Introduction Session -

ISO 13485:2016
14 AUG 2018
Sixmurs Group of Companies
 Pretest:
• What is Quality?
• Please mention clauses of ISO 13485:2016?
• What the advantage(s) of QMS implementation?

2
 ISO I3485
Concept
AGENDA

Clauses
ISO 13485
 ISO 13485 : 2016 : Medical devices —
Quality management systems —
Requirements for regulatory purposes

1. Focusing on Quality Management System of Medical Device

2. Fulfill regulatory purposes

4
 What is “Quality”?

5
Quality is….
• A characteristic that a product or service must have
and desire by Customer.

Example:

Small & Simple

Easy to use Good design

6
 What is Quality Management System

“A quality management system (QMS) is a collection

of business processes focused on consistently
meeting customer requirements and enhancing their
satisfaction. It is aligned with an organization's
purpose and strategic direction”
(ISO 9001:2015)

7
Why is QMS needed?

Required by regulation.
Required at almost territorial

But the important is…..

8
Effective QMS result

• Safe / reliable product

Product • Meet with customer needs

• Happy & satisfied customer

Customer • Get adding value of product

• Strong reputation
Business • Increase profits and market

9
Where is implementation scope of ISO 13485?

Final
Installation & Decommissio
Servicing ning &
Disposal
Storage &
Distribution

Production

Design &
Development ISO 13485 can be used in one or more stage
of product lifecycle including the related
party, e.g. supplier / vendor, Conformity
Assessment Bodies (CABs), etc.

10
Bad Implementation of ISO 13485 Example

11
Compatibility with other management systems

• ISO 13485 doesn’t include requirement specific to

other management system
• Enable to align or integrate with other management
system
• ISO 13485 doesn’t specific on product technical
requirement

12
 Example: Production of Surgical Gown

• Risk Management (ISO 14971) • Cleanroom for • Validation (empty, • Transport Validation
• Design Input, Design Output, Production & Lab loaded chamber) : (ISO • Product Registration
Design Review, Design
Prerequisite

(ISO 14644) 11135)

Verification, Design Validation • Biological Indicator
(ISO 11138)
• Chemical Indicator (ISO
11140) • CPAKB

Design &
Manufac- Product
Develop- Sterilization
turing Placement
ment
Post Process Control

• Continuous improvement • Resistance to • EO sterilization • Post Market Control •ISO

microbial (ISO residual (ISO 10993) Surveillance & 13485
22610 & ISO • Biocompatibility of Vigilance (compliant
22612) Product (ISO 10993) handling, recall, FSCA)
• Tensile strength & • Sterility test (ISO • Regular production
elongation (ISO 11737) reporting
9073)

13
 ISO I3485
Concept
AGENDA
Clauses
ISO
13485
 Take action to improve process
Act performance

Clause 5
Management
Responsibility

Clause 8
Clause 4
Clause 6
Check Measurement, Quality Resource Plan
Analysis and
Improvement
Management Management
System
Monitor and measure Establish the objectives and
processes and product against processes necessary to deliver
policies, objectives and results in accordance with
requirements for the product Customer requirements and
and report the results. the organization’s policies.

Clause 7
Product
Realization

Implement the processes

Do
15
 Clause 5
Management
Responsibility

Clause
Clause 4
4
Clause 8
Clause 6
Measurement, Quality
Quality Resource
Analysis and
Improvement
Management
Management Management
System
System

Clause 7
Product
Realization

16
General Requirement
• establish, document, implement, maintain a QMS
and maintain its effectiveness.
• determine criteria and process needed to ensure
QMS is effective
• When chooses to outsource any process that affects
product conformity to requirements, it shall
monitor and ensure control over such processes.

17
 • Define resource
needed
• Assign
Management
Representative
• Set job
description

Example Org. Chart

18
 • Establish job description for
every position  approved by
responsible person
• Set requirement for certain
position
• Describe responsibility and
authority
• Maintain the records

Example Job Description

19
Documentation
Lev
el 1
–
Qu
alit
y
Ma
Levelnua
2 – SOP
l

Level 3 – Work Instruction,

Master Batch Record, Form

Record, Batch Record/Device Historical File

20
Quality Manual

• Establish scope of the QMS, including details of and

justification for any exclusion or non-application
• Documented procedures for QMS
• The quality manual shall outline
the structure of the documentation
used in the QMS

21
 Example of QMS Scope

“The company’s operation covers design development,

manufacturing, packaging, testing and repackaging of Medical
Device Products. Generally products type which produced at the
compay are divided into 2 categories i.e. electromedic product group
and non-electromedic group. Product detail is listed in Distributed
Product Master List.”

“The scope of certification for The Company’s quality management

system is “design, production and supply of orthopaedic trauma
fixation implant and instruments”

22
Medical Device File
Each medical device type or family, shall establish and
maintain :
a. general description, intended use/purpose, and
labelling, including any instructions for use;
b. specifications for product;
c. specifications or procedures for manufacturing,
packaging, storage, handling and distribution;
d. procedures for measuring and monitoring;
e. requirements for installation (if any);
f. procedures for servicing

23
Control of Document

SOP number & its version

Effective date ex: training before “Effective”
SOP Tittle

Review & approved before issued

Distribution List  control distribution

Periodic review vs current condition

Formal format (font type, font size, language,

document format, paper size, etc.)
Example SOP Format
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Control of Document
Numbering System for Document/Record

Quality Production Material Engineering HR & GA Finance & Marketing

Operations Management Accounting

01 02 03 04 05 06 07

A Quality General PPIC Engineering Human Finance Marketing

Assurance Resources

B Quality Production & Purchasing Utility General Accounting --

Control Assembly Affairs

C Design Dev. Packaging Warehouse -- -- Tax --

& Validation

D Regulatory Sterilization -- -- -- -- --
Affairs

25
Control of Document
Example Control of Document Distribution:

1. Document Master List 2. Distribution List

4. Password & restriction access (soft file)

ORIGINAL CONTROLED COPY OBSOLETE
3. Stamp
26
Control of Record
• Records shall be maintained
• Document procedures to define the controls needed
• Define and implement methods for protecting confidential
health information
• Records shall remain legible, readily identifiable and
retrievable. Changes to a record shall remain identifiable.
• Retain the records for at least the lifetime
of the medical device as defined,
or as specified by applicable regulatory
requirements, but not less than two years
from the medical device released

27
Control of Record
• Use of permanent ink with blue or black color and may
not use erasable ink, non-waterproof ink, and pencil.
• Using specific format date, time, duration  Example:
14/08/18, 14 Aug 18, 14.00, 4’ 15”
• Recording shall clear, permanent, readable, accurate,
complete and correct.
• Don’t use marks such as ditto (--"--) or curly brackets.
• Don’t use of correction fluid. The original data should
not be removed and shall be read clearly. If necessary
write an explanation or justification for the change

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 Clause
Clause 5 5
Management
Management
Responsibility

Responsibility

Clause 8
Clause 4
Clause 6
Measurement, Quality Resource
Analysis and
Improvement
Management Management
System

Clause 7
Product
Realization

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Management Commitment

 communicating to the organization the importance of

meeting customer as well as applicable regulatory
requirements;
 establishing the quality policy;
 ensuring that quality objectives are established;
 conducting management reviews;
 ensuring the availability of resources

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QUALITY POLICY

 Establishing & communicating Quality Policy

Put at “strategic” area

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QUALITY POLICY

32
QUALITY OBJECTIVE

• Annual target from management

• Descript & control thru Key
Performance Indicator

33
MANAGEMENT REVIEW
• Document procedures for management review.
• Review QMS at documented planned intervals to
ensure its continuing suitability, adequacy and
effectiveness.

34
MANAGEMENT REVIEW

INPUT PROCESS OUTPUT

a. feedback a. Criteria of a. improvement needed to maintain

b. complaint handling attendance the suitability, adequacy, and
c. reporting to regulatory authorities b. Interval of Meeting effectiveness of the quality
d. Audits
management system and its
e. monitoring and measurement of
processes
processes
b. improvement of product related to
f. monitoring and measurement of
customer requirements
product
c. changes needed to respond to
g. corrective action
applicable new or revised
h. preventive action
regulatory requirements
i. follow-up actions from previous
d. resource need
management reviews
j. changes that could affect the quality
management system
k. recommendations for improvement
l. applicable new or revised regulatory
requirements.

35
 Clause 5
Management
Responsibility

Clause 8
Clause 4 Clause 6
Clause 6
Measurement, Quality Resource
Resource
Analysis and
Management Management
System Management
Improvement

Clause 7
Product
Realization

36
Provision of resources

Adequate resources must be available to maintain an

effective QMS and meet regulatory and customer
requirement

 People
 Training
 Infrastructure (building, work space, utility, etc)
 Work Environment
 Information
 Suppliers for Materials
 Partners for Services
 Equipment
 Financial

37
Human Resources

• Competence, awareness & training

• Establish a Job Description (JD) for all position
• Establish a Training Matrix for all position and level
• Establish a Training Plan & Schedule
• Establish a Training Evaluation

38
Infrastructure

Purpose : achieve conformity to product requirements,

prevent product mix-up and ensure orderly handling of
product.
• buildings, workspace and associated utilities;
• process equipment (both hardware and soft ware);
• supporting services (such as transport, communication,
or information systems)

39
40
 Clean Room at Medical Device Manufacturing
Non-woven
Incoming
Polypropylene Fabric
Material
atau
Clean Room

Production
Process
Sterilization Paper Plastic Film

Primary
Packaging
Corrugated Box

Secondary Sterilization Machine

Packaging

Sterilization
Process
Surgical Gown Product

Finished
Product

41
ISO 14644-1 : Clean Room Classification
Clean Room Overview (ISO 14644-4)

Design & Commissioning

Building Layout

Equipment Layout

Clean room qualification

Clean room maintenance

Design & Commissioning (ISO 14644-4)

 Design AHU (Air

Handling Unit)
 Design facility &
building
 Design equipment
 Personnel flow
 Building & Facility Layout

Principle:
 Easy to clean
 Not reacting with product

Ceiling : epoxy paint

or sandwich panel

Cover lamp

Epoxy Floor
Equipment
layout
 Equipment Layout

Impact of layout
of clean room

Supply air - AHU

Return Filter

Summary
Equipment layout can’t
blocked air flow at clean
room
Clean Room Qualification

ISO 14644-2

 Particle count
 Air change
 Differences
Pressure
 Flow pattern
 integrity filter
 RH & T etc.
Clean Room Maintenance

ISO 14644-5
• Personnel & rquipmeny
flow
• Clean room gown
• Training personnel
• Sanitation program
• Monitoring
49
Validation & Qualification
• Any machine, equipment, production support system
that can affect the quality of products produced should
be performed of qualification process before use.
• Each production process, cleaning process, and
inspection process (analytical method), software that
can affect the quality of products produced must be
validated before use.
• Significant changes to facilities, equipment and
processes that may affect product quality shall be
qualified and/or re-validated.

50
 Qualification of Machine & Equipment

Design Installation Operational Performance

Qualification Qualification Qualification Qualification
Validation
• Validation is an evidentiary act in an appropriate
manner that any material, process, procedure, activity,
system, equipment or mechanism used in production
and control so always achieve the desired result.
• Subject  process (production, cleaning, analytical
method), software
• Type  prospective, concurrent, retrospective
• List of qualified & validated machine, equipment,
process

52
 Example Surgical Gown Manufacturing Process
Incubator LAF Autoclave Gas
Cabinet Chromatography
Oven

BIOBURDE BIO VISUAL

QUALIFI STERILITY PERFORMANC RESIDUAL
CATION N INDICATO E

VALIDATION

Clean Room
VALIDATION

WELDIN INSPECTI 2nd STERILIZ QC

CUTTING FOLDING PACKING
G ON PACKING ATION TESTING

Cutting Welding Sealer Leak Test Printing EO

Machine Machine Machine Machine Machine Sterilizer QUALIFI
Machine CATION
Printing
Machine

53
 Clause 5
Management
Responsibility

Clause 8
Clause 4
Clause 6
Measurement, Quality Resource
Analysis and
Improvement
Management Management
System
Clause 7
Product
Realization
Clause 7
Product
Realization

54
Planning of product realization
• Quality objectives and requirements for the product
• Establish processes and documents and to provide
resources specific to the product, including
infrastructure and work environment;
• Required verification, validation, monitoring,
measurement, inspection and test, handling, storage,
distribution and traceability activities specific to the
product together with the criteria for product
acceptance;
• Records needed to provide evidence that the realization
processes and resulting product meet requirement

55
 Design Development of Produc

DESIGN
DEVELOP- DEVELOP CONCEPT
DEVELOP- DESIGN DESIGN MARKET DESIGN
MENT MENT DESIGN REGISTRA
MENT VERIFICA- VALIDA- EVALUA- TRANSFE
PROPO- PLAN- (DESIGN -TION
(DESIGN TION TION TION R
SAL NING INPUT)
OUTPUT)

• Proposal • Timeline • Design Plan • Design • Product • Validation • Clinical trial • Registration • Mass
• Risk Final Prototype Process • Risk Pre- Production
Manage- Specifi- (production • IEC 60601 Manageme requisite
ment Plan cation trial) (for EL nt Report (exp. MCIT
Product) Reg)
• Dossier to
MoH
Registration

56
57
Planning of product realization

Establish criteria for the evaluation and selection of

suppliers
• based on the supplier’s ability to provide product
that meets the organization’s requirements;
• based on the performance of the supplier;
• based on the effect of the purchased product on
the quality of the medical device;
• proportionate to the risk associated with the
medical device.

58
Planning of product realization

Supplier
Evaluation

59
 Supplier Evaluation
Evaluated  Observation Score
Criteria
Item
A : Giving special price Supplier can giving A
Price B : Able to negotiate with certain price limit special price with
C : Unable to negotiate price range of MoQ base
A : Having capacity for Provital Supplier can produce A
B : Able to accept Provital’s order with limited 300 pc / day of Fetal
Supplies
capacity Monitoring Product
Capability
C : Unable to accept order from Provital

A : Registered facility with good maintain Supplier has been A

B : Registered facility with poor maintain obtained ISO 13485
Facility C : Not have facility and almost all product
already registered at
EU, US, CAN
A : Able to support Safety & Technical Data Supplier very open & A
B : Able to support Safety and/or Technical support for technical
Technical
C : Unable to support Safety & Technical Data data
Capability

A : Have documented procedure and applied to Supplier Quality A

achieve the defined Quality System System is well
B : Have documented procedure but not established
Quality implemented
System C : Not implement Quality System

Quality A : Able to send CoA in every delivery Supplier is able to send A

Record B : Able to send CoA only for new batch number CoA in every delivery
delivery
C : Unable to send CoA

60
 Supplier Re-evaluation

Risk Level Re-evaluation Period

High Risk 2 years
Medium
4 years
Risk
Low Risk No re-evaluation

Example Re-evaluation Program

61
Production and service provision
• documentation of procedures and methods for the
control of production
• qualification of infrastructure;
• implementation of monitoring and measurement of
process parameters and product characteristics;
• availability and use of monitoring and measuring
equipment;
• implementation of defined operations for labelling and
packaging;
• implementation of product release, delivery and post-
delivery activities
62
Production and service provision
• Record material used,
machine, personnel,
process parameters,
etc.
• Record using
appropriate document
Batch Record
Device History File
(DHF)

63
Production – Sterile Product Principle
Ensure any remain
microbe (if any) should
be complied with
acceptable level.

Standard limit of
bioburden / microbe
that applied at clean
room / controlled
room

Bioburden Control & Overkill Concept

Production – Sterile Product
Bio Indicator (BI)
An Inoculated carrier which contains a known population and
known resistance to the relevant sterilization process.
6 log reduction is the indicator for half-cycle
 6 log reduction : lethal process of 106 microorganism
 Half-cycle : needed time for kill 106 microorganism within ½
cycle of sterilization process

Self Contained Bio Indicator

Bacillus atrophaeus contained 106 Bacillus atrophaeus

65
Production – Sterile Product
Process Challenge Device (PCD)
 Item designed to assess
performance of
sterilization process.
 Type :
• Internal PCD
• External PCD

66
Production – Sterile Product
Process Challenge Device (PCD)
• Internal Process Challenge
Device (IPCD)
BI is located into the difficult to
reach area of product.
Ex gown: deepest folding.
• External Process Challenge
Device (EPCD)
BI is located at exterior of the
load and used for
microbiological monitoring of
routine production cycle.

67
 Example Sterilization Qualification – Flow Chart
Put BI at the “deepest”
position of Gown, then
seal
P1 P4 P7 P10 P13 P16

Put sealed gown into P2

P19

P5
P20

P17
P8 P11 P14
box, inline with BI
P3 P6 P9
configuration P12 P15 P18

Run sterilization with

several different time

Take processed BI then

incubate for 24 h.

Observe the growth of

spore (indicate with (+) : spore is growth
color change)
68
 Example Sterilization Qualification – Result
Steriliza- Σ BI
tion Time Picture Growth
60 min ++++

120 min +++

180 min No
Growth

69
 Example Sterilization Qualification – Result
Steriliza- Σ BI
Picture
tion Time Growth

240 min No
Growth

300 min No
Growth

360 min No
Growth

70
 Sterilization Qualification - Summary

No growth of BI at x min sterilization time

Sterilization process with 3h sterilization time has

been killed 106 Bacillus atrophaeus

Demonstrate Sterility Acceptance Level (SAL6 )

71
 EO Machine Performance Qualification

Empty Chamber Profile

Sub-Lethal (Fractional Cycle)
Mapping of
temperature & Half Cycle
RH distribution of Fractional cycle Full Cycle (Overkill)
chamber. with several
sterilization time 3 consecutive
batch to - Sterilization time
demonstrate is 2x from half
SAL6 cycle
- EtO residual
testing

*) ISO 11135 : 2014

72
Identification & Traceability

the ability to verify the history, location, or application

of a product by means of documented recorded
identification.
Area/Process Identification & Traceability
Material Received Supplier Delivery Order (DO) or
applicable documents
Work In Process Production Record, Production
  Batch Number
Finished Goods Delivery Order, Packing List, Sales
Order, Production Batch Number,
Delivery Log Book, Product Label
 Labelling

INCOMING PRODUCTIO
INSPECTION STORAGE WH STORAGE DISPACTH
MATERIAL N

74
 Labelling

INCOMING PRODUCTIO
INSPECTION STORAGE WH STORAGE DISPACTH
MATERIAL N

*) Only use material with release status for production allocation

*) Label is placed at the non movable part

75
 Labelling

INCOMING PRODUCTIO
INSPECTION STORAGE WH STORAGE DISPACTH
MATERIAL N

76
Labelling
INCOMING INSPECTIO STORAGE PRODUCTI
STORAGE DISPACTH
MATERIAL N WH ON

STERILIZATIO
CUTTING WELDING FOLDING PACKING 2nd PACKING
N
78
 Product Label

Finding CPAKB
mostly

ly
difference
n between
o
approved label
le

with actual label

p
am
ex

79
 n ly n ly
o o
p le p le
a m a m
ex ex

80
 l y
o n
l e
p
a m
ex

81
 Batch Numbering Example

A B C C 0 0 0 0 0

Product Code Sequence

Code Description Code Description

A Product Group 00 Year of production (last 2
B Product Code (1st 2 digit) digits)

CC Product Variant Code 000 Batch serial no.

• Non Electro-medic products code start from A to N; Electro-

medic products start from M to Z
• Additional suffix “T” for Trial Product & “R” for Reworked
Product
82
 Raw Material Numbering

X 0 0 0 - X 0 0 - 0 0

Material Code Sequence

Code Description Code Description

A Raw material code X Arrival Month (A – L)
B Packaging material code 00 Year of arrival (last 2
digits)
C Supporting material code
00 Arrival sequence

83
Control of monitoring and measuring
equipment
• Measuring equipment shall be calibrated or verified at
specified intervals, or prior to use,
• Measuring equipment be adjusted or re-adjusted as necessary
• Identification in order to determine its calibration status
• Safeguarded from adjustments that would invalidate the
measurement result
• Protected from damage and deterioration during handling,
maintenance and storage

84
 Master List Instrument

Calibration Schedule

Calibration Label
85
 Clause 5
Management
Responsibility

Clause 8
Measurement,
Clause 8
Clause 4
Clause 6
Analysis Quality
Analysis and
Measurement,
Resource
and
Management Management
Improvement
Improvement
System

Clause 7
Product
Realization

86
What should be monitored or measured?

 Customer feedback – are we meeting customers’

expectation?
 Product conformity – only products meeting
specification are released
 Process conformity – process are executed according
to QMS, regulations and standards
 Characteristic and trend of processes – Quality
Assurance

87
Customer Feedback

• Customer feedback on product

• Customer Feedback is not same with Customer
Complaint
• Both positive and constructive feedback
• Customer constructive feedback shall roll back to
design and development process

88
Customer Feedback
Method of obtaining and using feedback must be
determined
• Example field observation, customer survey, customer
call center, etc.
• Know your customers before making changes based on
feedback
• Ensure it shows a trend before making changes to
design

89
Reporting to regulatory authorities
 Post Market Surveillance : a proactive activity that is
conducted in order to ensure the conformity of quality,
safety and performance of the product during placed in
the market and also conformity assessment against
baseline data during product registration.
 Vigilance is action taken in response to the case of
incidents that occurred due to the use of medical
devices that cause injury or death to the patient.
 Field Safety Corrective Action (FSCA) is an action taken
by the product owner to reduce the risk of serious
injury or death related to the health of the medical
device user

90
 Criteria of adverse event that mandatory to be
reported
• The adverse event has been occurred.
• The adverse event is suspected caused by medical
device that has been used to the patient.
• Serious threat to public health.
• Death of patient, user or other person
• Serious deterioration health condition for user and
other person.
• Condition that can causing death or serious injury
to the user if it occurs repeatedly.

91
Timeline for Reporting
• No more than 48 hours for incident that causes a serious
threat to the public health
• No more than 10 days for incident that causes death,
serious deterioration health condition for patient, user and
other person.
• No more than 30 days for incident that may trigger death,
serious deterioration health condition for patient, user and
other person.

92
Internal Audit
• Tool to measure effectiveness of QMS and compliance to
standards and regulations.
• Auditors must be adequately trained
• Auditors must be independent
• Documented procedure must be established.
- Planning and executing audits
-Reporting results and follow up
-Record maintenance
• Audit frequency must be determine based on importance
and criticality of the process/activity
• No excuse for not conducting internal audit. Can seek
outside help.
• Audit finding shall go through CAPA system/process
93
 Example Annual Plan Internal Audit

94
Control of non-conforming product
• Non-Conforming Product (NCP) must be segregated (quarantine)
to prevent unintended use
• A documented procedure is required to ensure:
 Action is taken to remove the defect from good products
 Product is disposition accordingly (scrap, rework, etc)
 Who can make the decision and authorized for disposition
• Corrected/reworked product must be re-inspected according to
current procedures
• For rework product, a procedure indicating how to perform
rework must be developed and approved prior to rework

95
Corrective And Preventive Action
• Correction: Action taken to correct an immediate problem
• Corrective Action: Action taken to prevent reoccurrence of a
problem that has already taken place
Need to investigate the root cause of the problem to fix the issue
• Preventive Action: Pro-active action taken to prevent a potential
problem
Analysis data and trend to catch non conformities before it
occurs.

96
Corrective And Preventive Action
What can cause the non conformity?
Example
• Procedure/work instruction was not followed or not clear
• Missing or wrong tool/material use
• Equipment fail
• Software contains error
• Employees mistake – not trained?
• Improper manufacturing process
• Etc.

97
Corrective And Preventive Action

98
Corrective And Preventive Action

• 5 Whys
Ask “Why?”, “Why?”, “Why?”, “Why?”, “Why?”

• Fish Bone Diagram

99