was scaled to the re-

quired facility footprint. This approach

assumed that a traditional technology

facility is in place and single-use technol-

7,000,000

6,000,000

5,000,000

4,000,000

3,000,000

2,000,000

1,000,000

400,000

350,000

300,000

250,000

200,000

150,000

100,000

50,000

Supply chain Supply chainUse phase Use phaseEnd of life End of life

Glo

bal w

arm

ing

po

ten

tial (k

g C

O2eq

)

GWP - TraditionalGWP - Single useCED - Single use CED - Traditional

Cu

mu

lati

ve e

nerg

y d

em

an

d (

MJe

q)

Figure 2: Cumulative energy demand (CED) and global warming potential (GWP) for

the production of a monoclonal antibody in a full process train at 2000-L scale with

assumed mAb titre of 6 g/L. Impacts grouped by life cycle stage (supply chain, use

phase, and end-of-life).



ogy is adapted to the existing facility.

A variety of single-use technology from

different manufacturers is available. This

study systematically used GE technology

(i.e., WAVE Bioreactor system and Rea-

dyToProcess components) wherever ap-

propriate due to the greater availability

of internal data, and to support an effort

to identify opportunities for environmen-

tally conscious product design.

This study did not address any poten-

tial differences in labor requirements.

Life-cycle inventory analysis

The main body of data used in this study

was derived in collaboration with Bio-

Pharm Services and can be considered

industry average based on a combination

of primary and secondary sources. Data

on production of single-use components

were obtained primarily from GE Health-

care. Data on transportation, packaging,

and end-of-life were gathered through a

combination of supplier data (GE Health-

care) and expert interviews. Additional

secondary data were obtained from the

ecoinvent 2.2 life-cycle inventory data-

base (11).

The life-cycle assessment models were

developed in SimaPro Analyst version

7.2.4 life-cycle assessment software (12).

The inventory data were analyzed using

several impact assessment methodolo-

gies. Cumulative energy demand (CED)

3,000,000

Cu

mu

lati

ve

en

erg

y d

em

an

d(M

Jeq

)G

lob

al

wa

rmin

g p

ote

nti

al

(kg

CO

2e

q)

2,500,000

1,500,000

2,000,000

1,000,000

500,000

Single use

Traditional

Single use

Traditional

160,000

140,000

120,000

100,000

80,000

60,000

40,000

20,000

Support

CIP

/SIP

system

UP

01 Fer

men

tatio

n (N-2

)

UP

02 Fer

men

tatio

n (N-1

)

UP

04 D

epth

filtr

atio

n cla

rifica

tion

UP

05 B

ioburd

en re

ductio

n I

UP

06 P

rote

in A

UP

07 V

irus i

nactiv

atio

n

UP

08 B

ioburd

en re

ductio

n II

UP

09 N

o tank

bioburd

en re

ductio

n

UP

10 C

aptu

re IE

X

UP

11 Flo

w th

rough IE

X

UP

12 V

iral fi

ltrat

ion

UP

13 U

F/DF

UP

14 Ste

rile

filtrat

ion II

UP

03 B

iore

acto

r

0

0

Figure 3: Cumulative energy demand (CED) and global warming potential (GWP) for

the production of a monoclonal antibody in a full process train at 2000-L scale with

assumed mAb titre of 6 g/L. Impacts displayed by unit operation.



was calculated using the Cumulative En-

ergy Demand v1.07 method and includes

the total life cycle energy requirements

including production and distribution of

energy that is consumed across the life

cycle, reported in units of megajoule-

equivalents (MJ-eq). Lifecycle global

warming potential (GWP) was calculat-

ed using the IPCC 2007 100a method and

is reported as CO2-equivalents (CO

2-eq),

including all greenhouse gases specified

in the Kyoto Protocol using 100 -year time

horizon global warming potentials from

the Intergovernmental Panel on Climate

Change 4th Assessment Report (13).

Water usage (withdrawal) is reported in

kilograms (kg) and was calculated using

a custom impact assessment method that

evaluates the withdrawal of freshwater

(and saltwater, if any) across the lifecy-

cle of the system being studied.

Key assumptions

To maintain sterility, traditional durable

equipment must be cleaned and steamed

in place (CIP/SIP) between each batch.

This requires a large amount of process

water, water for injection (WFI), acids,

and bases. The energy and supporting

equipment required are all considered

in this analysis. Single-use components

that contact media do not require rig-

orous cleaning and sterilization, but

instead are pre-sterilized by off-site Co-

balt-60 irradiation. The transport of sin-

gle-use components to and from the fa-

cility is included as well as the facility’s

operating energy, the Co-60 source, and

the concrete required for the irradiation

cell. These impacts are allocated to each

irradiated component as a mass fraction

of irradiation facility throughput.

The traditional durable equipment is

(200,000,000)

Single use Traditional

Supply chain Use phase End of life

Wate

r u

sag

e (

kg

)

200,000,000

400,000,000

600,000,000

800,000,000

1,000,000,000

Figure 4: Water usage for the production of a monoclonal antibody in a full process train

at 2000-L scale with assumed mAb titre of 6 g/L. Impacts grouped by life cycle stage

(supply chain, use phase, and end-of-life).



nominally assumed to have 10 -year

lifetimes, after which 25% of the equip-

ment is re-used while the remainder is

either recycled (90%) or landfilled (10%).

600,000,000

500,000,000

400,000,000

300,000,000

200,000,000

100,000,000

Single use

Traditional

Wate

r u

sag

e (

kg

)

Support

CIP

/SIP

system

UP

01 Fer

men

tatio

n (N-2

)

UP

02 Fer

men

tatio

n (N-1

)

UP

04 D

epth

filtr

atio

n cla

rifica

tion

UP

05 B

ioburd

en re

ductio

n I

UP

06 P

rote

in A

UP

07 V

irus i

nactiv

atio

n

UP

08 B

ioburd

en re

ductio

n II

UP

09 N

o tank

bioburd

en re

ductio

n

UP

10 C

aptu

re IE

X

UP

11 Flo

w th

rough IE

X

UP

12 V

iral fi

ltrat

ion

UP

13 U

F/DF

UP

14 Ste

rile

filtrat

ion II

UP

03 B

iore

acto

r

Figure 5: Water usage for the production of a monoclonal antibody in a full process train

at 2000-L scale with assumed mAb titre of 6 g/L. Impacts displayed by unit operation.

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The single-use process trains contain

components that are designed to be used

once and then discarded. The exceptions

are the replacement of single-use chro-

matography columns, which are typi-

cally reused for several batches depend-

ing on the number of cycles per batch.

In this case, a recommended usable life

for a ReadyToProcess Capto S 2.5 chro-

matography column is 20–50 cycles. The

LCA model assumed 7 cycles per batch

for Protein A and 5 cycles per batch for

ion exchange chromatography (at 2000 -

L scale). The number of cycles for tradi-

tional chromatography is assumed to be

two cycles per batch for both Protein A

and ion exchange chromatography.

Several assumptions were made regard-

ing treatment at end-of-life. For single-use

components such as cellbags, �lters, and

connectors, disposal was assumed to oc-

cur by hazardous waste incineration with-

out waste heat recovery. Non-hazardous

waste was sent to land�ll or wastewater

treatment. Process water was assumed to

be used once without recovery.

Use-phase electricity was assumed to be

from an average US grid mix. Selection of

an average European electricity grid mix

exhibits lower environmental impacts but

does not lead to any discernable shift of

relative magnitudes between single-use

and traditional process technology.

The fuel mix for generation of WFI was

composed of different ratios of fuel oil,

natural gas and electricity. The default

mixture was equally weighted for fuel oil

and natural gas at 45% each while elec-

tricity was weighted at 10%.

Sensitivity and uncertainty analyses

The sensitivity of the LCA results to

variations in key assumptions was exten-

sively analyzed using a Plackett-Burman

experimental design. Lifetime of durable

equipment was varied from 5–25 years.

Chromatography column lifetimes were

varied from 10–100 cycles. Transporta-

tion distances were varied from 5–25

miles (local), 1000–5000 miles (domes-

tic), and 1500–7500 miles (international).

Different ratios of WFI fuel mixes were

examined. Equipment reuse was varied

from 0–25%. Equipment recycling was

varied from 50–100%. Co-60 irradiation

facility parameters were varied as well.

None of the variations in key assumptions

had a signi�cant effect on the study con-

clusions. The detailed results of the sen-

sitivity and uncertainty analyses will be

reported in a subsequent publication.

results and disCussion

Figure 2 shows the cumulative energy

demand (CED) and global warming

potential (GWP) for single-use versus

traditional durable process technology

for the full process train with a 2000 -L

working volume. The results are cat-

egorized by life-cycle stage. The sup-

ply chain phase includes materials and

manufacturing of all process equipment

and consumables required to support a

10 -batch mAb production campaign. The

use phase includes all impacts that occur

during mAb production, including clean-

ing and sterilization of traditional du-

rable equipment between batches. The

end-of-life phase includes the disposal

of consumables and the disposal, re-use,

or recycling of allocated portions of du-

rable components.

A substantial majority of the life cycle

environmental impacts occur during the



use phase. Note that the comparative

CED and GWP results are very similar

because almost all of the GWP is related

to energy production and consumption.

The single-use process train exhibits

38% lower GWP during use phase (and

34% lower GWP across all life-cycle stag-

es) compared to a traditional durable

process train. The corresponding re-

duction in CED is 38% during use phase

and 32% across all life-cycle stages. Sup-

ply chain GWP and CED impacts are

slightly higher for single-use compared

with traditional process technology due

to the increased manufacturing required

to provide the consumable components

used in a single-use approach. However,

supply-chain impacts represent <11% of

the life-cycle CED impact and <5% of the

life GWP impact. Environmental impacts

from the end-of-life stage represent <1%

of overall life cycle impacts.

Figure 3 shows the CED and GWP im-

pacts for single-use vs. traditional process

technology categorized by unit operation.

The most substantial impacts (38–40% of

both GWP and CED) are related to the

support CIP/SIP system, which includes

the CIP/SIP infrastructure and common

support activities such as process water

and HVAC requirements (the main dif-

ference between process approaches in

this category is the amount of energy re-

quired to generate WFI and steam). The

use of single-use process technology ex-

hibits lower CED and GWP impacts com-

pared to traditional durable technology in

all unit operations except Protein A and

ion-exchange chromatography, which are

higher for single-use since several single-

use columns must be used in parallel to

reach this scale.

Figure 4 shows water usage catego-

rized by life cycle stage. Substantial wa-

ter savings are realized during the use

phase for single-use process technol-

ogy due to the reduction or elimination

of cleaning and sterilization between

batches. Figure 5 shows water usage cat-

egorized by unit operation. As expected,

water usage is dominated by activities

related to the support CIP/SIP system.

Single-use process technology exhib-

its lower water usage in all unit opera-

tions except Protein A and ion exchange

chromatography, again due to the need

for parallel chromatography columns at

this scale. Note also that the majority of

water usage in the UP 03 Bioreactor is

for media, so the primary water usage

savings of single-use process technol-

ogy is due to the shift from steam heat-

ing to electrical heating. The negative

water usage during the end-of-life stage

ref lects credit related to the re-use and

recycling of durable components.

The results in Figures 2–5 focus on the

2000 -L working volume scale. Similar

results were obtained at 100 -L and 500 -L

scales, and the process technology com-

parisons discussed in this section apply

to all three scales.

ConClusions and

reCoMMendations

The study has shown that a shift from tra-

ditional durable process technology to

single-use process technology can result in

substantial reductions in cumulative energy

demand, global warming potential, and wa-

ter usage for the production of monoclonal

antibodies, in addition to improving flex-

ibility and productivity. Although single-use

process technology introduces a need for



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the production, distribution, and disposal of

single-use components, this approach also

reduces or eliminates the need for large

quantities of steam, process water, and wa-

ter for injection. The LCA model developed

for this study is dynamic and offers the po-

tential for further exploration of different

bioprocess conditions and “what if” sce-

narios. The detailed insights gained in this

comprehensive study offer the potential for

further improvements in environmentally

conscious product and process develop-

ment for biopharmaceutical manufacturing.

referenCes

1. C. Mintz, “Single-use, disposable products: A ‘state of the industry’ update”, Life Science Leader, July 29 (2009), www.medicaldesignonline.com/download.mvc/Single-Use-Disposable-Products-A-State-Of-0001?user=20&source=nl:24985#, accessed Sept. 14, 2011.

2. M. Fuller and H. Pora, BioProcess Int. 6 (10), 30–36 (2008).

3. H. Haughney and J. Hutchinson, Gen.

Eng. News, 24 (8) 2004. 4. L. Leveen, Amer. Pharma. Review, 12

(6), 72–78 (2009).

5. A. Sinclair et al,. supplement to

BioPharm International 21 (11), s4–s15 (2008).

6. M. Mauter, BioProcess Int. 7 (3), 18–29 (2009).

7. B. Rawlings and H. Pora, BioProcess

Int. 7 (2), 18–25 (2009). 8. ISO 14040, Environmental

management —Life cycle Assessment—Principles and Framework, 2006.

9. ISO 14044, Environmental management —Life cycle Assessment—Requirements and Guidelines, 2006.

10. Dr. Pascal Lesage (researcher, CIRAIG), Dr. Dirk Böhm (director, large-scale biotech operations, Merck Serono), Ekta Mahajan (senior engineer, Genentech Inc.)

11. ecoinvent Centre, The Life Cycle Inventory Data version 2.2. Swiss Centre for Life Cycle Inventories (2010).

12. PRe Consultants, http://pre.nl.13. IPCC, “Climate Change 2007:

The Physical Science Basis,” contribution of working group I to The Fourth Assessment Report of

the Intergovernmental Panel on

Climate Change, S. Solomon, et al., Eds, (Cambridge University Press, Cambridge, United Kingdom, and New York, NY, USA, 2001). BP

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