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9.2 Regulatory Strategy for Medical Devices in the EU 205
Rule 6
All surgically invasive devices intended for transient use are classied as class IIa unless
they:
— are intended specically to control, diagnose, monitor or correct a defect of the heart
or of the central circulatory system through direct contact with those parts of the body,
in which case they are classied as class III,
— are reusable surgical instruments, in which case they are classied as class I,
— are intended specically for use in direct contact with the heart or central circulatory
system or the central nervous system, in which case they are classied as class III,
— are intended to supply energy in the form of ionising radiation in which case they are
classied as class IIb,
— have a biological eect or are wholly or mainly absorbed in which case they are classi-
ed as class IIb or
— are intended to administer medicinal products by means of a delivery system, if such
administration of a medicinal productis done in a mannerthat is potentially hazardous
taking account of the mode of application, in which case they are classied as class IIb.
Rule 7
All surgically invasive devices intended for short-term use are classied as class IIa unless
they:
— are intended specically to control, diagnose, monitor or correct a defect of the heart
or of the central circulatory system through direct contact with those parts of the body,
in which case they are classied as class III,
— are intended specically for use in direct contact with the heart or central circulatory
system or the central nervous system, in which case they are classied as class III,
— are intended to supply energy in the form of ionizing radiation in which case they are
classied as class IIb,
— have a biological eect or are wholly or mainly absorbed in which case they are classi-
ed as class III,
— are intended to undergo chemical change in the body in which case they are classied
as class IIb, except if the devices are placed in the teeth or
— are intended to administer medicines, in which case they are classied as class IIb.
Rule 8
All implantable devices and long-term surgically invasive devices are classied as class IIb
unless they:
— are intended to be placed in the teeth, in which case they are classied as class IIa;
— are intended to be used in direct contact with the heart, the central circulatory system
or the central nervous system, in which case they are classied as class III,
— have a biological eect or are wholly or mainly absorbed, in which case they are classi-
ed as class III,
— are intended to undergo chemical change in the body in which case they are classied
as class III, except if the devices are placed in the teeth,
— are intended to administer medicinal products, in which case they are classied as
class III,
— are active implantable devices or their accessories, in which cases they are classied as
class III,
— are breast implants or surgical meshes, in which cases they are classied as class III,
— are total or partial joint replacements, in which case they are classied as class III,
with the exception of ancillary components such as screws, wedges, plates and instru-
ments or
— are spinal disc replacement implants or are implantable devices that come into contact
with the spinal column, in which case they are classied as class III with the exception
of components such as screws, wedges, plates and instruments.
Figure 9.6 (Continued)
206 9 Medical Devices
ACTIVE DEVICES
Rule 9
All active therapeutic devices intended to administer or exchange energy are classied
as class IIa unless their characteristics are such that they may administer energy to or
exchange energy with the human body in a potentially hazardous way, taking account of
the nature, the density and siteofapplication of the energy,in which case they are classied
as class IIb.
All active devices intended to control or monitor the performance of active therapeutic
class IIb devices, or intended directly to inuence the performance of such devices are
classied as class IIb.
All active devices intended to emit ionizing radiation for therapeutic purposes, including
devices that control or monitor such devices or that directly inuence their performance,
are classied as class IIb.
All active devices that are intended for controlling, monitoring or directly inuencing the
performance of active implantable devices are classied as class III.
Rule 10
Active devices intended for diagnosis and monitoring are classied as class IIa:
— if they are intended to supply energy that will be absorbed by the human body, except
for devices intended to illuminate the patient’s body, in the visible spectrum, in which
case they are classied as class I,
— if they are intended to image in vivo distribution of radiopharmaceuticals or
— if they are intended to allow direct diagnosis or monitoring of vital physiological pro-
cesses, unless they are specically intended for monitoringofvital physiologicalparam-
eters and the nature of variations of those parameters is such that it could result in
immediate danger to the patient, for instance variations in cardiac performance, res-
piration, activity of the central nervous system, or they are intended for diagnosis in
clinical situations where the patient is in immediate danger, in which cases they are
classied as class IIb.
Active devices intended to emit ionizing radiation and intended for diagnostic or ther-
apeutic radiology, including interventional radiology devices and devices which control
or monitor such devices, or which directly inuence their performance, are classied as
class IIb.
Rule 11
Software intended to provide information that is used to take decisions with diagnosis or
therapeutic purposes is classied as class IIa, except if such decisions have an impact that
may cause:
— death or an irreversible deterioration of a person’s state of health, in which case it is in
class III or
— a serious deterioration of a person’s state of health or a surgical intervention, in which
case it is classied as class IIb.
Software intended to monitor physiological processes is classied as class IIa, except if it is
intended for monitoring of vital physiological parameters, where the nature of variations
of those parameters is such that it could result inimmediate danger to the patient, in which
case it is classied as class IIb.
All other software is classied as class I.
Rule 12
All active devices intended to administer and/or remove medicinal products, body liquids
or other substances to or from the body are classied as class IIa, unless this is done in
a manner that is potentially hazardous, taking account of the nature of the substances
involved, of the part of the body concerned and of the mode of application in which case
they are classied as class IIb.
Rule 13
All other active devices are classied as class I.
Figure 9.6 (Continued)
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9.2 Regulatory Strategy for Medical Devices in the EU 207
SPECIAL RULES
Rule 14
All devices incorporating, as an integral part, a substance which, if used separately, can
be considered to be a medicinal product, as dened in point 2 of Article 1 of Directive
2001/83/EC, including a medicinal product derived from human blood or human plasma,
as dened in point 10 of Article 1 of that Directive, and that has an action ancillary to that
of the devices, are classied as class III.
Rule 15
All devices used for contraception or prevention of the transmission of sexually transmit-
ted diseases are classied as class IIb, unless they are implantable or long-term invasive
devices, in which case they are classied as class III.
Rule 16
All devices intended specically to be used for disinfecting, cleaning, rinsing or, where
appropriate, hydrating contact lenses are classied as class IIb.
All devices intended specically to be used for disinfecting orsterilisingmedicaldevices are
classied as class IIa, unlessthey are disinfecting solutions or washer-disinfectors intended
specically to be used for disinfecting invasive devices, as the end point of processing,
in which case they are classied as class IIb.
This rule does not apply to devices that are intended to clean devices other than contact
lenses by means of physical action only.
Rule 17
Devices specically intended for recording of diagnostic images generated by X-ray radia-
tion are classied as class IIa.
Rule 18
All devices manufactured utilising tissues or cells of human or animal origin, or their
derivatives, which are nonviable or rendered non-viable, are classied as class III, unless
such devices are manufactured utilising tissues or cells of animal origin, or their deriva-
tives, which are non-viable or rendered non-viable and are devices intended to come into
contact with intact skin only.
Rule 19
All devices incorporating or consisting of nanomaterial are classied as:
— class III if they present a high or medium potential for internal exposure,
— class IIb if they present a low potential for internal exposure and
— class IIa if they present a negligible potential for internal exposure.
Rule 20
All invasive devices with respect to body orices, other than surgically invasive devices,
which are intended to administer medicinal products by inhalation are classied as class
IIa unless their mode of action has an essential impact on the ecacy and safety of the
administered medicinal product or they are intended to treat life-threatening conditions,
in which case they are classied as class IIb.
Rule 21
Devices that are composed of substances or of combinationsofsubstancesthat are intended
to be introduced into the human body via a body orice or applied to the skin and that are
absorbed by or locally dispersed in the human body are classied as:
— class III if they, or their products of metabolism, are systemically absorbed by the
human body to achieve the intended purpose,
— class III if they achieve their intended purpose in the stomach or lower gastrointestinal
tract and they, or their products of metabolism, aresystemicallyabsorbed by the human
body,
— class IIa if they are applied to the skin or if they are applied in the nasal or oral cavity
as far as the pharynx, and achieve their intended purpose on those cavities and
— class IIb in all other cases.
Rule 22
Active therapeutic devices with an integrated or incorporated diagnostic function that sig-
nicantly determines the patient management by the device, such as closed-loop systems
or automated external debrillators, are classied as class III.
Figure 9.6 (Continued)
208 9 Medical Devices
Rule 6
Surgically invasive-
transient use.
Rule 8
Surgically invasive Long
term use and implantable
devices
Intended to be
placed in teeth
IIa
IIb
III III III III III III III III
Intended to be used in
direct contact with heart
or central circulatoiry/
nervous system
biological effect
or are wholly or
mainly absorbed
Intended to undergo
Chemical change in
body (NOT in teeth)
Intended to
administer
medicinal
products
Active implantable
devices or their
accessoires
Breast implants,
surgical meshes,
total or partial joint
replacement,
except components
such as screws,
wedges, plates and
instruments
Spinal disc
replacement or
implants in contact
with spinal column
ATTENTION
Rule 4 for invasive
devices that come into
contact with injured
mucous membrane.
IIa
IIb
unless
unless
OR
OR OR OR OR OR OR OR OR
OR
OR
OR
OR
OR
OR
OR
I
IIb IIb IIb
III III
Reusable surgical
instrument
Intended to administer
medicines in a
potentially hazardous
manner
Intended to supply
energy/ionizing
radiation
Biological effect-
mainly or wholly
absorbed
Intended specifically for
use in direct contact
with the heart or central
circulatory system or
central nervous system
Intended specifically to
control/diagnose/monitor/
correct a defect or heart or
central circulatory system
through direct contact
Figure 9.7 Illustrative Decision charts for classification of invasive devices. Source: MDCG
2021-24 / European Union/Licensed under CC BY 4.0.
Figure 9.6. The device must be assigned the highest class that applies under the
various rules. Decision charts illustrating the application of classication rules
6 and 8 for invasive devices are shown in Figure 9.7. Refer to MDCG 2021-24
Guidance on classication of medical devices for detailed guidance and examples
of device classication (further reading section at the end of this chapter).
The classication of in vitro diagnostic devices is based on seven rules which are
presented in Figure 9.8. As with general medical devices, the application of the
individual rules is dependent on the intended purpose of the IVD. As a general-
isation, IVDs intended to ensure the safety of blood and tissue donations (blood
grouping and infectious disease tests) are assigned to the highest risk class, while
specimen containers, general reagents and IVD instruments such as automated
immuno-chemistry analysers are placed in the lowest risk class, whereas the
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9.2 Regulatory Strategy for Medical Devices in the EU 209
Rule 1
Devices intended to be used for the following purposes are classied as class D:
— detection of the presence of, or exposure to, a transmissible agent in blood, blood
components, cells, tissues or organs, or in any of their derivatives, to assess their
suitability for transfusion, transplantation or cell administration;
— detection of the presence of, or exposure to, a transmissible agent that causes a
life-threatening disease with a high or suspected high risk of propagation;
— determining the infectious load of a life-threatening disease where monitoring is
critical in the process of patient management.
Rule 2
Devices intended to be used for blood grouping, or tissue typing to ensure the immunolog-
ical compatibility of blood, blood components, cells, tissue or organs that are intended for
transfusion or transplantation or cell administration, are classied as class C, except when
intended to determine any of the following markers:
— ABO system [A (ABO1), B (ABO2), AB (ABO3)];
— Rhesus system [RH1 (D), RHW1, RH2 (C), RH3 (E), RH4 (c), RH5 (e)];
— Kell system [Kel1 (K)];
— Kidd system [JK1 (Jka), JK2 (Jkb)];
— Duy system [FY1 (Fya), FY2 (Fyb)];
in which case they are classied as class D.
Rule 3
Devices are classied as class C if they are intended:
(a) for detecting the presence of, or exposure to, a sexually transmitted agent,
(b) for detecting the presence in cerebrospinaluid or blood of an infectiousagent without
a high or suspected high risk of propagation,
(c) for detecting the presence of an infectious agent, if there is a signicant risk that an
erroneous result would cause death or severe disability to the individual, foetus or
embryo being tested, or to the individual’s ospring,
(d) for pre-natal screening of women to determine their immune status towards transmis-
sible agents,
(e) for determining infective disease status or immune status, where there is a risk that
an erroneous result would lead to a patient management decision resulting in a
life-threatening situation for the patient or for the patient’s ospring;
(f) to be used as companion diagnostics,
(g) to be used for disease staging, where there is a risk that an erroneous result would
lead to a patient management decision resulting in a life-threatening situation for the
patient or for the patient’s ospring,
(h) to be used in screening, diagnosis, or staging of cancer,
(i) for human genetic testing,
(j) for monitoring of levels of medicinal products, substances or biological components,
when there is a risk thatan erroneous result will lead to a patient managementdecision
resulting in a life-threatening situation for the patient or for the patient’s ospring,
(k) for management of patients suering from a life-threatening disease or condition,
(l) for screening for congenital disorders in the embryo or foetus and
(m) for screening for congenital disorders in new-born babies where failure to detect and
treat such disorders could lead to life-threatening situations or severe disabilities.
Rule 4
(a) Devices intended for self-testing are classied as class C, except for devices for the
detection of pregnancy, for fertility testing and for determining cholesterol levels, and
devices for the detection of glucose, erythrocytes, leucocytes and bacteria in urine,
which are classied as class B.
(b) Devices intended for near-patient testing are classied in their own right.
Figure 9.8 The rules for classification of IVDs.
210 9 Medical Devices
Rule 5
The following devices are classied as class A:
(a) products for general laboratory use, accessories that possess no critical characteristics,
buer solutions, washing solutions, and general culture media and histological stains,
intended by the manufacturer to make them suitable for in vitro diagnostic procedures
relating to a specic examination;
(b) instruments intended by the manufacturerspecicallyto be used for in vitrodiagnostic
procedures;
(c) specimen receptacles.
Rule 6
Devices not covered by the above-mentioned classication rules are classied as class B.
Rule 7
Devices that are controlled without a quantitative or qualitative assigned value are
classied as class B
Figure 9.8 (Continued)
diagnostic reagents used on the instruments will be assigned to the relevant class
based on its intended purpose.
9.3 Regulatory Strategy for Medical Devices in the US
Regulation of medical devices in the US was introduced with the Medical Device
Amendments to FDC Act in 1976. These are supported by regulations published in
21 CFR parts 800–899. The Center for Devices and Radiological Health (CDRH) is
the responsible section within the FDA for regulation of devices.
9.3.1 Classification of Devices
As in Europe, classication of devices plays a central role in the regulation of
devices in the US. However, there are a number of dierences compared to the
European approach. First of all, responsibility for classication rests with the
FDA rather than with manufacturers. When the regulations were introduced,
the FDA mandated expert advisory panels (classication panels) to consider the
dierent types of devices that existed on the market at that time. The FDA provided
classication questionnaires to act as guidelines for the panels when assessing
the devices. In determining the safety and eectiveness of a device for purposes
of classication, the classication panels had to consider the intended user, the
intended use/conditions of use, the risk-to-benet ratio, and the reliability of the
device. Proposals for classication of devices that could be grouped based on shared
intended use and technical features were passed on to the FDA Commissioner,
together with recommendations for exemptions or application/development of
appropriate performance standards. After nal consideration by the FDA, ocial
classications and ancillary information relating to regulation of the device types
were published as regulations in 21 CFR Parts 862–892. The outcome of this process
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9.3 Regulatory Strategy for Medical Devices in the US 211
was that all medical devices, irrespective of their type, were classied into one of
three classes.
9.3.1.1 Class I
Class I devices are considered low-risk devices and represent approximately 50% of
all devices regulated by the FDA. A device is assigned to Class I if general controls
are sucient to provide reasonable assurance as to the safety and eectiveness of
the device. Devices that are not life-supporting or life-sustaining or for a use which
is of substantial importance in preventing impairment of human health, and which
do not present a potential unreasonable risk of illness or injury may also be placed in
Class I, even if there is insucient information available to determine if additional
controls are necessary to assure safety and eectiveness. The general controls which
Class I devices are subject under the FDC act include sections 501 adulteration
(contamination/cleanliness), 502 misbranding (false or misleading claims), 510
registration (establishment registration, inspection, pre-market notication),
516 banned devices, 518 notication and other remedies (administrative actions
on defective devices), 519 records and reports (reporting of defects and adverse
incidents) and 520 general provisions (good manufacturing practices as dened by
the Quality System Regulation). In practice, most Class I devices are exempt from
the pre-market notication requirements of section 510k of the act unless they
are life-supporting, life-sustaining or for a use that is of substantial importance in
preventing impairment of human health, while some devices may also be exempt
from compliance with the Quality System Regulation.
9.3.1.2 Class II
Class II devices areviewed as moderate-risk devices and representthe majority of the
remaining devices. Adevice is assigned to Class II if there is sucientinformation to
establish special controls to augment the general controls and so provide reasonable
assurance of the safety and eectiveness of the device. The special controls include
the use of performance standards, the issuing of guidance documents and other
measures as appropriate. The FDA themselves may develop performance standards,
which following consultation, are published in the Federal Register. Alternatively,
they can recognise existing standards developed by national or international bod-
ies in similar fashion to the harmonised standards recognition procedure practised
by the EU. Class II devices are generally subject to 510k pre-market notication
requirements unless they have been specically deemed to be exempt. The FDA
website maintains a database of 510k exempt devices which can be accessed from
their website.
9.3.1.3 Class III
Class III devices are considered high-risk and are usually technologically innovative
devices. A device is assigned to Class III if it is considered that a combination of
general and special controls is not sucient to assure the safety and eectiveness
of the device and it is life-supporting, life-sustaining, for use that is of substantial
importance in preventing impairment of health or presents a potential unrea-
sonable risk of illness or injury. Classication of implants or life-supporting or
life-sustaining devices as other than Class III requires a positive justication for not
212 9 Medical Devices
doing so. All Class III devices must go through a pre-market approval process to
establish the safety and eectiveness of the device.
9.3.2 Classification of New Devices
Manufacturers of new devices can determine the classication of their device by
comparing its intended use and technological features to those of device types that
have been already classied. The CDRH section of the FDA website contains a
database of existing classications that can be easily searched. Careful attention
must be paid to the intended use in particular, as this can have a big bearing on how
a device is regulated. For example, a HCG test system for detection of pregnancy
is regulated as a Class II device whereas a HCG test system for any other purpose
such as detection or monitoring of certain types of cancer is regulated as a Class III
device. The trawl of device classications will usually result in the identication of
an existing device type that is ‘substantially’ equivalent to the new device, enabling
the same classication to be applied. However,in cases of technologically innovative
devices, it may not be possible to identify an existing predicate device. The device
will be viewed by default as a Class III device in such circumstances. However,
a manufacturer of a new or indeed an existing Class III device may petition the
FDA for a down-classication based on supporting objective scientic evidence as
to its safety and eectiveness. The FDA itself is also pro-active in the re-assessment
of Class III devices as market experience is gained as regards their performance,
reliability and safety.
9.4 Development of Devices
The development of drugs and devices share a common goal of producing prod-
ucts that are safe and eective. However, they dier in the approaches used for
product development. Drugs rely heavily on research to identify new active sub-
stances, which are then subjected to extensive testing to establish their safety and
eectiveness. The development of devices on the other hand relies on the applica-
tion of technology to realise a product that meets an identied need. Thus, good
design processes are central to the creation of devices that are capable of satisfying
user needs and regulatory requirements.
Some form of quality system must be employed to ensure that devices satisfy the
regulatory requirements for safety and eectiveness. At its most basic, a quality
system may be applied to nal test and inspection of nished product. However,
signicant product failure at this stage in the manufacturing process will be quite
costly, as most of the labour, raw material and other manufacturing overheads
will have been added to the product by this time. By applying a quality system
to the complete manufacturing process the risk and cost of product failures can
be reduced. This focuses on ensuring that all raw materials are suitable and that
manufacturing processes are robust and reliable. Thus, problems can be identied
at an early stage, before signicant manufacturing cost is incurred. Manufacturing
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9.4 Development of Devices 213
Design and development Manufacture Finished product
Cost (raw materials, labour, overheads)
Full quality assurance system
Design controls Manufacturing QA QC testing
Process flow
Figure 9.9 Illustration of the principle of the application of a full quality assurance system
to minimise product failures and reduce cost.
QA systems are essential to assure processes such as sterilisation or freeze-drying,
where a strategy of nal inspection of all product cannot be used because of the
destructive nature of the testing (breaking of seals). However, a manufacturing
QA system is not focused to eliminate problems inherent in the design of the
products. Unfortunately, many device failures on the market have been traced back
to shortcomings in the initial design. The most eective way to address this is to
employ a full quality assurance system that covers both design and manufacture.
By applying the design control elements of a full QA system, problems with the
design can be identied and eliminated at the earliest stage so that only reliable
robust products that meet their intended use get transferred to production. These
basic principles are illustrated in Figure 9.9.
9.4.1 Design Controls
European regulations do not specically require developers to adopt design controls,
but it is the preferred way to ensure that safe and eective devices are developed.
Thus, European manufacturers will tend to follow the design control procedures
that are set out in section 7.3 of ISO 13485. Manufacturers of Class II and Class III
devices for the US market are legally obliged to adopt the design controls that are set
out in 21 CFR Section 820.30 of the Quality System Regulation (QSR). Most Class I
devices are exempt from the design control elements of the QSR except for devices
automated with computer software and a number of specied devices such as sur-
gical gloves. As illustrated in Figure 9.10, the design control elements of the 2016
version of ISO13485 are now virtually identical to the QSR. Consequently, the FDA
are proposing to amend Part 820, through incorporating by reference the quality
management system requirements of ISO 13485 2016. Thus, compliance with the
standard will be recognised as compliance with what will then be referred to as
the quality management system regulation (QMSR), and any variations in emphasis
214 9 Medical Devices
ISO 13485
7.3 Design and Development
7.3.2 Design and Development Planning
7.3.3 Design and Development Inputs
7.3.4 Design and Development Outputs
7.3.5 Design and Development Review
7.3.6 Design and Development Verication
7.3.7 Design and Development Validation
7.3.8 Design and Development Transfer
7.3.9 Control of Design and Development Changes
7.3.10 Design and development les
21 CFR
820.30 Design Controls
b) Design and Development Planning
c) Design Input
d) Design Output
e) Design Review
f) Design Verication
g) Design Validation
h) Design Transfer
i) Design Changes
j) Design History File
Figure 9.10 Comparison of headings of the design control elements of ISO13485 and
the QSR.
between the two standards, will no longer be a concern. As a basic step, manufac-
tures will usually establish an overall design control procedure that describes how
they address the elements of the standard when developing their devices.
9.4.2 Design and Development Planning
Manufacturers are required to establish and maintain plans that describe the
design and development activities and dene the responsibilities and authorities for
completion of the design. i.e. what must be, who must do it. A simplied outline
of the stages that a development project may go through is shown in Figure 9.11,
but the activities can vary considerably depending on the type and complexity
of the device involved. Although the bulk of the activity may be conned to a
core (R&D) development team, the project will invariably involve interaction with
other groups within the organisation, such as marketing for identifying customers
needs, manufacturing and quality control for design transfer requirements and
regulatory aairs for regulatory matters. These technical interfaces must be clearly
dened in the plans. The plans should also identify key milestones and design
review checkpoints, and, for eective coordination and management, will normally
contain estimates of the time required for each task. Gant charts are frequently used
as a planning tool for presenting an overview of the information as it enables the
display of the task, the schedule, the progress, the responsibility and the milestones
on a single chart. This is illustrated in Figure 9.12 where the tasks from Figure 9.10
are transformed into a hypothetical Gantt chart.
9.4.3 Design Input
Design input is the process of collecting the various requirements that a device must
meet, and translating them into a set of performance and other specication that
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