1. IN PERSON
IVD Technology: What have been the
biggest technological advances in
assay development during the past
few years?
Fabrice Sultan: Assay development
continues to challenge the IVD indus-
try, which must bring accurate, reliable,
robust, and cost-effective assays from
the conceptual phase to the end-user.
The use of magnetic microspheres
and polymer beads as the solid phase in
automated immunoassays—resulting in
automation, faster reactions, increased
sensitivity, and shorter time per assay—
has been one of the biggest technologi-
cal advances. The technical capability
to develop and produce, on an industri-
al scale, one bead or one microsphere
for one application could explain, at
least in part, the increasing demand in
the field of microsphere technology.
For instance, our production capabil-
ities allow us to produce batches larger
than 6 kg for some of our magnetic mi-
crospheres used in immunoassays, and
up to 12 kg for polymer beads used in
immunoturbidimetric assays or latex
agglutination on slides. To produce ef-
ficient and reproducible immobilization
of immunoglobulin or other ligands,
such as proteins, lipids, or polysaccha-
rides, we offer the choice of working on
many different surfaces—hydrophobic
or hydrophilic, carboxyl-modified,
amino-modified, or thiol-modified.
Different surface chemistries, of course,
should be considered and evaluated in
preliminary screening protocols. How-
ever, the solid phase is, without a doubt,
a critical and important part of the assay.
How have magnetic microspheres and
polymer beads contributed to the area
of assay development?
With ELISAs (enzyme-linked im-
munosorbent assays) or with coated
tubes, you can work in two dimensions.
The main advantage of using magnetic
or polymer microspheres is that they
allow you to work in three dimensions,
dramatically increasing the surface and
sensitivity, and the high reaction kinetics
of your assay.
The evolution of assay development
To keep pace with advances in detection technologies,
assay manufacturers must remain resourceful.
Over the last decade, automation and other technological break-
throughs have revolutionized the clinical diagnostics laboratory.
Driven by a demand for both higher throughput and reproducibility, as
well as for lower costs per test and smaller sample size requirements,
instrument manufacturers have made significant progress in alleviat-
ing many former testing bottlenecks.
While these advances have ultimately benefited patient care, they
have also created challenges for assay manufacturers. To take advan-
tage of increased laboratory capability and instrument sensitivity, as
well as refinements to traditional testing methods, new assays must
also continually evolve. In addition, IVD manufacturers need to forge
strong relationships with customers and researchers to be able to an-
ticipate the next trends in assay development,
To learn more about how technology changes are affecting assay
manufacturers, IVD Technology editor Richard Park spoke with Fab-
rice Sultan, PhD, international marketing and sales manager at Estapor
Microspheres, a division of Merck Chimie SAS (Fontenay Sous Bois,
France). In this interview, Sultan discusses the impact of miniatur-
ization, multiplexing, and molecular diagnostics on assays. He also
talks about the state of the European testing market, and how manu-
facturers can—and must—build better research relationships with
academia.
Fabrice Sultan, PhD, is international
marketing and sales manager at
Estapor Microspheres, a division of
Merck Chimie SAS (Fontenay Sous
Bois, France). He can be reached at
fabrice.sultan@merck.fr.
For In Vitro Diagnostics Development & Manufacturing
R
2. Magnetic beads are probably the most
powerful tools for IVD manufacturers
looking to automate their immunoassays
because many types of proteins and lig-
ands can be easily attached to their sur-
faces. And the surface for the reaction
mixture is much higher than with clas-
sical ELISA plates or coated tubes.
What factors must IVD manufactur-
ers consider when developing assays
for their instrument systems?
When developing immunoassays,
IVD manufacturers must consider not
only the accuracy and reproducibility of
a new immunoassay reagent, but also its
stability and ease of adaptation.
We must consider two types of stabil-
ity. The classical stability of the reagent
in the cartridge should be around 12–18
months. And once the cartridge is
opened, the reagent stability should be
at least one or two months.
You can validate a product if you ob-
tain the same reproducibility results.
However, some immunoassay reagents
have a very short stability once the car-
tridge is opened. If a reagent has a shelf
life of 20 or 24 months when the cartridge
is closed, but only two weeks once it is
opened, it can be very difficult to sell.
What other assay development trends
do you see?
The latest trends are geared toward
achieving classical, common goals: sen-
sitivity and signal-to-noise ratio. Both
must be higher than they are now.
Specificity of an immunoassay must
be better. The dynamic range must be
increased, especially if you want to de-
tect a very low concentration of analyte.
Any assay technology that enables the
end-user to eliminate, or at least reduce,
the number of false-positive results is
always extremely advantageous. Also,
the cost of the assay must be lower, to
answer the economic pressures on both
IVD companies and clinical labs, and
also on patients.
From several studies, we know that
labor accounts for 50–70% of the total
cost of tests. The most logical way to re-
duce this cost is the automation of com-
mon bioassays and immunoassays. Of
course, new automated tests can also
show better results than semiautomated
or manual ones.
How can IVD manufacturers address
these challenges?
A complete market survey is essential
before IVD manufacturers begin de-
signing and developing a new assay
product. Of course, a company’s strate-
gy will be different for a me-too product
than for a truly innovative one. For the
first, cost and services are the keys to
success. For the second, manufacturers
need to answer the following questions:
What is the clinical utility of this new
assay? What is the test volume? What
are the sales by geographic region and
the total profits? What market share do
I want to reach? What could be the pos-
sible alternative with a new technology
in the near future?
IVD companies must be faster than
ever and provide a broad menu of diag-
nostic tests. Time to market should be re-
duced to a minimum. It’s very easy now
for some big IVD companies to exter-
nalize part of their R&D to launch new
assays in a shorter period. But the chal-
lenge will be to keep the production
internal.
I can see two main options. IVD com-
panies can employ their own staff and
capabilities, or they can accomplish this
through codevelopment with other com-
panies or with universities. Any type of
collaboration must be a win-win agree-
ment. For example, large companies can
offer name recognition and a worldwide
sales force or distribution network,
which are both key advantages for small
IVD companies. And small IVD com-
panies can offer increased flexibility,
more freedom, and access to intellectu-
al property.
There have been a number of these
types of collaborations. For example,
Roche Diagnostics (Basel, Switzerland)
and Prionics AG (Schlieren, Switzer-
land) have worked together on a test for
bovine spongiform encephalopathy.
Beckman Coulter Inc. (Fullerton, CA)
and R&D Systems (Minneapolis) have
signed an agreement for developing as-
says and assay components for Beck-
man Coulter’s Access immunoassay
systems.
To secure sources of critical raw ma-
terial—both in quality and quantity—
IVD manufacturers should evaluate and
validate two possible suppliers: one
main supplier, and a secondary supplier
for the solid phase, the antibodies, or the
antigen. Of course, for some companies,
secondary antibodies and substrate sup-
plies must be secure, too.
We know that the cost to validate each
critical raw material is very high. But
this is critical for IVD manufacturers.
For security reasons, many IVD compa-
nies now produce their own antibodies
or antigens. And some of them have
their own solid-phase production. Of
course, doing so is much more secure,
but at what cost?
Do you expect IVD manufacturers
to continue forming these types of
collaborations?
Oh, yes. I can add to my examples
others like the ongoing partnership be-
tween Abbott (Abbott Park, IL) and
Axis-Shield Plc (Dundee, UK), as well
as the collaboration between Dade
Behring Inc. (Deerfield, IL) and The
Binding Site Ltd. (Birmingham, UK).
Merck partners with academics in
order to develop new magnetic particles
and polymer beads. We are always work-
ing with our customers to optimize our
products with their immunoassay
reagents.
Partnering with Academia
How important is it for IVD and di-
agnostics component manufacturers
to form relationships with academic
researchers to develop assays?
It’s fundamental to have an excellent
network between IVD manufacturers,
academic researchers, and hospital or
blood bank centers. From our viewpoint,
the majority of IVD manufacturers have
been working with academic researchers
in developing assays. Many new bio-
markers, like NT-proBNP, which has a
clinical utility for acute coronary syn-
drome, have been discovered by acade-
mic researchers. And after this research
has been conducted, diagnostics compa-
IN PERSON
3. nies have the opportunity to add new im-
munoassay reagents to their test menu.
One possibility for IVD manufactur-
ers is to establish, or even share, scien-
tific laboratories. For example, in France
there are a number of Unités Mixtes de
Recherches, or joint research units,
which are very efficient scientific col-
lectives between IVD companies like
bioMérieux or Bio-Rad France and
well-known scientific institutes like the
CNRS (French Center for Scientific
Research). Such collaborations can
increase the possibility of finding
new biomarkers or developing new
immunoassays.
How do IVD manufacturers go about
developing and nurturing these rela-
tionships with academia?
There are a few different ways. A
company can sign financial agreements
with academic researchers—to develop
a new immunoassay on a new biomark-
er, for example. Companies can also as-
sist researchers with grants or fellow-
ships. And again, I think having IVD
staff share the scientific laboratory with
scientific researchers is very important.
These scientists spend two to four
years in our lab working directly with
our R&D department. This is a very
common arrangement in France. We
share the results of the research with the
university.
It is the case in France, as I’m sure it
is in the rest of the world, that researchers
lack money. As a result, they need to find
new ways to obtain financing to contin-
ue their scientific work.
The sense that I get when speaking
with academic scientists is that they
are always seeking out industry
partnerships to commercialize their
projects.
Yes. I think that the development of a
new immunoassay can be viewed as a
two-step process. The first step involves
academics in the discovery of new bio-
markers with clinical utility. And after
some years—because it’s a long
process—it might be possible for a
company to use the results of this re-
search to develop its own immunoassay
reagent.
Adopting Molecular
Diagnostics
How have developments in molecular
diagnostics and pharmacogenomics
affected assay development?
In my opinion, diagnostics develop-
ments using the polymerase chain reac-
tion (PCR) and related methods will
have an impact primarily in the field of
infectious diseases. Immunoassays for
detecting HIV or a specific antigen can
easily be created by using classical
methods.
More and more molecular diagnostic
reagents have come onto the market in
recent years. Instead of detecting an an-
tibody or antigen, these types of tests
bind the nucleic acids from the cells and
amplify them through PCR or a similar
method. The infectious disease is then
detected and computed using the con-
tent of nucleic acid.
But for cardiac markers, en-
docrinology, drugs of abuse, or fertili-
ty tests, molec-ular diagnostics is not
having much of an effect on assay de-
velopment. These are sophisticated
methods. Of course, they are already
being used by many hospitals. But I
cannot think of any IVD manufacturers
that are poised to offer a large menu of
assays that use this kind of technical
approach.
In March of last year, some of the
foundational PCR patents, which are
owned by Roche Diagnostics, began
to expire. As additional Roche PCR
patents enter the public domain, do
you think more IVD companies will
embrace molecular diagnostics?
Probably, yes, because one limit so
far to developing such assays has been
cost. If you have to pay for the develop-
ment and the production, and the mar-
keting and the sales of such reagents—
and then you also have to pay for the
patent—in the end, profits will be very
low. And if the profit is low, many com-
panies might not consider the assays to
be wise investments.
But with the disappearance of fees for
PCR use, we probably will see more and
more molecular diagnostic reagents and
instruments coming onto the market in
the next few years.
How about further into the future?
Do you think that these technologies
will have more of an impact as they
mature? Say, in 10 years from now?
In the next decade, we will likely see
many IVD manufacturers working with
multiplexing assays, quantitative lateral-
flow assays, biochips, biosensors, and mi-
crofluidics. We will also see important
developments in the point-of-care field.
The Next Generation of IVDs
What future assay development chal-
lenges do you anticipate facing?
Miniaturization of immunoassays is
a major goal in medical diagnostics,
but also in food and environmental
analysis. There is an important need for
multiplex analyses with three main char-
acteristics: a high degree of automation,
fast analysis, and a small volume of
sample reagents.
Will IVD manufacturers in the assay
market become more involved with
nanotechnology and microarrays?
Yes, I think so. There’s been a lot of
cooperation in these areas between big
IVD companies working on classical
immunoassay instruments and some
new players in this field. In nanotech-
nology, there have been collaborations
regarding biochips and biosensors, as
well as microfluidics.
The business managers at large diag-
nostics companies have to keep an eye
on these new technologies because they
may prove to be a very efficient way to
reduce the costs of analysis. For exam-
ple, instead of using 10 or 20 ml of blood
to detect the HIV or hepatitis virus, in
the next few years, we may need only
a few microliters. And if the sample is a
few microliters, we will also need only
a few microliters of reagent.
What trends can we expect to see with
the use of magnetic microspheres and
polymer beads in assay development?
We are continuing to develop both
magnetic and polymer beads with new
surfaces in order to allow developers to
optimize and obtain the best reagents. But
we are also working on new types of
beads,suchasthoseusingmolecularprint.
With molecular printing, instead of using
an antibody or an antigen cut onto the
