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9
Medical Devices
9.1 Chapter Introduction
Medical devices cover the most diverse array of products in the healthcare
manufacturing sector. They range from simple devices such as bandages, tooth-
brushes or spectacles, through life-maintaining active implantable devices such
as heart pacemakers, to the most sophisticated diagnostic imaging and minimally
invasive surgical equipment. There is also considerable variation in the underlying
technology applied. Devices can rely on any combination of mechanical, electronic
or chemical/biochemical action to achieve their purpose. Thus, in contrast to drugs,
a more exible regulatory approach is required to adequately address safety and
eectiveness concerns for this product sector. Regulatory strategies are built around
the classication of devices according to risk, a corresponding tiered application
of regulatory requirements, and the use of appropriate standards to demonstrate
compliance. This chapter examines the application of these principles to the
development of devices.
9.2 Regulatory Strategy for Medical Devices in the EU
Harmonised regulation of devices was introduced in the EU in the 1990s via
Directives on Active Implantable Medical Devices (AIMD’s), Medical Devices
(MD’s) and In Vitro Diagnostics (IVD’s). These have now been replaced by two
Regulations, Regulation (EU) 2017/745 on Medical Devices (MDR) and Regulation
(EU) 2017/746 on In Vitro Diagnostic Medical Devices (IVDR), which came into
force on 26 May 2021 and 26 May 2022 respectively. Certicates issued under the
previous Directives remain valid, subject to conditions, up to 31 December 2028 for
lower risk medical devices and 27 May 2025 for IVDs, whereas transitions up to 26
May 2027 apply to IVDs that require Notied Body involvement for the rst time
under the IVDR. The regulations share a similar structure as illustrated in Table 9.1.
Medical Product Regulatory Aairs: Pharmaceuticals, Diagnostics, Medical Devices,
Second Edition. John J. Tobin and Gary Walsh.
© 2024 WILEY-VCH GmbH. Published 2024 by WILEY-VCH GmbH.
196 9 Medical Devices
Table 9.1 Comparison of the main heading of the MDR and IVDR.
MDR IVDR
Chapter I Scope and Denitions Introductory Provisions
Section 1 Scope and Denitions
Section 2 Regulatory Status of
Products and Counselling
Chapter II Making Available on the Market and
Putting into Service of Devices,
Obligations of Economic Operators,
Reprocessing, CE Marking
Making Available on the Market and
Putting into Service of Devices,
Obligations of Economic Operators,
CE Marking, Free Movement
Chapter III
Identication and Traceability of Devices, Registration of Devices and
of Economic Operators, Summary of Safety and Clinical Performance,
European Database on Medical Devices
Chapter IV
Notied Bodies
Chapter V
Classication and Conformity Assessment
Section 1 Classication
Section 2 Conformity Assessment
Chapter VI Clinical Evaluation and Clinical
Investigations
Clinical Evidence, Performance
Evaluation and Performance Studies
Chapter VII
Post-Market Surveillance, Vigilance and Market Surveillance
Section 1 Post- Market Surveillance
Section 2 Vigilance
Section 3 Market Surveillance
Chapter VIII Cooperation Between Member
States, Medical Device Coordination
Group, Expert Laboratories,
Expert Panels and Device Registers
Cooperation Between Member
States, Medical Device Coordination
Group, EU Reference Laboratories
and Device Registers
Chapter IX
Condentiality, Data Protection, Funding and Penalties
Chapter X
Final Provisions
Annex I
General safety and performance requirements
Annex II
Technical documentation
Annex III
Technical documentation on post-market surveillance
Annex IV
EU declaration of conformity
Annex V
CE marking of conformity
Annex VI
Information to be submitted upon the registration of devices and
economic operators and, core data elements to be provided to the UDI
database together with the UDI-DI and the UDI system
Annex VII
Requirements to be met by notied bodies
Annex VIII
Classication rules
Annex IX
Conformity assessment based on a quality management system and
on assessment of technical documentation
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9.2 Regulatory Strategy for Medical Devices in the EU 197
Table 9.1 (Continued)
MDR IVDR
Annex X
Conformity assessment based on type examination
Annex XI Conformity assessment based
on product conformity
verication
Conformity assessment based on
production quality assurance
Annex XII
Certicates issued by a notied body
Annex XIII Procedure for custom-made devices Performance evaluation, performance
studies and post-market performance
follow-up
Annex XIV Clinical evaluation and post-market
clinical follow-up
Interventional clinical performance
studies and certain other performance
studies
Annex XV Clinical investigations
Annex XVI List of groups of products without an
intended medical purpose
To achieve ecient harmonisation across Member States, the regulations main-
tain the common strategy originally employed by the directives of just specifying
general safety and performance requirements that devices must meet. As such the
regulations only dene legal requirements as regards the end results or goals that
must be attained but allow exibility as to the methods or solutions that a manu-
facturer may employ in achieving these goals. The fundamental objective behind
the requirements is to ensure that only devices that are safe and eective for their
intended use may be marketed. Details of some of the requirements dier between
the two regulations, but many of the key elements can be summarised as shown in
Table 9.2.
As can be seen, risk management systems play a central role in determining
the details of what is necessary to ensure that a specic device is safe and t
for purpose. Following completion of the appropriate assessment procedure (see
Chapter 10), device manufacturers must draw up a declaration of conformity with
the requirements of the regulations and ax the CE Mark as evidence to the user
that the device is in conformance with the regulations and can be legally marketed
in the EU.
The CE Mark is not specic to medical devices but is used generally to indicate to
European consumers that a product conforms to applicable European performance
and safety requirements.It can be found on electrical equipment, children’s toys and
safety equipment among other products.
198 9 Medical Devices
Table 9.2 Summary of key elements of the general safety and performance requirements as
foundinAnnexItotheMDRandIVDR.
MDR IVDR
Chapter I
General Requirements
1. Safe & Eective Devices
Devices shall achieve the performance intended by their manufacturer and shall be designed
and manufactured in such a way that, during normal conditions of use, they are suitable for
their intended purpose. They shall be safe and eective and shall not compromise the clinical
condition or the safety of patients, or the safety and health of users or, where applicable, other
persons, provided that any risks which may be associated with their use constitute acceptable
risks when weighed against the benets to the patient.
2. Risk reduction versus benet-risk ratio
The requirement to reduce risks as far as possible means the reduction of risks as far as
possible without adversely aecting the benet-risk ratio.
3. Risk Management System
Manufacturers shall establish, implement, document and maintain a risk management
system. This shall apply as a continuous iterative process throughout the entire lifecycle of a
device.
4. Risk Control
Risk control measures shall conform to safety principles and risk reduction measures shall
follow
(a) eliminate or reduce risks as far as possible through safe design and manufacture;
(b) where appropriate, take adequate protection measures, including alarms if necessary,
in relation to risks that cannot be eliminated; and
(c) provide information for safety (warnings/precautions/contra-indications) and, where
appropriate, training to users.
5. Risk reduction related to use error
In eliminating or reducing risks related to use error, the manufacturer shall:
(a) reduce as far as possible the risks related to the ergonomic features of the device and the
use environment (design for patient safety), and
(b) give consideration to the technical knowledge, experience, education, training and use
environment, and the medical and physical conditions of intended users (design for lay,
professional, disabled or other users).
6. Performance over intended lifetime
The devices must retain their performance characteristics over their claimed lifetime under
the normal stresses associated with their use.
7. Stability during storage and transport
The devices must be designed manufactured and packaged so as to maintain their
performance characteristics under the intended conditions of transport and storage.
8. Foreseeable risks and undesirable eects
All known and foreseeable risks, and any undesirable eects shall be minimised and be
acceptable when weighed against the evaluated potential benets.
9. Devices without a medical purpose
(cosmetic)
Devices must present little or no risk
Chapter II
Requirements regarding design and
manufacture
Chapter II
Requirements regarding performance,
design and manufacture
9. Performance characteristics
Establish sensitivity, specicity, precision,
accuracy, traceability to reference materials/
standards, etc.
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9.2 Regulatory Strategy for Medical Devices in the EU 199
Table 9.2 (Continued)
MDR
IVDR
10.Chemical, physical and biological properties
Minimise the risk due to physical or chemical incompatibilities or use of substances that are
carcinogenic, mutagenic or reproductive toxins (CMRs)
11. Infection and microbial contamination
Minimise the risk of infection to patients, users and, where applicable, other persons.
Requirements for sterile devices.
12. Devices incorporating medicines or
substances absorbed/dispersed in the body
Requires evaluation of what happens to the
substance in the body.
13/12. Devices incorporating materials of biological origin
Measures as regards traceability or prevention of infection as appropriate.
14/13. Construction of devices and interaction with their environment
If the device is intended for use in combination with other devices or equipment, the whole
combination shall be safe, etc.
15/14. Devices with a diagnostic or measuring function
Provide sucient accuracy, precision and stability, etc. Use SI units.
16/15. Protection against radiation
Measures to prevent unintended exposure to radiation (lasers, x-ray, etc).
17/16. Electronic programmable systems
Requirements for software.
18/17. Active devices and devices connected to them / Devices connected to or
equipped with an energy source
No interference with other electronic equipment.
19. Particular requirements for active
implantable devices
20/18. Protection against mechanical and thermal risks
21. Protection against the risks posed to
the patient or user by devices supplying
energy or substances
22. Protection against the risks posed by devices use by lay persons / self-testing /
near patient testing
Take account of the skill of the user, enable verication that the device is functioning and
indicate if an error has occurred.
Chapter III
Requirements regarding information supplied with the device
23/19. Label and instructions for use
Species content and format. E.g.
Labels must display a Unique Device Identier (UDI) and Lot No. or Serial No.
Use of symbols promoted
Instructions for use may be provided electronically where appropriate
Figure 9.1
The CE
Mark.
The basic mark is illustrated in Figure 9.1. Depending on the type of
product it may be accompaniedby the identication numberof the Noti-
ed Body responsible for performing specied conformity assessment
tasks (see Chapter 10).
200 9 Medical Devices
The strategy of reliance on achieving end results as opposed to specifying the
methods for achieving the results was vital to ensuring a smooth transition to
compliance with the original directives, particularly considering the diversity in
the types of devices and technologies that exist. So also was the exibility in the
conformity assessment procedures that may be used to establish compliance with
the requirements. This was particularly important for older devices, which may
have been developed before accepted design practices or norms were available.
These approaches have been preserved in the superseding regulations.
9.2.1 Use of Standards to Establish Conformity
Although the regulations allow exibility in the methods and solutions that a man-
ufacturer may employ to full the general safety and performance requirements,
the regulations promote the use of standards as the preferred method to establish
conformity. Specically, they stipulate that Member States shall presume compli-
ance with the requirements in respect of devices that are in conformity with relevant
harmonised standards, aprinciple that extends across manyother product types that
are subject to EU regulatory controls.
At European level, standards are developed through the European Commit-
tee for Standardization (CEN) or the European Committee for Electrotechnical
Standardization (CENELEC) in the case of electrical standards. They comprise
representatives from the national standards organisations of each Member State,
plus Switzerland, Norway and Iceland. Draft standards are prepared, usually with
input from relevant industry associations, and circulated to the member bodies for
comment. Following the inclusion/rejection of comments, nal drafts are adopted
as European Norms (EN) by majority vote using a weighted voting system. Member
bodies must then adopt or reference the standards as national standards without
alteration and abandon any pre-existing national standards that may conict with
the international standard.
Standards may be developed at global level through the International Standards
Organisation (ISO) or the equivalent International Electrotechnical Commission
(IEC) for electrical equipment. These contain representatives from standards bodies
worldwide. The process for developing standards is similar to that at European
level. A 75% vote in favour is required before a standard may be adopted as an
International Standard (IS). Where no appropriate international standards exist,
manufacturers may rely on relevant national standards. For example, standards
established by the US National Committee for Clinical Laboratory Standards
(NCCLS) are widely used by manufacturers worldwide for establishing the perfor-
mance of IVD reagents.
The European Commission has mandated CEN/CENELEC to develop many
standards to support manufacturers in the realisation of the safety and performance
requirements of the Regulations. If the Commission determines that an adopted
standard is t for this purpose, then a reference is published in the Ocial Journal
of EU, which elevates the status of the standard to that of a harmonised standard
for European regulatory purposes.
Lists of harmonised standards for dierent regulatory purpose may be accessed at
https://single-market-economy.ec.europa.eu/single-market/european-standards/
harmonised-standards_en.
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9.2 Regulatory Strategy for Medical Devices in the EU 201
However, the text of the standards is not published, as they are protected by copy-
right and must be purchased through sales outlets of the standardisation bodies.
The regulations also provide for theestablishment of Common Specications (CS),
which dene specic requirements for certain high-risk devices and certain criti-
cal tasks (e.g. designation of Notied Bodies). Such CS are developed in consulta-
tion with the Medical Device Coordination Group (MDCG), a body which is also
established by the regulations. The nalised CS is then published as implementing
regulations.
The single most important standard that has relevance for all medical
device manufacturers is ISO 13485, ‘Medical devices – Quality management
systems – Requirements for regulatory purposes’. It originated from the more
familiar ISO 9001 standard, ‘Quality management systems – Model for quality
assurance in design, development, production, installation and servicing’, that is
used by organisations in general. However, it diers from ISO 9001 in that its pri-
mary objective is to provide a ‘harmonized’ model for quality management system
requirements that satisfy international medical device regulations.Consequently, its
main focus is on maintaining the eectiveness of the quality management system as
opposed to ISO 9001, where continuous improvement and customer satisfaction are
fundamental drivers of the system. This stems from the precept that, in accordance
with regulatory requirements, medical device must be safe and eective for their
intended purpose before being placed on the market and thus product improvement
or customer satisfaction should be less of an issue post-launch. There is also a
strong emphasis on risk management to ensure that devices are safe and eective.
In common with ISO 9001 it applies a Plan-Do-Check-Act (PDCA) methodology
to processes as illustrated in Figure 9.2. The main headings of the standard are
outlined in Figure 9.3.
9.2.2 Classification of Devices
The range of devices regulated under the MDR and IVDR can vary from the simple
devices that poselittle or no riskto patient or user health to thosethat are life critical.
It is not economically feasible, nor justiable in practice to subject all devices to the
same level of regulatory control. Instead, a tiered approach has been adopted that
Plan
Do
Check
Act
Establish the objectives and processes necessary to deliver results in
accordance with customer requirements and the organization policies.
Implement the processes.
Monitor and measure processes and products against policies, objectives
and requirements for the product and report the results.
Take actions to improve process performance.
Figure 9.2 PDAC model.
202 9 Medical Devices
4. Quality Management System
4.1 General Requirements (Implement quality system and continually improve it)
4.2 Documentation Requirements (Quality Manual, control of documents and records)
5. Management Responsibility
5.1 Management Commitment (Show evidence of top management commitment)
5.2 Customer Focus (Meet the requirements and satisfy your customers)
5.3 Quality Policy (Have top management express quality intentions)
5.4 Planning (Set quality objectives and plans to meet objectives)
5.5 Responsibility, Authority and Communication (Dene duties, appoint a Quality
Manager, communicate eectiveness of system)
5.6 Management Review (Review performance and eectiveness of system)
6. Resource Management
6.1 Provision of Resources (Provide necessary resources to meet requirements)
6.2 Human Resources (Competence and training)
6.3 Infrastructure (Provide facilities, equipment, and support services)
6.4 WorkEnvironment and contamination control(Manage combination of human and
physical factors)
7. Product Realization
7.1 Planning of Product Realization (Plan and develop processes to produce product)
7.2 Customer-Related Processes (customer requirements, orders & communication)
7.3 Design and Development (Design Plans, Inputs,Outputs, Reviews, Verication,Val-
idation & Change)
7.4 Purchasing (Evaluate suppliers, verify supplies)
7.5 Production and Service Provision (controlof production, process validation, product
status)
7.6 Control of Monitoring and Measuring Equipment (Calibrate measuring equipment
for valid results)
8. Measurement, Analysis, and Improvement
8.1 General (Plan, measure, analyse, and improve processes)
8.2 Monitoring and Measurement (customer feedback, internal audits, process moni-
toring, nished product release)
8.3 Control of Nonconforming Product (Prevent useor delivery of nonconforming prod-
uct)
8.4 Analysis of Data (Analyse eectiveness and identify improvements)
8.5 Improvement (Corrective action, preventative action)
Figure 9.3 Main headings of ISO 13485:2016.
adjusts the level of regulatory oversight to the degree of potential hazard ascribed to
the use of the device. This is illustrated in Figure 9.4.
Fundamental to this strategy are procedures for classication of devices into one
of four categories, class I, IIa, IIb or III under the MDR or class A, B, C or D under
the IVDR. Manufacturers must classify their devices according to criteria and rules
set out in Annex VIII to the regulations.
As a rst step for devices other than IVD’s, the manufacturer must clearly dene
the intended use of the device in terms of the following:
● Degree of invasiveness.
● Mode of action – active or passive device.
● Duration of contact with the patient.
● Impact on the body – local vs. systemic eect.
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9.2 Regulatory Strategy for Medical Devices in the EU 203
C
IIb
B
IIa
A
I
III
D
Regulatory
requirements
Risk
Figure 9.4 Relationship between risk and classification of medical devices.
Invasiveness: Under invasiveness criteria, devices may be categorised as
non-invasive, invasive through a body orice (mouth, eye, ear,etc. or a permanent
articial opening such as for a colostomy bag), or surgically invasive. Note: Any
device that is intended to penetrate the skin such as a syringe needle is considered
a surgically invasive device.
Mode of action: Activedevices depend on a sourceof electrical energy orother power,
excluding gravity or the patient to perform their function.
Duration of contact: Devices are considered transient if intended for continuous use
for less than 60 minutes, short term if intended for continuous use for not more
than 30 days and long term if intended for continuous use for more than 30 days.
Devices that are intended to be introduced into thebody or toreplace an epithelial
surface or the surface of the eye by a surgical procedure for more than 30 days are
considered implants.
Impact on the body: The impact on the body may be dened as local if the eect
is conned to the site around the area of application of the device or systemic
if eects may spread throughout the body as is the case when the circulatory or
central nervous systems are involved.
A general illustration of how these criteria impact the risk classication is shown
in Figure 9.5.
Having identied the characteristics of the device, the manufacturer must
then apply the classication rules. There are 22 rules, 4 for non-invasive devices,
4 for invasive devices, 5 for active devices and 9 special rules. These are shown in
Duration of contact
Long termTransient
Surgically invasiveNon-invasive
ActivePassive
SystemicLocal
Low
RISK
High
Impact on body
Invasiveness
Mode of action
Figure 9.5 Impact of device characteristics on risk classification.
204 9 Medical Devices
NON-INVASIVE DEVICES
Rule 1
All non-invasive devices are classied as class I unless one of the rules set out hereinafter
applies.
Rule 2
All non-invasive devices intended for channelling or storing blood, body liquids, cells or
tissues, liquids or gases for the purpose of eventualinfusion,administrationor introduction
into the body are classied as class IIa:
— if they may be connected to a class IIa, class IIb or class III active device; or
— if they are intended for use for channelling or storing blood or other body liquids or for
storing organs, parts of organs or body cells and tissues, except for blood bags; blood
bags are classied as class IIb.
In all other cases, such devices are classied as class I.
Rule 3
All non-invasive devices intended for modifying the biological or chemical composition of
human tissues or cells, blood, other bodyliquids or other liquids intended for implantation
or administration into the body are classied as class IIb, unless the treatment for which
the device is used consists of ltration, centrifugation or exchanges of
gas, heat, in which case they are classied as class IIa.
All non-invasive devices consisting of a substance or a mixture of substances intended to
be used in vitro in direct contact with human cells, tissues or organs taken from the human
body or used in vitrowith human embryos before their implantationor administration into
the body are classied as class III.
Rule 4
All non-invasive devices which come into contact with injured skin or mucous membrane
are classied as:
— class I if they are intended to be used as a mechanical barrier, for compression or for
absorption of exudates;
— class IIb if they are intended to be used principally for injuries to skin that have
breached the dermis or mucous membrane and can only heal by secondary intent;
— class IIa if they are principally intended to manage the micro-environment of injured
skin or mucous membrane; and
— class IIa in all other cases.
This rule applies also to the invasive devices that come into contact with injured mucous
membrane.
INVASIVE DEVICES
Rule 5
All invasive devices with respect to body orices, other than surgically invasive devices,
which are not intended for connection to an active device or which are intended for con-
nection to a class I active device are classied as:
— class I if they are intended for transient use,
— class IIa if they are intended for short-term use, except if they are used in the oral cavity
as far as the pharynx, in an ear canal up to the ear drum or in the nasal cavity, in which
case they are classied as class I and
— class IIb if they are intended for long-term use, except if they are used in the oral cavity
as far as the pharynx, in an ear canal up to the ear drum or in the nasal cavity and are
not liable to be absorbed by the mucous membrane, in which case they are classied as
class IIa.
All invasive devices with respect to body orices, other than surgically invasive devices,
intended for connection to a class IIa, class IIb or class III active device, are classied as
class IIa.
Figure 9.6 The rules for classification of medical devices in the EU.
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