Management of Changes to a
Medical Device
Regulatory Affairs
Cochlear Limited
• Regulatory Position
• Cochlear’s implementation of change management
• Change Scope
• The concept of significant vs non-significant change
• Approval requirements for significant changes
• Differences between jurisdictions
• Reference material
Change Management
Key Principles
• A device shall have clinical benefits
• A device shall be as safe as
practicable
• The benefit/risk ratio of a device
should be larger than one
The focus of Regulatory Controls
Regulatory Audit
Quality Management System - Risk Management
Premarket
Classification – Conformity Assessment
Postmarket Surveillance
Conformity Assessment (continued)
Registration
Listing
Essential Principles
Standards
Device Specification
Design Control
Design verification and validation
Clinical Evidence
STED
Declaration of conformity
Adverse Event Reporting
Complaint Management
Maintenance and Service
Corrective and Preventive Actions
Postmarket clinical follow up
New products to the market,
while recognising that changes occur,
Regulatory Baseline
• Medical Devices are approved on the basis
of the information submitted to the
regulators and the assumed design and
manufacturing status at that time
• Changes post submission must be
assessed for requiring approval and/or
reporting
Change Management at Cochlear
Changes are assessed using
CHANGE ASSESSMENT PROCEDURE
12654AG
which identifies the regulatory implication
of the change.
Assessment of changes
Product status covered by change control• Product on the market
• Product submitted for regulatory approval
• Product submitted for clinical trials
Changes requiring considerations• Manufacturing processes, facilities, equipment
• Manufacturing requirements, procedures
• Design and performance specifications
• Materials
• Labelling
Generic Change Process
A systematic and documented assessment is performed by Cochlear Q&R
Change Request
ReviewProposed Change Change Design
Change Note
Review
Change
implementationChange complete
Change
Assessment
Advisory
Change
Assessment
Binding
Assessment of changes
CHANGE ASSESSMENT PROCEDURE E12654AG
SIGNIFICANT CHANGE means a change that could potentially affect the
safety or effectiveness of a medical device. It includes a change to any of the
following:
• the manufacturing process, facility or equipment;
• the manufacturing quality control procedures, including the methods, tests or
procedures used to control the quality, purity and sterility of the device or of
the materials used its manufacture;
• the design of the device, including its performance characteristics, principles
of operation and specifications of materials, energy source, software or
accessories;
• the intended use of the device, including any new or extended use, any
addition or deletion of a CONTRA-INDICATION for the device, and any
change to the period used to establish its expiry date, and
• major changes to the facilities such as an additional operational location
Changes - Japan
Minor changes in a medical device are exempted from an application for partial
change as long as such changes do not directly affect the effectiveness and
safety of the medical device such changes would be:
a) Changes not related to the medical device itself
b) Changes which affect the structural materials, external appearance etc but
which does not affect the performance, electrical rating, safety etc
c) Change, addition or elimination of auxiliary equipment or accessories
which are not stand-alone medical devices, as the change does not affect
the performance, electrical rating, safety etc
d) Changes in material, form, dimensions, or position of parts not contacting
the patient body
e) Minor changes which do not affect the safety, performance or essence of
the device
f) Minor changes in the method of operation or use of the medical device
due to any of the changes (a) to (e)
Prerequisites for Assessement
Clear and unambiguous description
Reason – why is the change important?
Impact analysis – what is affected?
Incremental risk analysis – which tests?
Generic Change Assessment Process
A systematic and documented
assessment is performed by
Cochlear Q&R
Generic Change Process
A systematic and documented
assessment is performed by
Cochlear Q&R
Change to a
device or its
manufacturing
processes
due to Field
Action ?
Assess change. Is it significant?
Is the safety and effectiveness of
the device potentially affected?
File Changes - CLTD
Regional Report ?
in manufacturing
processes?
in design or design
specifications ?
Mechanical
Electrical
Software, etc
in indication
for use /
labelling?
Go to
Chart A
Go to
Chart
C
Go to
Chart E
No
Yes
Yes
Yes
Yes
No
Yes
MAIN CHART
M1
M2
M3M4 M5 M6
Approval required
in Facilities?
Go to
ChartG
Yes
new equipment or
materialbeing
added?
only changes
to the quality
control criteria?
to a quality control
procedure, criteria or
validation test
specification?
in design or
performance
specifications?
Chart A
Go to
Chart C
Go to
Chart B
No
No
Yes
Yes
No
No
Yes
No
A1 A2 A3
A4
A5A6
Identical to present?
eg. replacement or for
capacity. YesYes
Approval Required
No
Could the
process change affect
the safety and effectiveness
of the device?
Yes
NoCould the
change affect
the process where
used?
Yes No
A6
A7
File Changes - CLTD
Regional Report ?
Is there equivalent or
better assurance of safety and
effectiveness?
in design or
performance
specifications?
Could the change affect
the safety and effectiveness
of the device?
Approval RequiredChartB
Go to
Chart C
Yes
Yes No
Yes
No
No
B1
B2 B3
File Changes - CLTD
Regional Report ?
in control
mechanism?
in operating
principle?
in the design?
in packaging
in the performance
specifications?
affect indication for
use?
Is clinical evidence
requierd?
Chart C
No
No
No
No
Yes
No
No
Yes
Yesin software or
firmware?
Approval Required
No
Yes
Yes
Yes
No
No
No
Yes
C1
C2
C3
C4
C5
C6 C7
C8
C9
Could the change affect
the safety and effectiveness
of the device?
File Changes - CLTD
Regional Report ?
in materials? Chart DYesYes
From
Chart D
of animal or
human origin?
in the type or
formulation?
in material supplier?
in contact with
the body?
Chart D
No
No
Yes Approval Required
Yes
No
are additional
biocompatibility
tests required?
absorbed or remain in
body > 30 days?
changes in design
or performance
specifications?
Go to
Chart C
No
YesYes
No
Yes
YesNo
No
No
ordered to the same
specifications/
Yes
Yes
No
No
Yes
D1
D2
D3 D4 D5
D6 D7
D9
D10
Could the change affect
the safety and effectiveness
of the device?
Could the change affect
the safety and effectiveness
of the device?
File Changes - CLTD
Regional Report ?
affect indication
for use?
is it to existing
warnings and
precautions?
addition or
deletion of
contraindications?
Chart E
No
No Yes
improvement of
clarity?
Yes
Yes
Extension of expiry
date?
Approval Required
No
No
YesNo
Yes
No
E1
E2
E3
E4
E5
E6
Could the change affect
the safety and effectiveness
of the device?
File Changes - CLTD
Regional Report ?
is new
manufacturing
facility
being added?
Is the present facility
expanded?
Are any critical
process locations
changed
Could the change affect
the safety and effectiveness
of the device?
Approval Required
Chart F
No
No
Yes
Yes
Yes
Yes
No
No
F1
Are high risk product
processes affected?Yes
NoFile Changes - CLTD
Regional Report ?
F2
F3
F4
F5
FDA Change Assessment Process
Identify the modification and
the reason for it
Conduct risk analysis
Define testing that will assess
the impact of the modification
an safety and effectiveness
Choose the regulatory
pathway from the options
below
Change(s)
that does not
affect S&E
Preclinical
only
Preclinical and
potentially limited
confirmatory
clinical
Change(s)
that enhance
the S&E
Manufact.
Site
Change
Supplement
New clinical
and ptentially
some new
preclinical
Manufacturing
change
affecting S&E
New clinical
and new
preclinical
New original
PMA
Panel track
Supplement
180 day
supplement
Real-Time
Supplement
30-Day/135-
Day
Supplement
Special
supplement
Changes
Being
Effected
Annual
Report
Summary
New Products must be approved
Changes to current products must be
assessed for regulatory implications
Changes must be properly executed and
documented
References• Europe - NB-MED/2.5.2/Rec2 Reporting of
design changes and changes of the quality system
• GUIDANCE FOR INDUSTRY, Guidance for the Interpretation of Significant Change of a Medical Device, Health Canada , 2003/03/02
• USA, FDA - Guidance for Industry, Modifications To Devices Subject to Premarket Approval – The PMA Supplement Decision Making Process Draft Guidance
Change Assessment
Key Regulations for Cochlear
• FDA – 21CFR14 Premarket
Approval of Medical Devices
• EUROPE – AIMD& MD
Directives 90/385/EEC,
93/45/EEC
• Australia – Therapeutic
Goods (Medical Devices)
Regulation 2002
• Canada – Medical Device
Regulation
Yes
no - see guidance
yes
yes
Regulations Reference to changes
????
FDA 21CFR814
• Sec. 814.39 PMA supplements.
• (a) After FDA's approval of a PMA, an applicant shall submit a PMA supplement for review and
approval by FDA before making a change affecting the safety or effectiveness of the device for which
the applicant has an approved PMA, unless the change is of a type for which FDA, under paragraph
(e) of this section, has advised that an alternate submission is permitted or is of a type which, under
section 515(d)(6)(A) of the act and paragraph (f) of this section, does not require a PMA supplement
under this paragraph. While the burden for determining whether a supplement is required is primarily
on the PMA holder, changes for which an applicant shall submit a PMA supplement include, but are
not limited to, the following types of changes if they affect the safety or effectiveness of the device:
• (1) New indications for use of the device.
• (2) Labeling changes.
• (3) The use of a different facility or establishment to manufacture, process, or package the device.
• (4) Changes in sterilization procedures.
• (5) Changes in packaging.
• (6) Changes in the performance or design specifications, circuits, components, ingredients, principle
of operation, or physical layout of the device.
• (7) Extension of the expiration date of the device based on data obtained under a new or revised
stability or sterility testing protocol that has not been approved by FDA. If the protocol has been
approved, the change shall be reported to FDA under paragraph (b) of this section.
FDA 21CFR814 – cont’d
• (b) An applicant may make a change in a device after FDA's approval of a PMA for the device without
submitting a PMA supplement if the change does not affect the device's safety or effectiveness and
the change is reported to FDA in postapproval periodic reports required as a condition to approval of
the device, e.g., an editorial change in labeling which does not affect the safety or effectiveness of the
device.
• (c) All procedures and actions that apply to an application under 814.20 also apply to PMA
supplements except that the information required in a supplement is limited to that needed to support
the change. A summary under 814.20(b)(3) is required for only a supplement submitted for new
indications for use of the device, significant changes in the performance or design specifications,
circuits, components, ingredients, principles of operation, or physical layout of the device, or when
otherwise required by FDA. The applicant shall shall include information relevant to the proposed
changes in the device. A PMA supplement shall identify each change and explains the reason for
each such change.
FDA 21CFR814 – cont’d
• (f) Under section 515(d) of the act, modifications to manufacturing procedures or
methods of manufacture that affect the safety and effectiveness of a device subject to
an approved PMA do not require submission of a PMA supplement under paragraph (a)
of this section and are eligible to be the subject of a 30-day notice.
A 30-day notice shall describe in detail the change, summarize the data or information
supporting the change, and state that the change has been made in accordance with the
requirements of part 820 of this chapter.
The manufacturer may distribute the device 30 days after the date on which FDA
receives the 30-day notice, unless FDA notifies the applicant within 30 days from receipt
of the notice that the notice is not adequate. If the notice is not adequate, FDA shall
inform the applicant in writing that a 135-day PMA supplement is needed and shall
describe what further information or action is required for acceptance of such change.
The number of days under review as a 30-day notice shall be deducted from the 135-
day PMA supplement review period if the notice meets appropriate content requirements
for a PMA supplement.
Europe - NB-MED/2.5.2/Rec2
• The Medical Devices Directives variously require in different Annexes that where a
Notified Body has been involved in the approval of the quality system or the device
design / type, the manufacturer must inform the Notified Body of “substantial“ changes
to the quality system and/or changes to the device which could affect compliance with
the essential requirements or the intended use.
• It is not practicable to specify in general terms what types of change are or are not
“substantial“. For instance, a change in colour may be purely cosmetic in some cases,
yet be “substantial“ in other cases where it is the means for drawing attention to
warnings, functions etc. Instead, it is recommended that the manufacturer have a
system for categorising changes as substantial or not and informing the Notified Body as
appropriate, and that the Notified Body reviews the operation of this system as part of
routine surveillance.
• The manufacturer should establish, maintain and apply a procedure for categorizing and
documenting any changes to the design / device and/or quality system as either
“substantial“ or not substantial.”
Europe cont’d
There is a recognition of Substantial Changes per below:
• “Changes are “substantial“ and (depending on the chosen conformity assessment route)
the manufacturer must inform the Notified Body where:
• (i) for product changes, the change would affect conformity with
– (a) the essential requirements and/or
– (b) the conditions prescribed for the intended use of the device.
The matters for the manufacturer to consider when deciding whether or not particular
changes are “substantial“ include the following:
• - for device changes
• - does the change introduce new hazards which have not been previously addressed?
• - does the change adversely affect the risk associated with existing hazards?
• - does the change alter the details on intended use and/or compliance with the essential
requirements given in the design / type approval dossier submitted to the Notified Body?
• - does the change mean that the device will have different end users or be used in a
different manner?
• - does the change mean that the clinical data for the original device is not sufficient to
confirm conformity of the changed device with the required characteristics and
performance?
Canada
"significant change" means a change that could reasonably be expected to affect
the safety or effectiveness of a medical device. It includes a change to any of
the following:
(a) the manufacturing process, facility or equipment;
(b) the manufacturing quality control procedures, including the methods, tests or
procedures used to control the quality, purity and sterility of the device or of
the materials used in its manufacture;
(c) the design of the device, including its performance characteristics, principles of
operation and specifications of materials, energy source, software or
accessories; and
(d) the intended use of the device, including any new or extended use, any
addition or deletion of a contra-indication for the device and any change to the
period used to establish its expiry date.
Canada cont’d
Application for a Medical Device Licence Amendment
34. If the manufacturer proposes to make one or more of the following changes,
the manufacturer shall submit to the Minister, in a format established by the
Minister, an application for a medical device licence amendment including the
information and documents set out in section 32 that are relevant to the
change:
(a) in the case of a Class III or IV medical device, a significant change;
(b) a change that would affect the class of the device;
(c) a change in the name of the manufacturer;
(d) a change in the name of the device;
(e) a change in the identifier of the device, including the identifier of any medical device
that is part of a system, test kit, medical device group, medical device family or
medical device group family;
(f) in the case of a Class II medical device, a change in the medical conditions,
purposes or uses for which the device is manufactured, sold or represented.
Canada cont’d
Obligation to Inform
43. (1) Every manufacturer of a licensed medical device
shall, annually before November 1 and in a form
authorized by the Minister, furnish the Minister with a
statement signed by the manufacturer or by a person
authorized to sign on the manufacturer's behalf
(a) confirming that all the information and documents supplied by the
manufacturer with respect to the device are still correct; or
(b) describing any change to the information and documents supplied
by the manufacturer with respect to the device, other than those to
be submitted pursuant to section 34.
Australia
(3) For the purpose of enabling the examination to be carried out, the
manufacturer must have available:
(a) information, in writing, in relation to the following matters in relation to the
kind of medical device:
(i) the design;
(ii) the production process;
(iii) the intended performance; and
(4) If, after examination by the Secretary of the design of a kind of medical device,
the manufacturer makes a substantial change to the design, or the intended
performance, of the kind of device, the manufacturer must:
(a) notify the Secretary, in writing, of the change; and
(b) arrange for examination of the change by the Secretary to assess
whether the design, or the intended performance, of the medical device, as
changed, complies with the applicable provisions of the essential principles.