Module 14: Design Development and Certification of Medical Devices

Module 14: Design Development and Certification of Medical Devices

Date: 20th – 22th November 2023 Module: 14 of the TOPRA MSc Design Development and Certification of Medical Devices

Module Leader: Jason Collins, Helen Erwood

©The Organisation for Professionals in Regulatory Affairs 2023 Presentations are supplied to delegates for their personal reference and are the copyright of the speaker and The Organisation for Professionals in Regulatory Affairs. The presentations must not be copied, stored in a retrieval system or transmitted in any form without prior permission from TOPRA. Agreement must be reached with TOPRA before any part of this material is reproduced, abstracted, stored in a retrieval system or transmitted in any form by any means – that is, electronic, mechanical, photocopying, recording or otherwise.

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Masterclass: Lecture 1

Principles of the design and development of medical devices

Helen Erwood, Director RA, ESPL

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AN OVERVIEW OF: ● GOOD DESIGN PRACTICE in DESIGN and DEVELOPMENT processes – Identifying a NEED – PLANNINGthe design process – EXPEDITING the process – experimental DESIGN – Design CONTROLS PRINCIPLES OF THE DESIGN AND DEVELOPMENT OF MEDICAL DEVICES

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PRINCIPLES OF THE DESIGN AND DEVELOPMENT OF MEDICAL DEVICES

AN OVERVIEW OF: ● The REGULATORY FRAMEWORK – ISO standards – Notified body expectations – Guidances: EU / UK, FDA, IMDRF

● DOCUMENTING data and decisions

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PRINCIPLES OF THE DESIGN AND DEVELOPMENT OF MEDICAL DEVICES

NOTE: ● MUCH OF WHAT WE WILL LOOK AT IN THIS LECTURE WILL BE EXPANDED IN FURTHER DETAIL IN SPECIFIC SUBJECT LECTURES THROUGHOUT THE COURSE

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GOOD DESIGN PRACTICE

IDENTIFY THE UNMET NEED (I): ● What will the device do? – Is this a recognised unmet need? – Understand the disease state / physical condition

● Who is the user? – Patient? – Home carer? – Healthcare provider?

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GOOD DESIGN PRACTICE

IDENTIFY THE UNMET NEED (II): ● How will it help support the patient? – Will it be used with other devices?

● Are there existing devices available that have a similar role? – …but which do not fulfil the required function completely?

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GOOD DESIGN PRACTICE

WHAT WILL THE PRINCIPLE BENEFIT BE? ● Better procedures – More efficient procedure – More effective use of facilities ● Reduced time in hospital – Moves patient care from clinic to home ● Patient is back to work and play faster – Patient can self-treat / self-monitor – Patient has more independence / mobility

DEFINE WHAT SUCCESS IS!

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GOOD DESIGN PRACTICE: ONGOING TRENDS IN MEDICAL TECHNOLOGY…

 Diagnostics that guide therapies  From lab to desktop  From clinic to home  Reduced input from healthcare providers  Patients direct their own healthcare

 Direct-to-patients apps  Minimise hospital stay  Better outcomes at lower cost  Evidence-based outcomes  Connectivity and remote monitoring for HCPs

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GOOD DESIGN PRACTICE: Device discovery: the innovation process

From Durfee / Iaizzo2016

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GOOD DESIGN PRACTICE

DESIGN FEASIBILITY ● First step in the design process – BRAINSTORMING – LOOKING AT CONCEPTS

● OFTEN CALLED A PRODUCT INITIATION REQUEST – A PROCESS FOR FORMALLY DOCUMENTING AN IDEA

● Assessment by a MULTIDISCIPLINARY team

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GOOD DESIGN PRACTICE - DESIGN PLANNING

● Time schedule ● Milestones

• Goals and objectives • Organisational responsibilities • Tasks • Resources

● COMMUNICATIONS! …when notifications should occur

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GOOD DESIGN PRACTICE

DESIGN PLANNING ● TOOLS

– GANTT CHARTS / PERT CHARTS – CHECKLISTS – STANDARDS AND GUIDELINES

● TIMESCALES – ? If everything works out how long will it take (best case) – ? What’s the most likely duration? (most probable) – ? If almost everything goes wrong how long will it take (worst case)

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The “Waterfall” flow chart (you will see this again!_)

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GOOD DESIGN PRACTICE

DESIGN INPUTS ● What are they? – PHYSICAL AND PERFORMANCE REQUIREMENTS THAT ARE THE BASIS FOR PRODUCT DESIGN

– THE INTENTIONS FOR YOUR DEVICE

– THEY ARE NOT SOLUTIONS

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GOOD DESIGN PRACTICE

DESIGN INPUTS ● Must be UNAMBIGUOUSLY: – COMPREHENSIVE – REALISTIC – DEFINED

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GOOD DESIGN PRACTICE

DESIGN INPUTS ● Must identify; – CRITICAL FUNCTIONALITY – PERFORMANCE – SAFETY AND RELIABILITY

– …taking into account the users’ needs and the intended use

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GOOD DESIGN PRACTICE

DESIGN INPUTS – considerations ● TARGET PRODUCT PROFILE (TPP) – Instructions for Use (IFU) – Usability / human factors studies ● Device CLASSIFICATION and guidances – EU, USA, IMDRF etc

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GOOD DESIGN PRACTICE

DESIGN INPUTS – considerations ● ERGONOMIC requirements ● GENERAL SAFETY AND PERFORMANCE REQUIREMENTS CHECKLIST – Identify the ISO STANDARDS relevant to the device

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GOOD DESIGN PRACTICE

DESIGN INPUTS ● INTERNALLY IMPOSED GSP REQUIREMENTS – Based on market research – Clinical trials – Competitor products – Contractual requirements ● EXTERNALLY IMPOSED GSP REQUIREMENTS – CUSTOMER NEEDS – STATED AND IMPLIED – REGULATORY / STATUTORY – ENVIRONMENTAL requirements

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GOOD DESIGN PRACTICE

DESIGN INPUTS ● HUMAN FACTORS STUDIES – Nowadays more important than ever

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DOCUMENTING THE DEVICE DEVELOPMENT

DEVICE DEVELOPMENT INFORMATION IS USED: ● TO CONSTRUCT THE DESIGN HISTORY FILE ● TO SUPPORT PATENT ACTIVITIES

IT IS REALLY IMPORTANT TO RECORD: ● DESIGN DECISIONS ● DESIGN CONTROLS

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THE IMPORTANCE OF DOCUMENTING THE DEVICE DEVELOPMENT

● DESIGN DECISIONS – INVESTIGATIONS THAT WORKED – AND THOSE THAT DID NOT

– LEARNINGS FROM THE DATA GENERATED – And how they influenced the next steps – RISKS MITIGATED / NEW RISKS IDENTIFIED – To understand the WHOLE picture – STUDIES TO CONFIRM COMPLIANCE WITH REGULATORY STANDARDS – Mandatory requirement! – INNOVATIVE APPROACHES – What clever solutions have you used?

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TARGET PRODUCT PROFILE (TPP)

● ORIGINATES FROM PHARMACEUTICALS – Strategic development tool – Template described by US FDA (2007)

● Links the statements in the Instructions for Use…. …. with the supporting data

…. and identifies minimally acceptable data

● Used in parallel with the GSPR CHECKLIST

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IMDRF guidance 2019 ● Product name, address of manufacturer ● Intended purpose and intended user ● Performance intended by the manufacturer ● Residual risks (contraindications, warnings etc) ● Specifications required to use the device – (the expected degree of accuracy) http://www.imdrf.org/docs/imdrf/final/technical/imdrf-tech-190321-pl-md-ivd.pdf Start to prepare your initial IFU (1) .. and design aspects..

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Start to prepare your initial IFU (2) ..and design aspects..

● Identification of any medicinal substances / items of biological origin ● Details on preparatory treatment or handling required before it can be used (e.g. sterilisation). ● Training requirements for user ● How to verify if the device has been installed / set up properly – Maintenance requirements – Consumable components – Calibration requirements – Methods for eliminating risks encountered when installing, calibrating or servicing the device. ● Special storage / handling requirements

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Start to prepare your initial IFU (3) ..and design aspects..

● If sterile – what to do if the package is damaged ● Instructions for: – Sterilisation – if required. – Re-use / cleaning / disinfection / packaging – How to identify when the device can no longer be re-used.

● Information on use with other devices

● Radiation protection information

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● Warnings, precautions and limitations of use – Related to actual or foreseeable risks Start to prepare your initial IFU (4) ..and design aspects..

● How to dispose of the device and its components

● Information on when a lay person should consult a healthcare professional

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Your initial IFU

● In the early stages of development, you will not have all the information that you need, but this should prompt you to identify a need within your DESIGN PLAN

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GENERAL SAFETY & PERFORMANCE REQUIREMENTS (GSPR)

A CRITICAL REGULATORY / PLANNING DOCUMENT USED TO IDENTIFY: ● REQUIREMENTS RELEVANT TO THE DEVICE ● THE ISO AND OTHER REGULATORY STANDARDS APPROPRIATE TO THOSE REQUIREMENTS ● THE TYPE OF DATA (Later the actual data) THAT WILL CONFIRM COMPLIANCE WITH THE RELEVANT STANDARDS

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GENERAL SAFETY & PERFORMANCE REQUIREMENTS (GSPR)

• Annex 1 of the MDR

• See attachment in your notes

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GOOD DESIGN PRACTICE

Why are ISO standards so important? ● Internationally agreed standards that need to be followed for specific aspects of medical device design and control ● Some of the KEY STANDARDS: – ISO 13485: 2016 - QUALITY MANAGEMENT SYSTEMS – ISO 14971: 2019 - RISK MANAGEMENT – ISO 10993 series - BIOLOGICAL EVALUATION OF MEDICAL DEVICES – ISO 14155: 2011 - GCP – IEC/TR 80002 series and developing ISOs - MEDICAL DEVICE SOFTWARE – IEC 62366 series and associated ISOs: APPLICATION OF USABILITY ENGINEERING TO MEDICAL DEVICES – ISO 16142-1: 2016/2017 – General and additional specific essential principles – IVD medical devices

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ISO 10993

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GOOD DESIGN PRACTICE

DON’T FORGET!

OTHER REGULATORY INTERFACES

● THE MACHINES DIRECTIVE

● THE PERSONAL PROTECTIVE EQUIPMENT DIRECTIVE

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GOOD DESIGN PRACTICE

DESIGN INPUTS ● RISK MANAGEMENT (ISO 14971) – AN ONGOING PROCESS – VERY IMPORTANT FROM THE START ● Identify

– PERCEIVED risks – IDENTIFIED risks ● MITIGATE THE RISKS – Secondary assessments to mitigate further? – Feedback to the IFU

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GOOD DESIGN PRACTICE

DESIGN OUTPUTS

● US LEGISLATION 21CFR 820.3 (g): – “Design output means the result of a design effort at each design phase and at the end of the total design effort..”

– “The total finished design output consists of the device, its packaging and labeling, and the device master record” (DMR)

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GOOD DESIGN PRACTICE

DESIGN OUTPUTS ● When?

– End of the feasibility process – Product performance specification (PPS) [also TPP] – Prior to performing biocompatibility testing – Development of test protocol or method (output) – .. Which is then used to conduct the testing (input) – Prior to conducting a Human Factors / User Study – Manufacture of prototype (output)

– At the end of the design transfer phase – These outputs serve as inputs to manufacturing and product realisation

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GOOD DESIGN PRACTICE

DESIGN OUTPUTS ● Regulated under ISO 13485 / ISO 9001 / 21CFR 820.30(d) ● Design outputs must – Meet design input requirements – Provide information for product realisation – Contain or refer to acceptance criteria – Identify critical device characteristics essential to the safe and proper use of the device. – Including handling, storage, maintenance etc.

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GOOD DESIGN PRACTICE

DESIGN OUTPUTS ● OUTPUTS MUST ALSO BE VERIFIED AS SUITABLE! – Before becoming final product specifications and production.

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GOOD DESIGN PRACTICE

TYPICAL DESIGN OUTPUTS (1) ● Bill of materials (BOM) ● Engineering drawings ● Test methods and protocols ● QA specifications / inspection procedures ● Product specifications ● Assembly procedures ● Installation and servicing procedures

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GOOD DESIGN PRACTICE

TYPICAL DESIGN OUTPUTS (2) ● Component and materials specifications ● Equipment calibration and preventive maintenance requirements ● Results of risk analysis ● Results of biocompatibility testing ● Prototypes for verification and / or validation ● Results of verification.

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GOOD DESIGN PRACTICE

DESIGN VALIDATION ● Validation

– Confirmation by examination and provision of evidence that the particular requirements for a SPECIFIC INTENDED USE can be consistently met. ● DESIGN validation – Confirmation that the device meets the user needs and intended uses. – Did I make the right product and can I prove it?

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TYPICAL VALIDATION STUDIES • • Clinical studies / clinical evaluations

Simulated use testing / Human Factors testing

• Information on substantially equivalent devices

• Transit trails to determine packaging stability

Stability studies

• Performance and functional tests

•

Literature searches

Biocompatibility tests

•

•

• Review of labelling for USABILITY and ease of understanding • Review of product packaging and its role in protection

• Software validation (beta testing)

Risk analysis from the user perspective

•

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GOOD DESIGN PRACTICE

DESIGN TRANSFER ● A critical part of product realisation – …and often poorly done.

● The manufacturing function must be involved in the design phase – To avoid failures in design transfer

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GOOD DESIGN PRACTICE

DESIGN CHANGE: IMPROVEMENT AND OPTIMISATION ● Must be properly documented ● Supported by a change management process, including: – Request form – Engineering change order

● ALL CHANGES reflected in the DESIGN HISTORY FILE

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DESIGN CONTROLS

WHAT ARE THEY?

● A set of documented methods for ensuring that: – what you think you are developing is what you wanted to develop in the first place and – what finally comes off the production line is what the customer needs and wants, and – you can legally market and distribute it.

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Suggested further reading

● Baumgarten D: Brainstorming techniques to jumpstart device designs (available online, first issued 2013) ● Cambridge Consultants: Good Design Practice for medical devices and equipment 2 (https://www-edc.eng.cam.ac.uk/downloads/gooddesignpractice2.pdf ● Durfee WK, Iaizzo PA: Medical Device Innovation Handbook (available online) ● Busch et al: Optimizing the innovation and development process of medical devices - a study based on angiographic equipment (available online) ● Green Guru: Ultimate guide to design controls for medical device start-ups (2018) https://www.greenlight.guru/blog/design-controls ● Teixiera MB: Design Controls for the Medical Device Industry (2021) ● USFDA: Design Control Guidance for Medical Device Manufacturers (1997 - latest version 2018)

© TOPRA and Dr Helen Erwood ESPL Regulatory Consulting

helen@espl-regulatory.com

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Risk Assessment and Risk Management

ISO 14971: 2019

MEDICAL DEVICES

RISK MANAGEMENT AND RISK ASSESSMENT

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Legislation

 ISO 14971: 2019 : risk management

 The EU MDR (2017/735) and UK Medicines and Medical Devices Act 2021

 FDA 21CFR 820.30: Quality system regulation

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Regulatory requirement for RISK MANAGEMENT

 MDR 2017/745

 Annex 1 – GSPR: Multiple references to RISK !

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Managing risk

 Risk Management Planning

 Risk Analysis  Tools to help with this

 Risk Management Reporting  Risk Register

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RISK MANAGEMENT

◦ Not new – always been required by law ◦ Within the medical device regulations ◦ As a key feature of : ◦ ISO 13485 : Quality Management Systems ◦ ISO 14971…

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ISO 14971: 2019

History…

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ISO 1471: 2019

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RISK MANAGEMENT ….

 An important expectation of EU Notified Bodies and the FDA

 Aim – to develop a safe medical device  There is no such thing as an MD without risk

 SAFETY = FREEDOM FROM UNACCEPTABLE RISK

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Regulatory requirements for RISK MANAGEMENT

 You must have…

 An SOP on risk management procedures

 A risk management plan

 A risk register

 Methods for assessing and mitigating risk  Theoretical, actual, potential..

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What is RISK MANAGEMENT?

 Your risk management process must cover the WHOLE lifecycle of your device

Lifecycle management

Risk analysis

Risk evaluation

Risk control

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What is RISK MANAGEMENT?

 The lifecycle risks…

Everyday use

End of life support

Transport & Distribution

Concepts

Design

Production Sterilisation

Installation

Training

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What is RISK MANAGEMENT?

 The lifecycle risks…

Everyday use

End of life support

Transport & Distribution

Concepts

Design

Production Sterilisation

Installation

Training

 All of this must be documented

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What is RISK MANAGEMENT?

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What is RISK MANAGEMENT?

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RISK ANALYSIS

 what is risk?

 ISO 14971…

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RISK MANAGEMENT

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RISK MANAGEMENT

◦ …the identification, understanding, control and prevention of failures that can result in HAZARDS when people use medical devices.

◦ When designing a new device, manufacturers are: ◦ Expected to identify possible hazards ◦ Under normal conditions ◦ Under fault conditions

◦ Calculate potential risks ◦ Under both normal and fault conditions

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RISK MANAGEMENT

IF A RISK IS JUDGED TO BE UNACCEPTABLE…?

• IT MUST EITHER BE ELIMINATED…

…0R REDUCED TO ACCEPTABLE LEVELS

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RISK MANAGEMENT

◦ Helps to assure safety of the device

◦ Contributes to the consistency of the manufacturing process.

◦ Identification of design problems before distribution eliminates costs associated with recalls.

◦ Offers a measure of protection from product liability damages

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WHEN DEVICES FAIL…

Parker Wachman LLP

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WHEN DEVICES FAIL…

Scar capsules from failed breast implants

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RISK MANAGEMENT – a broad subject

 Spectres  SOCIAL

RISK LIST IMPACT SCALE  Budget  Schedule  Reputation  Health & Safety  Quality  Scope  Security / Data protection  Environment

 POLITICAL  ECONOMIC

 COMMERCIAL  TECHNOLOGY  REGULATION  ENVIRONMENT  SAFETY / SECURITY

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RISK CONCEPTS

Annex C of ISO 14971…

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RISK CONCEPTS

Examples of hazards

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RISK CONCEPTS

Examples of events and circumstances

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RISK CONCEPTS

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Estimating RISK for a medical device

 Probability of occurrence of harm (Po)  It’s the harm that matters

 Severity of harm (S)

Always START by assuming that the device is supplied unpackaged and assume that no risk controls are in place…

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RISK ANALYSIS

Hazard Traceability Matrix

No. Hazard

Reasonably foreseeable risk

Hazardous situation

Harm

Po S

Risk acc?

Risk control options analysis

Risk control measure

Verification of effectiveness

Implem?

R-Po

R-S

Risk acceptable?

R - Residual

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Tools for analysing

1. How can you estimate risk? a) Published standards or articles b) Statistical references c) Tests d) Results of investigations e) Expert assessment IMPORTANT: The probability of occurrence of a hazardous situation is not the same as the probability of occurrence of harm.

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Tools for analysing

1. Ishikawa fishbone diagram

Thanks to TempLab

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Fishbone production example

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FMEA..

 Failure Modes and Effects Analysis

 Originates from 1940S…

 One of the tools that can be used to help assess risk management  But… it cannot be used solely for assessing risk in accordance with ISO 14971

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What is FMEA?

Example assessment ◦ BUT! FMEA only focuses on FAILURES of systems

Ref No.

Function Process Step What are we analysing

Failure mode

Potential cause

Potential Impact (effects) Impact on key output variables e.g., local or system effects

Severity

Probability estimate

Detection mode

Ease of detection

Risk level

Further investigs

Mitigation actions

Unique number!

What has gone wrong? What could go wrong?

What might cause this?

How severe is this effect to customers stakeholders

e.g.,frequency

The existing controls that will prevent or detect the failure

RPN – risk priority no. S x P x D

Further actions

Actions needed to mitigate the risk(s)

needed to define the failure

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RISK ASSESSMENT … is an iterative process..

RISK = PROBABILITY +SEVERITY

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Inherent elements of RISK

◦ Use in / for patients ◦ Requires human intervention ◦ Design and performance ◦ Misuse and abuse

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Inherent elements of RISK

◦ Use in / for patients ◦ Underlying disease state / physical condition ◦ Some immunocompromised ◦ Requiring treatment or diagnosis ◦ Requires human intervention ◦ Self-administered or given by healthcare provider ◦ Usability / intuitive use?

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Inherent elements of RISK

◦ Design and performance ◦ Day to day performance and reliability ◦ Choice of materials ◦ Manufacturing consistency

◦ Misuse and abuse ◦ …the device may not be actually used as intended…

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STEPS IN THE RISK MANAGEMENT PROCESS

Risk Management plan

• Risk analysis • Risk evaluation

Risk Assessment

• Reduce and mitigate risk

Risk control

Evaluate overall residual risk

Risk management review

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THE RISK MANAGEMENT PROCESS

..here’s the full chart…

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THE RISK MANAGEMENT PROCESS

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THE RISK MANAGEMENT PROCESS

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THE RISK MANAGEMENT PROCESS

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RISK ANALYSIS / RISK EVALUATION

 Determine the level of risk  High, medium, low  Identify and list characteristics that could affect safety  Identify associated hazards  Arising from correct intended use  And from foreseeable mis-use  Determine the potential SOURCE or CAUSE of the hazard  Assign a level of risk to each identified hazard  Plus probability and severity

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RISK ANALYSIS / RISK EVALUATION

 Determine the ACCEPTABILITY of each risk  Eliminate or reduce each risk AS FAR AS POSSIBLE  Re-design  Process validation  Process variability reduction  Labelling / user education  Evaluate the controls and solutions adopted (risk reduction measures)  Re-assess the acceptability of each risk

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OVERALL RESIDUAL RISK

 Evaluate the OVERALL risk for acceptability

 DOCUMENT the process!

 CONTINUE TO MONITOR

 Were your original assumptions correct?  Do the risks remain acceptable throughout the life cycle of the device?

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Risk Management activities in more detail ISO 14971

This is far too small, so let’s go through it step by step…

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Risk Management activities – ISO 14971

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Risk Management activities – ISO 14971

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Risk Management activities – ISO 14971

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Risk Management activities – ISO 14971

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Inherently risky procedures example: Brachytherapy treatment of liver cancer

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HUMAN FACTORS…

HUMAN ERROR IS THE CAUSE OF MOST ACCIDENTS… ◦ Some sources state that human error is the cause in 90% of accidents!

◦ In the medical device environment, such errors can cause serious injury or death

◦ THE DESIGN TEAM MUST HAVE A GOAL OF ENSURING THAT ANY DEVICE IS EASY AND SAFE TO USE.

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Use-related hazards…

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Human factors studies are very important in risk assessment

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Use-related hazards…. and why they arise…

 Use of the device requires:  physical, perceptual or cognitive abilities that exceed the abilities of the user  The use environment affects operation of the device  this is not properly recognised or understood by the user.

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Use-related hazards… and why they arise…

 The use environment impairs the ability of the user to use the device in such a way that the user cannot interact with it  The device is inconsistent with the user’s expectation or intuition about how the device operates.  The device is used in a way that was not anticipated .. Or as anticipated but inappropriately.

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Simulated use study of ICU equipment

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THE BEST WAY TO CONTROL ERRORS

IS TO STOP THEM BEFORE THEY OCCUR

• By designing the MEDICAL DEVICE so that the error will not occur in the first place

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THE BEST WAY TO CONTROL ERRORS IS TO STOP THEM BEFORE THEY OCCUR

• The US FDA identifies 4 steps for this: 1. Identify anticipated / unanticipated use-related hazards 2. Describe how hazardous use scenarios occur 3. Develop and apply strategies to control use-related hazards 4. Demonstrate safe and effective device use (simulated use testing)

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4 common problems to avoid… (according to the US FDA)

1. Ignoring ISO 14971: 2019 ◦

Reduction of risks “as far as possible” and not ALARP ◦ Establish risk control measures for ALL risks and not just for those that are unacceptable. ◦ Perform a risk / benefit analysis for all risks ◦ Risk reduction must go beyond the information provided to the user. 2. Treating risk management and design controls as distinct processes.

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4 common problems to avoid… (according to the US FDA)

3. USING FMEA AS A RISK MANAGEMENT MODEL FOR MEDICAL DEVICES ◦ This is effective for measuring failure modes and reliability but it doesn’t fully align with ISO 14971. ◦ Use ISO 14971 as the basis of your risk management process

4. Treating risk management as a checklist item ◦ It’s much broader than that!

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Conclusions

1. RISK ASSESSMENT AND RISK MANAGEMENT ARE KEY ACTIVITIES FROM THE VERY START OF ANY DESIGN PROCESS ◦ ..and the process must be continued throughout the life cycle of a product

2. RISK MANAGEMENT IS PART OF NORMAL LIFE ◦ It’s something we do every day ◦ It’s required across all industries

The methods used for devices are no different to other industries!

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Suggested further reading ◦ ISO 13485:2016 – Quality Management Systems ◦ ISO 14871:2019 + A11 2021 – Risk Management ◦ TeixieraMB: Design Controls for the Medical Device Industry (2021) ◦ US FDA: Design Control Guidance for Medical Device Manufacturers (1997 – LATEST VERSION 2018) ◦ Wiklund M et al: Medical Device Use Error - Root Cause Analysis (CRC Press 2016)

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How observant do we need to be?

https://www.youtube.com/watch?v=ubNF9QNEQLA

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Another observation exercise for you to try… The Monkey Business Illusion

https://www.youtube.com/watch?v=IGQmdoK_ZfY

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Masterclass: Lecture 3

Choice of materials for medical devices

Helen Erwood, Director RA, ESPL

The Organisation for Professionals in Regulatory Affairs

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CHOICE OF MATERIALS FOR MEDICAL DEVICES

WHAT WE WILL LOOK AT: ● THE MAIN FACTORS THAT INFLUENCE CHOICE

● PROPERTIES OF MATERIALS

● MATERIALS TESTING

● OTHER FACTORS INFLUENCING CHOICE – USING VARIOUS EXAMPLES

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DESIGN FLEXIBILITY… MECHANICAL PROPERTIES ● These determine suitability for use for many types of device, e.g…. – Stiffness, robustness, yield strength – Behaviour under different environmental conditions.. Cold, hot, humid, altitude – Loading conditions: – Compression/tension FACTORS INFLUENCING CHOICE OF MATERIALS

– Continuous / cycled use – Repeated / single use

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FACTORS INFLUENCING CHOICE OF MATERIALS

DESIGN FLEXIBILITY… SURFACE PROPERTIES ● Very important in relation to:

– Friction – Bonding – Labelling – Printing – Persistence in / on the body

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FACTORS INFLUENCING CHOICE OF MATERIALS

DESIGN FLEXIBILITY… PHYSICAL PROPERTIES ● Such as: – Transparency – Density – Electrical conductivity – Whether it can be sterilised – without it being damaged

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FACTORS INFLUENCING CHOICE OF MATERIALS

DESIGN FLEXIBILITY… CHEMICAL PROPERTIES ● These influence:

– Resistance to degradation caused by various factors.. – Moisture, UV light, acidic / alkaline conditions, lubricants, solvents

– Corrosion resistance – Coating requirements

Diagram by Bruce Blausen

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FACTORS INFLUENCING CHOICE OF MATERIALS

DESIGN FLEXIBILITY… RHEOLOGICAL PROPERTIES ● Particularly during manufacture: – Melt temperature – Viscosity – Shrinkage – Component stability ● …and for medical device formulations

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FACTORS INFLUENCING CHOICE OF MATERIALS

BIOCOMPATIBILITY (ISO 10993) ● Potential effects in relation to use: – Long or short term – Implantability – Skin contact – Leachables and extractables – Interaction when co-administered with medicines

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FACTORS INFLUENCING CHOICE OF MATERIALS

SAFETY IN HANDLING ● Potential effects in relation to use

SHIELDING CAPABILITY ● e.g. radiotherapy

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© Roswell Park

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FACTORS INFLUENCING CHOICE OF MATERIALS

STERILISATION, DISINFECTION AND CLEANING ● Effect of biocides / sterilisation processes on device materials – alcohol, bleach and peroxide

– sterilisation methods including autoclaving, gas plasma and Ethylene oxide (EtO). – Repeated exposure can cause many plastic medical devices to craze or crack, lose critical properties or change colour.

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FACTORS INFLUENCING CHOICE OF MATERIALS

STERILISATION, DISINFECTION AND CLEANING ● Metals – resistance to harsh cleaners and various sterilisation techniques, – increases weight and design restrictions. ● Semi-crystalline polymers -polypropylene, polyethylene, polyamides – lighter and easily moulded, better chemical resistance than amorphous polymers - polycarbonate and acrylonitrile-butadiene-styrene.

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FACTORS INFLUENCING CHOICE OF MATERIALS

Substances that can influence the microenvironment

● Prevention of microbial adhesion

● Sequestration of microbial nutrients.

● Alteration of charge properties

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FACTORS INFLUENCING CHOICE OF MATERIALS: AESTHETICS

COLOUR ● VISUAL language used to encourage correct use – Important to make the device “appealing” – COLOUR CHANGE, to indicate functionality

FEEL ● TACTILE features used to encourage correct use – Difference in materials that are disposable and those that are not SOUND ● AURAL features used to encourage correct use – Materials used to make audible clicks to indicate successful operation

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FACTORS INFLUENCING CHOICE OF MATERIALS

COST $$$ ● Always an important factor ● Related to availability and supplier negotiation – Consider potential conflicts with performance and safety ● Cost per unit - affected by many factors – amount required per device – Additives needed, if any – Ease and speed of manufacture with the material – Also if secondary operations are required – Transport costs for shipping; weight and distance

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FACTORS INFLUENCING CHOICE OF MATERIALS

SUPPLY ● Availability (e.g. does it include a rare metal?) ● The extent of information and data that they can provide – For example: – Risk assessment information – FMEAs – Mould flow, fatigue, creep calculations for specific grades of material – Leachables and extractables ● Geographical location ● Viability of the manufacturer ● Sustainability

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REGULATORY STATUS ● Compliance with approved standards – For example pharmacopoeial grade polyolefins ● Materials containing “problem” ingredients – Safety concerns = HSE related factors – [Most recently in pharmaceutical packaging – nitrosamines..] ● Environmental factors – Disposal and waste management – Recycling – Transport and disposal of waste materials FACTORS INFLUENCING CHOICE OF MATERIALS

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ISO 10993 compliance for materials…

Biological evaluation of medical devices: • Evaluation and testing within a risk management process • Biocompatibility testing aspects • Framework for identification and quantification of potential degradation products • Identification and quantification of degradation products from polymeric medical devices, ceramics, metals and alloys • Establishment of allowable limits for leachable substances

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ISO 10993 compliance for materials…

Biological evaluation of medical devices: Chemical characterization of materials Physicochemical, morphological and topographical characterization of materials Nanomaterials

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ISO compliance for materials…

Other important standards ● ISO/TS 21726:2019(en)

Biological evaluation of medical devices — Application of the threshold of toxicological concern (TTC) for assessing biocompatibility of medical device constituents ● SCENIHR: The safety of medical devices containing dehp- plasticized pvc or other plasticizers on neonates and other groups possibly at risk ● ASTM F3268-18a: Standard Guide for in vitro Degradation Testing of Absorbable Metals ● ISO/TS 20721:2020(en): Implants for surgery — General guidelines and requirements for assessment of absorbable metallic implants

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Novel materials…

EXAMPLES: ORIGAMI ENGINEERING http://www.smithsonianmag.com/innovation/new-material-could make-medical-devices-that-expand-collapse-180958454/

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NANOMATERIALS..

NANOTECHNOLOGY: • Designing and making anything whose use depends on specific structures at the NANOSCALE: • 100nm or less • Including devices or systems made by manipulating individual atoms or molecules which contain very small structures

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NANOMATERIALS..

NANOMATERIALS: • Materials with at least one external dimension that measures 100nm or less, or with internal structures measuring 100nm or less • Particles, tubes, rods, fibres

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NANOMATERIALS..

HOW THE REGULATORS RESPOND: • FDA

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NANOMATERIALS..

HOW THE REGULATORS RESPOND: • EU

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NANOMATERIALS..

EU RECOMMENDATIONS:

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● CHOICE OF MATERIALS HAS A CRUCIAL IMPACT ON ALL ASPECTS OF THE FUNCTIONALITY / USABILITY OF A DEVICE IT IS REALLY IMPORTANT TO RECORD: ● The DESIGN DECISIONS underlying choice of materials, and… as previously discussed – INVESTIGATIONS THAT WORKED AND THOSE THAT DID NOT – LEARNINGS FROM THE DATA GENERATED – RISKS MITIGATED / NEW RISKS IDENTIFIED – STUDIES TO CONFIRM COMPLIANCE WITH REGULATORY STANDARDS – INNOVATIVE APPROACHES ● DESIGN CONTROLS Reminder! DOCUMENTING THE DESIGN PATHWAY

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Use of device materials for drug delivery

EXAMPLE - TREATMENT OF LIVER CANCER • Embolisation with device beads

• Chemoembolisation beads+chemotherapy

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Suggested further reading ● Cambridge Consultants: Good Design Practice for medical devices and equipment2 (available online) ● Davis JR, Handbook of Materials for Medical Devices, Publ ASM, 2003 • EU SCENIHR; Guidance on the Determination of Potential Health Effects of Nanomaterials Used in Medical Devices2015 http://ec.europa.eu/health/scientific_committees/emerging/docs/scenihr_o _045.pdf ● ISO 10993 – Biological evaluation of medical devices; in particular parts 1, 6, 7, 9 and 12-19. ● USFDA: https://www.fda.gov/science-research/nanotechnology programs-fda/nanotechnology-guidance-documents

© TOPRA and Dr Helen Erwood ESPL Regulatory Consulting

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Design Planning and Design Control

21 st November 2023

Jonathan Bradshaw

Head of Development and Systems Engineering - OOONO Medical A/S

The Organisation for Professionals in Regulatory Affairs The Organisation for

Professionals in Regulatory Affairs

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Learning Outcomes

• The key distinctions between different types of design control, and their importance in delivering safe and effective medical devices.

• Understand how design control can be used effectively whilst promoting the growth of knowledge and design space.

• The role of effective design planning in ensuring appropriate inputs are developed.

• How design inputs are translated into design outputs through an iterative design process.

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What is Design Control?

”…an interrelated set of practices and procedures that are incorporated into the design and development process, i.e., a system of checks and balances.”

”…make systematic assessment of the design an integral part of development.”

”…increase the likelihood that the design transferred to production will translate into a device that is appropriate for its intended use.”

FDA Design Control Guidance

The Organisation for Professionals in Regulatory Affairs

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What is Design Control?

...a common sense approach

Proof that you have designed safe product that meets user needs and requirements!

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