Regulatory+change+management+a++2010 10-18+jmb

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


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



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



of the device?



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



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



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.

Regulatory+change+management+a++2010 10-18+jmb

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