In vitro diagnostics (IVD) is the analysis of medical

samples, such as blood, tissues, or urine, that are taken

from patients or healthy individuals. After a medical
examination, one of the first steps is often to take a
blood sample and send it to the laboratory to carry out
a number of tests. These are IVD tests because many
were originally performed in a test tubein vitro is
Latin for in glass. IVD tests are used to make a correct
diagnosis for proper treatment (evidence-based
medicine), but are also used extensively to follow up
the treatment.
The IVD Directive
The IVD Directive (98/79/EC)
1
is the third in a series
of European Directives on medical devices intended to
provide regulations for the safe manufacture, supply,
and use of devices in Europe. It has 24 articles and 10
annexes. The articles cover general items such as
scope and definitions, placing products on the market
and putting them into service, free movement of CE-
marked goods in European Union (EU) countries, ref-
erence to harmonized standards, vigilance and inci-
dent reporting, conformity assessment procedures,
registration responsibilities, authorized representative,
consequences of wrongly affixed CE marking, confi-
dentiality, etc. The purpose of the IVD Directive is to
ensure that only safe and functional products are sold
in the European market, with clearly outlined regula-
tions regarding manufacture, importing, and market-
ing. The Directive was published on December 7,
1998, and has been in effect since June 7, 2000. After
December 7, 2003, IVD products offered for sale in EU
member countries were required to conform to IVD
Directive requirements and to be IVD CE marked. In
the U.S.A., similar regulations have been in effect for
many years, as implemented by the FDA. However,
Europe places more emphasis on risk analysis than
other regulated markets.
IVD manufacturers
The European Diagnostic Manufacturers Association
(EDMA)
2
is the trade association that represents the
IVD (medi cal testi ng) i ndustry i n Europe. The
EDMA designates the IVD manufacturer as a pro-
ducer of analytical instruments and reagents for IVD
tests. The analytical instruments are the equipment
that automate the process and measure the result. Ac-
cessory products, such as the software programs used
to run the instrumentation, and control solutions to
check the performance of the systems, are also pro-
duced by the IVD industry. Together, the reagents, in-
struments, and accessories are referred to as in vitro
diagnostic systems.
Requirements of
manufacturers
All IVD devices must meet the essential require-
ments, which include both technical and labeling re-
quirements. The devices must be designed and man-
ufactured in such a way that, when used under the
conditions and for the purposes intended, they will
not compromise, directly or indirectly, the clinical
condition or the safety of the patients, the safety or
health of users or, where applicable, other persons, or
the safety of property.
1
Under Directives 93/42/EEC and 98/79/EC, a tech-
nical file for every IVD device must include risk
management, verification, and validation data.
The volume of technical documentation required
is proportionate to the risk category of the device.
The greater the risk, the higher the level of exter-
nal review required by an independent third party
called a notified body.
3
The philosophy of new ap-
proach European directives is based on the man-
agement of risk. Therefore, risk management is
probably the most important task within the tech-
nical documentation.
The risk analysis should look at the risks to the user,
the patient, third parties such as delivery and ser-
vice personnel, as well as possible damage to the en-
vironment. In order to determine the possible risk of
a device, there is a classification system of four lev-
els of risk requiring different actions on the part of
the manufacturer: 1) general (products not included
in the groupings below); 2) products for self-testing;
3) Annex II, List A (blood groups HIV [1 and 2];
HTLV I and II; and Hepatitis B, C, and D); and 4)
In Vitro Diagnostics (IVD) Compliance
and What It Means In Practice
by Sari Mannonen and Seppo Riikonen
Reprinted from American Biotechnology Laboratory August 2006
Annex II, List B (blood groups chlamydia, rubella,
cytomegalovirus, prostate specific antigen [PSA],
and toxoplasmosis).
All devices not listed in Annex II are
perceived to pose less risk. Pipettors
belong to this group (Class 1, gen-
eral). These devices do not require
the involvement of an independent
third partya certification body.
Even if the devices do not necessitate
third-party certification, manufactur-
ers must still operate a certified qual-
ity system for production and apply
the conformity procedures.
Medical device manufacturers must
operate and maintain a systematic
procedure to review postmarket surveillance. This can
include customer feedback, customer satisfaction stud-
ies, reaction from focus groups, or marketing surveys,
and should be in response to the design management.
Manufacturers must also implement preventive and
corrective action (CAPA) processes as a part of their
certified Quality Management System.
ISO 13485 and audit by the
ISO 9001 is a good starting point for applying ISO
13485, the quality management system for IVD medi-
cal devices. It could easily take 18 months to prepare all
the documentation and validation data required for the
documentation review. The audit will review both the
quality system requirements of ISO 9001/ISO 13485
and the technical documentation for IVD Directive
98/79/EC (Figure 1). There is normally a six-week pe-
riod after the initial audit to implement necessary
CAPA processes to close the possible findings. All
findings must close within three months of the initial
audit. Depending on the products being reviewed, the
assessment may consist of a team of auditors who may
visit multiple sites contingent on the nature of the or-
ganization and the activities it undertakes.
IVD medical devices
An IVD diagnostic medical device is defined by the
IVD Directive as any medical device which is a
reagent, reagent product, calibrator, control material,
kit, instrument, apparatus, equipment or system
whether used alone or in combination, intended by the
manufacturer to be used in vitro for the examination of
specimens including blood and tissue donations, de-
rived from the human body, solely or principally for the
purpose of providing information concerning a physio-
logical state of health or disease or congenital abnor-
mality or to determine the safety and compatibility
with potential recipients. The Directive applies
within the European Union and affects all clinical lab-
oratories performing human diagnostics. Pipettors are
generally understood to be general-purpose laboratory
equipment and are not included in the IVD or Medical
Device Directive. However, when pipettors and tips are
used in combination with IVD equipment or diagnostic
Figure 1 A certification body, Det Norske Veritas (DNV), has
audited Biohit production processes (a) to be compliant with IVD
Directive and ISO 9001/ISO 13485 (b).
a
b
a b
Figure 2 IVD CE-mark (a) and Biohit ISO 9001/ISO 13485/ISO 14001 mark (b).
certification body
ISO 9001 is a good starting point for applying ISO
13485, the quality management system for IVD medi -
cal devices. It could easily take 18 months to prepare all
the documentation and validation data required for the
documentation review. The audit will review both the
quality system requirements of ISO 9001/ISO 13485
and the technical documentation for IVD Directive
98/79/EC (Figure 1). There is normally a short transi-
tion period after the initial audit to implement neces-
sary CAPA processes to close the possible ndings. All
ndings must close within three months of the initial
audit. Depending on the products being reviewed, the
assessment may consist of a team of auditors who may
visit multiple sites contingent on the nature of the or-
ganization and the activities it undertakes.
tests, the pipettor and tip used are regarded as an IVD
accessory. In these cases, it is extremely important to
have IVD compliance for the entire system. This is sel-
dom fully understood and realized. Why certify/accredit
the test method or application, procedure, and analyzer
if the results may be jeopardized by having a low-qual-
ity, noncertified pipettor or a tip that might be the
largest source of error in the test system? Moreover,
since blood group determination and HIV tests are de-
fined as to highest-risk class (List A) for IVD products,
these reagents should be pipetted with a pipettor and
tips that are certified for IVD as well.
As such, general laboratory equipment is excluded from
the IVD Directive. However, if the products sold for
general laboratory use are employed for diagnostic ap-
plications, they must be validated accordingly. Require-
ments exist for manufacturers to sell devices in an ap-
propriate manner, and for users to select devices
suitable for diagnostic applications.
CE mark for conformity and
safety
The CE mark is a declaration by the manufacturer that
the product meets all of the provisions of the relevant
legislation implementing certain European Directives.
The CE mark is a mandatory European symbol for
specified product groups to indicate conformity with
the essential health and safety requirements set out in
European Directives. CE stands for Conformit Eu-
ropenneFrench for European conformity. Elec-
tronic devices, such as electronic pipettors, need to
have the CE mark according to the Electromagnetic
Compatibility Directive (EC Council Directive
89/336/EEC). This CE mark only proves that the de-
vice is electrically safe to use, and is not the same as
the IVD CE mark.
IVD CE mark
It is possible to declare the IVD CE mark by self-certi-
fication for Class I devices, such as pipettors. How-
ever, even if a certification body is not involved, every
manufacturer has to fulfill both the essential require-
ments in accordance with Annex I and complete a
Declaration of Conformity in accordance with the Di-
rective. In addition, manufacturers that are not EU
based must apply for the CE mark via an authorized
representative as per Article 14.2 of the Medical De-
vice Directive (93/42/EEC) and IVD Directive
(98/79/EC, Article 1). The IVD CE mark (Figure 2)
guarantees that the products meet identical quality
and purity requirements and thus guarantee maximum
reproducibility for experiments and analyses.
Non-Annex II devices
The IVD Directive has created the fundamental basis
to ensure that the quality of high-risk products is
tested and confirmed by a neutral third partya no-
tified body. Biohit Oyj (Helsinki, Finland) is one of
the few companies that is able to certify all of its liq-
uid handling devices, including electronic and me-
chanical pipettors and disposable tips, according to
IVD Directive 98/79/EC. Instead of self-certifying,
the company is ISO 9001/ISO 13485 audited and
certified by a certification body (Figure ). In addi-
tion, several global IVD manufacturers for whom the
company produces OEM products make regular IVD
audits to make sure that their OEM products fulfill
the IVD requirements. An IVD CE mark is printed in
each Biohit product or users manual (Figure 2 ). Un-
fortunately, some manufacturers print the CE mark
without knowing what it stands for and some have
self-certified themselves without having had a noti-
fied body audit. To be certain that the printed CE
mark is a symbol of the EC Directive, one should ask
the manufacturer to provide a CE certificate, which
should state where the products have been registered
and which certification body (Figure 1b) has granted
the certification. The CE registration must be done
in the same country in which the business of the
manufacturing company is registered.
Conclusion
Competent authorities may audit the technical docu-
mentation and manufacturing process of the IVD CE-
marked low-risk products even if the manufacturer is
self-certifying the products without having the benefit
of an audit by a notified body. These notified body au-
dits can result from feedback filed by a competitor or
end user, or audits may be done at random by the au-
Figure 3 All Biohit products, including electronic and me-
chanical pipettors and disposable tips, are certified according to IVD
Directive 98/79/EC.
1b
a
thorities. If the technical documentation is incom-
plete, the authority can force the manufacturer to re-
move the product from the market until the documen-
tation and processes conform to IVD requirements and
the revised documentation has been reviewed. There-
fore, the medical device manufacturer should always
maintain the detailed technical documentation to
demonstrate conformity with the essential require-
ments of the IVD Directive, including traceability of
the delivered products.
Health and safety officers today are well aware of the
duties of manufacturers and compliance with the law.
Laboratory managers look for reassurance that the pur-
chased products meet the high end-user expectations
and fulfill the current international and national stan-
dards and laboratory requirements. Most laboratories
are not only ISO 9001 or GLP certified, but also ac-
credited (ISO 17025) and IVD compliant. It makes
sense to demand the same from pipettors and tips. En-
suring that the pipettor and tips purchased are not only
manufactured according to ISO 9001/13485/14001 and
CE marked according to IVD reduces the risk of erro-
neous results. To make certain that the IVD product is
classified correctly and that the documentation is accu-
rately compiled, it is important that the company has
been audited by a certification body and that there is
documentation to support this.
References
1. In Vitro Diagnostic (IVD) Directive (98/79/EC),
http://europa.eu.int.
2. European Diagnostic Manufacturers Association
(EDMA), www.edma-ivd.be.
3. Notified bodies: http://europa.eu.int/comm/enterprise/
newapproach/legislation/nb/notified_bodies.htm.
Dr. Mannonen is Vice President, Sales and Marketing, and Mr. Ri-
ikonen is Director, Quality & Process Development, Biohit Oyj,
Laippatie 1, Helsinki 00880, Finland; tel.: +358 9 773 861; fax:
+358 9 773 86 200; e-mail: seppo.riikonen@biohit.com.
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CE/IVD compliant liquid handling system with Biohit pipettors and tips
For further information and a list of distributors visit www.biohit.com