Module 19: Regulation of In Vitro Diagnostic Medical Devices

Module 19: Regulation of In Vitro Diagnostic Medical Devices 18-20 April 2023

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Module 19: Regulation of In Vitro Diagnostic Medical Devices

Date: 18 – 20 April 2023

LOCATION: TOPRA OFFICE, LONDON, UK

Module Leader(s) : Nancy Consterdine & Stuart Angell

Day 1: Tuesday 18 th April 2023

Time

Activity

Speaker

Stuart Angell, IVDeology

13:00 – 13:30

Welcome and Introduction to Module

Lecture 1: Setting the Scene – EU Focus A regulatory and Industry Perspective To include UK CA

Stuart Angell, IVDeology

13:30 – 14:30

Nancy Consterdine, IVDeology

14:30 – 15:30

Lecture 2: Classification of IVD Devices

15:30 – 16:00

Afternoon break

Lecture 3: Conformity Assessment:

Nancy Consterdine, IVDeology

What are the different routes and how does a manufacturer select the route which is appropriate for their device?

16:00 – 17:00

Lecture 4: Quality Management System

Stuart Angell, IVDeology

What is an ISO 13485 QMS? Why is it needed? In which countries is it recognised? What about CMCAS? What about MDSAP?

17:00 – 18:00

Module 19: Regulation of In Vitro Diagnostic Medical Devices

Date: 18 – 20 April 2023

LOCATION: TOPRA OFFICE, LONDON, UK / ONLINE

Module Leader(s) : Nancy Consterdine & Stuart Angell

Day 2: Wednesday 19 th April 2023

Time

Activity

Speaker

Stuart Angell, IVDeology Nancy Consterdine, IVDeology Stuart Angell, IVDeology Nancy Consterdine, IVDeology

Review of Day 1: Interactive session to reflect on learnings from day 1, answer any questions and confirm understanding

09.00 – 09.30

Case Study: Apply learnings on classification, conformity assessment and QMS in a group setting using real life examples

09.30 – 10.30

10.30 – 10.45

Morning break

Ben Jacoby, Cambridge RA

Lecture 5: Technical Documentation What is it? How should it be compiled? What is STED? How to write a DoC. To include EU IVDR Lecture 6: Performance Data & Product Claims: What is the difference between Scientific Validity, Analytical Performance and Clinical Performance and how should the data be collected and analysed? What is the significance of your claim?

10.45 – 11:45

11:45 – 13:00

Maurizio Suppo

13.00 – 13:45

Lunch

Lecture 7: Post Market Surveillance, Vigilance and FSCA

Stephen Lee, ABHI

13:45 – 14:45

Case Study: (Includes afternoon break) Apply learnings on PMS, vigilance and FSCA in a group setting using real life examples

14:45 – 15:45

Stephen Lee, ABHI

Lecture 8: Risk Management What is ISO 14179? When is it needed and why? How to establish a RM policy, procedure and plan. When is a risk acceptable?

Stuart Angell, IVDeology

15:45 – 16:45

Lecture 9: Registration

What is required and why? What is EUDAMED and what are the requirements on UDI? Local country requirements versus EU – what is the difference?

Nancy Consterdine, IVDeology

16:45 – 17:45

Module 19: Regulation of In Vitro Diagnostic Medical Devices

Date: 18 – 20 April 2023

LOCATION: TOPRA OFFICE, LONDON, UK / ONLINE

Module Leader(s) : Nancy Consterdine & Stuart Angell

Day 3: Thursday 20 th April 2023

Time

Activity

Speaker

Review of day 2

Nancy Consterdine, IVDeology

Interactive session to reflect on learnings from day 2, answer any questions and confirm understanding Case Study: Apply learnings on performance data & product claims in a group setting using real life examples

09.00 – 09:30

Nancy Consterdine,

09:30 – 10.30

IVDeology

Morning break

10.30 – 10.45

Lecture 10: Other Regulated Markets Which are they? How are they different? How can we drive harmonisation? Who are IMDRF

Nancy Consterdine, IVDeology / Maurizio Suppo

10.45 – 12:30

Lunch

12:30 – 13.15

Lecture 11: Other Legislation

Nancy Consterdine, IVDeology

Beyond IVDR. What about REACH, RoHS WEEE, GDPR, Machinery Directive and more

13.15 – 14.15

Afternoon break

14:15 – 14.45

Lecture 12: Companion Diagnostics and the IVDR What this means for co-development and personalised medicine

14.45 – 15.45

Maurizio Suppo

15.45

Close of Module

18/04/2023

Masterclass

Setting the Scene – EU Focus

18-20 April 2023

Stuart Angell, Director and Co-Founder, IVDeology LTD

ENABLING AND PROMOTING EXCELLENCE IN THE HEALTHCARE REGULATORY PROFESSION

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Learning Outcomes

 Basic Overview  Provide a perspective from a Manufacturers point of view of the key challenges for the IVD Regulation

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Regulatory Framework

Innovation office/ General Advice

Device development

PS approval

Post Market Surveillance Compliance Vigilance

Where does the NCA fit in?

Performance Evaluation

CE Mark

Notified Bodies

Harmonised Standards and Common Specifications

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What’s the difference between a regulation and a directive?

Europa – the official website of the EU – explains the difference. A regulation is a binding legislative act. It must be applied in its entirety across the EU. A directive is a legislative act that sets out a goal that all EU countries must achieve. However, it is up to the individual countries to devise their own laws on how to reach these goals.

https://europa.eu/european-union/eu-law/legal-acts_en

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Setting the Scene – EU Focus

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Global Harmonisation

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Why was change needed?

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5 Key Challenges

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1. Product Classification

IVDD: 80% Self-declared, 20% NB scrutiny IVDR:20% Self-declared, 80% NB scrutiny Potential swing from general IVD to class C

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1. Product Classification

IVDD: List of high-risk disease states and conditions IVDR: Classification more on intended use, intended purpose Devil is in the detail Go/No-go decisions are being made

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2. Technical Documentation

• Annex I – General Safety and Performance Requirements • Annex II – Technical Documentation • Annex III – Post Market Surveillance

• Potential significant investment in time and resource • Harmonised approach with IMDRF STED • EU market access no longer the easy pathway

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2. Technical Documentation

Class B and C and D Technical Documents require NB review

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2. Technical Documentation

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2. Technical Documentation

• Notified Body Interaction • New engagements/Relocating/consolidation

• Availability challenges has been widely reported and experienced • Will have a financial, compliance and time impact on placement on market • Implementing acts and guidance • Standards Update

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3. Clinical Evidence

• Performance Evaluation mandatory for all IVDs • Clinical Evidence potentially required for all IVDs • Performance Evaluation

– Analytical Performance Report – Clinical Performance Report – Scientific Validity Report

(these are all new and have to be created) • Joining the dots up of design history •

Providing a narrative linking all parts of performance evaluation, risk and intended purpose

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IVD performance characteristics

Analytical Performance

Analyte

Device

Scientific Validity

Clinical Performance

Clinical condition

State of the Art

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Companion Diagnostics

Medicines legislation

Marketing Authorisation

Phase I trial

Phase II/III trial

Devices Authority review/notification Medicines Authority review

Medicines Authority opinion Medicines Authority review

Notified Body review

Analytical performance/ Scientific validity

CE mark (Companion Diagnostic)

Clinical performance study

Devices Regulation

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Setting the Scene – EU Focus

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4. Packaging

• Addition of UDI to labels • Readable format • Availability on all labels (e.g. small reagents) • Eudamed • Additional symbol in draft relevant of IVDs • Beware of the translation costs

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5. Quality Management System requirements

• Person Responsible for Regulatory Compliance • Post-Market Surveillance and Post-Market Follow Up Plan • Economic Operators

Building a QMS under the IVDR is just about jumping a hurdle,.. its jumping a hurdle onto a ledge. Greater time, resource and effort will be required in a post IVDR world

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Context

• 95% micro/SME*

• 70% of clinical decisions based on a result from an IVD*

• 40% of global medtech sales (€115b /€45b)*

• 10% UK Field Safety Notices

*BIVDA and Medtech Europe

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IVDR implementation roadmap/ heatmap

Consider the implications for your business

Will the IVDR apply?

Inform your senior managers

PreAssessment

Review technical documentation (including labelling and clinical evidence)

What will the IVDR intended purpose be?

Is the QMS adequate? When does it expire?

Review existing certificates

Gap Analysis

Review portfolio

Update technical documentation and labelling

Update roles and relationships (MAID and NB)

Update clinical evidence

Update QMS in line with IVDR

Workplan

Implement UDI

Update PMS

Cost/benefit analysis

Project management team

NB submission timetable

Supply chain provisions

Company structure

Implementation

PRRC

Regulatory updates

NB audits (inc unannounced)

Update senior managers

Product liability insurance

Review progress

IVDR training

Continue to review implementation plan

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So what about the UK?

The status so far… Post Brexit arrangements required a new approach

Consultation text published 26 th June 2022

Feedback from all stakeholders Response to specific questions Regulation implementation of 1 st July 2023

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UK MDR2002 and UKCA

MHRA Objectives The safety of medical devices The availability of medical devices, and

The likelihood of the UK being seen as a favourable place in which to carry out research relating to medical devices, develop medical devices, and manufacture or supply medical devices. • Support innovation

• International best practise • Stepwise transition process

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UK MDR 2002 transposed from EU IVDD • Use of CE marking either under IVDD, IVDR • Devices must be registered by 01 Jan 2021 • UKRP for non-UK manufacturers UKCA comes into force 01 July 2023 • All devices be UKCA marked for UK market • CE no longer accepted • Higher risk devices may need CA bodies to complete conformity assessment

Regulation to be published (Q1 2023?) • Similar to EU IVDR

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Transition Timelines

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Final words…

Hope is not a strategy EU IVDR Transition is here, but still so many challenged remain. Manufacturers should be well on their way through transitioning to IVDR.

Uncertainty remains for UK transition.

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Thank you very much

@ivdeology

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Masterclass

Risk Based Classification

Nancy Consterdine, Director IVDeology Ltd

www.ivdeology.co.uk info@ivdeology.co.uk

ENABLING AND PROMOTING EXCELLENCE IN THE HEALTHCARE REGULATORY PROFESSION

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Annex List II IVDs (high risk)

20% of IVDs Notified Body Interaction Required

Annex List I IVDs

Self-test general device

80% of IVDs Self-Declaration for CE marking

General In vitro diagnostics (low risk)

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Class D (high risk) e.g. ABO Blood typing

85% of IVDs Notified Body Interaction Required

Class C e.g. Malaria

Class B e.g. Flu A/B

Class A (low risk) e.g. Instruments, calibrators

15% of IVDs Self-Declaration for CE marking

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•Annex VIII •Series of 7 classification rules •Governed by intended purpose •Ordered assessment of device

•Follow the sequence in turn, identify not applicable or maybe applicable, justify most appropriate class

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Rule 1: Class D

• Transmissible agents • Blood, blood components, organs • High risk diseases • Determining infectious load of high-risk disease

E.g. Hepatitis B, C HIV 1

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Rule 2: Class D

• Blood grouping or tissue typing • Transplant or transfusion purposes • ABO, Rhesus, Kell, Kidd, Duffy systems

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Rule 3: Class C

• Sexually transmitted diseases • Life threatening Infectious disease • Companion diagnostic • Cancer screening • Genetic testing • TDM • Pre-natal and neonates

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Rule 4: Class C

• Self-test devices • Near-patient tests classified in their own right

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Rule 5: Class A

• General lab use • Non critical accessories • Reagents • Instruments • Specimen receptacles

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Rule 6: Class B

• Any not covered by rules 1-5

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Class 7: Class B

• Controls without a quantitative or qualitative value

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MDCG Guidance

Guidance on Classification Rules for in vitro Diagnostic Medical Devices under Regulation (EU) 2017/746 https://ec.europa.eu/health/sites/default/files/md_sector/docs/md_md cg_2020_guidance_classification_ivd-md_en.pdf

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• Significant upward shift of classification • Many IVDs will jump from a general (low risk device) to a class B or C • Increase in classification will result in: • Increased NB interaction • Greater level of technical documentation required • Increased surveillance

Additional Notified Body costs Decreased Notified Body availability Technical Documentation remediation

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Example #1.

• RNA Extracted from Whole Blood

Prognostic gene expression assay using RT-qPCR technology to assess long term clinical outcome in IBD (inflammatory bowel disease). The prognostic qualitative assay utilises gene expression data to generate a risk category that correlates with a patient’s risk of experiencing a frequently relapsing disease course. The risk score from the gene expression values is calculated using proprietary software. This prognostic risk score can then be used in conjunction with a patient’s clinical data to tailor the most appropriate course of therapy for an individual.

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Example #2

Total IgE reagent kit

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A two-step immunoassay intended for the quantitative detection of circulating Total IgE and allergen specific IgE in human sera. The total and specific IgE results are used as an aid in the diagnosis of IgE mediated allergic disorders in conjunction with other clinical findings.

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Example #3.

Antibodies to islet cells

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Immunofluorescent antibody (IFA) test to detect the presence of antibodies to islet cells in human serum.

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Example #4.

Diagnostic Instrument

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A real-time qualitative PCR assay for the detection of 7 somatic mutations in codons 12 and 13 of the human KRAS oncogene using the diagnostic instrument. The kit is intended for use with DNA extracted from formalin-fixed paraffin-embedded (FFPE) samples of colorectal cancer (CRC) or non-small cell lung cancer (NSCLC) samples acquired by resection, core needle biopsy (CNB) or fine needle aspiration (FNA).

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Further questions? We can help!

E: info@ivdeology.co.uk

www.ivdeology.co.uk

Thankyou

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Conformity Assessment

18 – 20 April 2023

Nancy Consterdine, Director, IVDeology Ltd

IVDEOLOGY APP IVD Regulation tool Available to download now

www.ivdeology.co.uk info@ivdeology.co.uk

ENABLING AND PROMOTING EXCELLENCE IN THE HEALTHCARE REGULATORY PROFESSION

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Learning Outcomes

 To understand the routes for conformity assessment  To understand the routes linked to the product classification  To understand the conformity assessment procedure for each route

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Definitions

 Category of Device – As defined by the relevant IVR codes according to Regulation (EU) 2017/2185

 Generic Device Group – 3rd level of the EMDN (one letter plus 4 digits with the most appropriate IVP code

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Conformity Assessment Procedures

 Device class determines which CAP are available

 Class A: no Notified Body involvement ● Exception: sterile class A IVD

 Class B: ● QMS audit, no (scheduled) surveillance audit ● Product assessment: representative sample per category  Class C: ● QMS with annual surveillance audit and unannounced audit ● Product assessment: representative sample per generic device group

 Class D: ● See Class C plus Verification by Reference Lab ● Batch release by notified body

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The Role of the Notified Body Assessment of Technical Documentation

 Product changes have to be approved by the NB ● Where such changes could affect the safety and performance or the prescribed conditions of use  Special cases:  Class D ● Verification of performance by European Reference Laboratory ● Includes testing by ERL  Self-testing devices  Companion Diagnostics: EMA involvement

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Conformity Assessment Procedures

 Class A ● Declaration of Conformity (Art. 17) ● Product : Technical Documentation (Annexes II and III) ● Incident reporting and post-production review ● Quality system risk management and other general requirements including the General Safety and Performance Requirements ● Quality Management System (details given) ● No notified body certification unless for sterile products

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Conformity Assessment Procedures – Class A

Sterile

EC Declaration of Conformity

Not sterile

Sterility (Annex IX or XI)

Notified Body

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Conformity Assessment Procedures

 Class D ● EC Declaration of Conformity (Annex IX) : Quality Assurance – Including assessment of technical documentation (complete Chapter 2) ● OR : EC Type Examination (Annex X) coupled to EC Declaration of Conformity (Annex XI) - Production Quality Assurance ● No sampling, each device Technical Documentation reviewed and approved by NB ● Batch verification ● Verification of design by Reference Lab

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Conformity Assessment Procedures – Class D

Notified Body

Manufacturer’s choice

QA (Annex IX) with assessment of technical documentation

EC Type Examination (Annex X)

Production QA (Annex XI)

(Chapter 2 Complete)

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Art. 50 Scrutiny procedure

 Class D products

 NB notifies the CA of certificates it has granted.

 CA may apply further procedures in ● Art. 40 Monitoring and re-assessment of NBs ● Art. 41 Review of NB assessment of Tech Doc and of Performance Evaluation ● Art. 42 Changes to designations and notifications ● Art. 43 Challenge to the competence of NBs ● Art. 89, 90 and 92 related to dealing with devices presenting an unacceptable risk to health and safety and non-compliant products

 MDCG may request scientific advice from experts

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Conformity Assessment Procedures

 Class C ● EC Declaration of Conformity (Annex IX) : Quality Assurance with parts of Chapter 2 – Sampled by Notified Body according to plan based on the generic device groups ● OR : EC Type Examination (Annex X) coupled to EC Declaration of Conformity (Annex XI) - Production Quality Assurance  Assessment made by Notified Body

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Conformity Assessment Procedures – Class C

Notified Body

Manufacturer’s choice

Full QA (Annex IX) with assessment of technical documentation (Parts of Chapter 2)

EC Type Examination (Annex X)

Production QA (Annex XI)

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Art. 50 Scrutiny procedure

 Class D products

 NB notifies the CA of certificates it has granted.

 CA may apply further procedures in ● Art. 40 Monitoring and re-assessment of NBs ● Art. 41 Review of NB assessment of Tech Doc and of Performance Evaluation ● Art. 42 Changes to designations and notifications ● Art. 43 Challenge to the competence of NBs ● Art. 89, 90 and 92 related to dealing with devices presenting an unacceptable risk to health and safety and non-compliant products

 MDCG may request scientific advice from experts

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Conformity Assessment Procedures

 Class C ● EC Declaration of Conformity (Annex IX) : Quality Assurance with parts of Chapter 2 – Sampled by Notified Body according to plan based on the generic device groups ● OR : EC Type Examination (Annex X) coupled to EC Declaration of Conformity (Annex XI) - Production Quality Assurance

 Assessment made by Notified Body

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Conformity Assessment Procedures – Class C

Notified Body

Manufacturer’s choice

Full QA (Annex IX) with assessment of technical documentation (Parts of Chapter 2)

EC Type Examination (Annex X)

Production QA (Annex XI)

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Conformity Assessment Procedures

 Class B ● EC Declaration of Conformity (Annex IX) : Full Quality Assurance ● Sample of product prior to issue of QMS Certificate – At least one device per category of devices covered by application ● Samples of technical documentation during certification period  Assessment made by Notified Body

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Conformity Assessment Procedures – Class B

Notified Body

Manufacturer

Annex IX (Quality Assurance) Chapters 1 and 3

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Conformity Assessment Procedures

 Devices for self-testing and near-patient testing ● Specific requirements apply – Demonstrate usability – Show studies – ...  Companion Diagnostics ● Involvement of European Medicines Agency (EMA)

 Both have Techncal Documentation reviewed for each device before certificate issued

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Annexes

 Annex IX ● Conformity Assessment based on a quality management system and on assessment of the technical documentation

 Annex X ● Conformity Assessment based on Type Examination  Annex XI ● Conformity Assessment based on Production Quality Assurance

 Note: EC Verification (Annex VI of IVDD) does not exist anymore

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Annex IX – QMS and Tech Doc

 Chapter I: Quality Management System ● 1. QMS to be implemented according to art. 10.8 ● 2. QMS assessment by NB. – Extensive list of QMS elements. – Audit. – Inform NB of substantial changes in the QMS ● 3. Surveillance ● Surveillance audit at least every 12 months – Unannounced audit (at least once in 5 years) – Class C and B: include assessment of technical documentation based on sampling plan

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Annex IX – QMS and Tech Doc

Chapter II: Assessment of Technical Documentation ● Classes B , C & D ● Section 4. Assessment of Technical Documentation – Complete review in accordance with Annexes II and III – Class B and C NB will issue a report on the assessment for device sampled For Class D ● Testing by reference lab (opinion within 60 days) ● NB issues Technical Documentation Assessment Report including Performance Evaluation Assessment Report ● Approval of changes (possibly with reference lab involvement) ● Batch release

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Annex IX – QMS and Tech Doc

Chapter II: Assessment of Technical Documentation ● 5. Specific types ● 5.1. Class C self-tests and Class B and C near-patient tests – Test reports, including studies with intended user – Data showing suitability of the device in view of intended purpose – NB Issues Technical Documentation Assessment Certificate – Change of product ● 5.2 Companion Diagnostics – NB consults with medicinal product CA or EMA – …

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Annex IX – QMS and Tech Doc

Chapter III: Administrative Provisions ● Manufacturer or AR keep at the disposal of CA for at least 10 years after the last device has been placed on the market: – the declaration of conformity, – the documentation referred to in the fifth indent of Section 2.1. and in particular the data and records arising from the procedures referred to in point (c) of Section 2.2., – the changes referred to in Section 2.4., – the documentation referred to in Sections 4.2. and point (b) of Section 5.1., and – the decisions and reports from the notified body

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Annex IX – QMS and Tech Doc

Chapter III: Administrative Provisions ● Each Member State shall make provision that this documentation is kept at the disposal of the competent authorities for the period indicated in the first sentence of the preceding paragraph in case the manufacturer, or his authorised representative, established within its territory goes bankrupt or ceases its business activity prior to the end of this period.

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Learning Outcomes: Recap

 To understand the routes for conformity assessment  To understand the routes linked to the product classification  To understand the conformity assessment procedure for each route

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Acknowledgements

Maurizio Suppo - Qarad

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Masterclass

Quality Management Systems

Stuart Angell, Managing Director and Co-founder IVDeology LTD

www.ivdeology.co.uk info@ivdeology.co.uk

ENABLING AND PROMOTING EXCELLENCE IN THE HEALTHCARE REGULATORY PROFESSION

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Learning Outcomes

 What is a Quality Management System  Why is it needed  MDSAP

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What does Quality actually mean?

Why do we need a Quality Culture?

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Insight

“all manufacturers should have a quality management system and a post market surveillance system which should be proportionate to the risk class and type of device in question” Art. 31

“There is no ‘one size fits all’ Quality Management System. The extent at which an organisation controls

their processes is dependent on the nature, size and complexity of an organisation.”

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General Obligations

“The quality management system shall cover all parts and elements of a manufacturer's organisation dealing with the quality of processes, procedures and devices. It shall govern the structure, responsibilities, procedures, processes and management resources required to implement the principles and actions necessary to achieve compliance with the provisions of this Regulation” (paragraph 8)

Insight

“Establishing a documented, controlled, repeatable process for organisation operations is key to establishing a safe and effective product design, development and manufacture.”

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The Origins Backstory… W. Edwards Deming: 14 Points for Quality Management 1.Create constancy of purpose for improving products and services. 2.Adopt the new philosophy. 3.Cease dependence on inspection to achieve quality. 4.End the practice of awarding business on price alone; instead, minimize total cost by working with a single supplier. 5.Improve constantly and forever every process for planning, production and service.

6.Institute training on the job. 7.Adopt and institute leadership. 8.Drive out fear. 9.Break down barriers between staff areas.

10.Eliminate slogans, exhortations and targets for the workforce. 11.Eliminate numerical quotas for the workforce and numerical goals for management. 12.Remove barriers that rob people of pride of workmanship, and eliminate the annual rating or merit system. 13.Institute a vigorous program of education and self-improvement for everyone. 14.Put everybody in the company to work accomplishing the transformation .

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ISO13485:2016

 ISO13485:2016 is still the standard of choice under IVD Regulation

• Is specific for the In Vitro Medical Device and Medical Device industry • Not yet harmonized under IVDR • Concept of QMS has been extended to economic operators • Requirement for a QMS is included in the conformity assessment annexes IX, X and XI

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Insight

“Understanding your inputs and outputs are essential for effective Quality Management. The processes within ISO13485 are interconnected and work collectively to ensure quality.”

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Where to begin..

• What does quality mean to you (Quality Policy)? • What do your customers or regulations need from you? • Defining quality objectives relevant to company vision • Describe how quality processes are run and interact with each other (Quality Manual, procedures) • Who is responsible for quality processes? • How are you recording your actions?

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The pushback…

Insight

 “ Why are we adding additional complexity?”  “We can’t afford to do this!”  “This is delaying getting products on market!”  “We only have 3 people in the company!”

“Effective implementation of a QMS will add value to any organisation.

Much of what is described in the

standard is already performed as part of natural company growth.”

 Here is why…

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The Benefits of a QMS: 3 examples

Document and Change Control

Risk Management

Supplier Management

Standardisation of processes and recording activity allows effective

Identification, assessing and controlling risk, allows the prevention of incidents that will have financial, safety and legal consequences

Organisations live or die on the quality of suppliers. A robust mechanism for supplier assessment and control will reduce risk of supply issues

delegation of actions, and enhanced ability to identify errors, risks and improvements

Consider the size, format and scope of the QMS specific to the requirements of the company

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Auditing…

A quality management system can be assessed by a notified body for conformity The certificate can be a useful mark of quality

Dave Spud

But

Internal auditing is essential to assess the state of the organization. The more you review the QMS the more efficient and compliant it will be.

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Medical Device Single Audit Programme • Demonstrate conformity of Quality Management Systems • Based on ISO13485:2016 • Essential for Canadian registration • Supports Japan, Australia, USA and Brazil registration

Insight

“Good example of global harmonisation approach, this is highly recommend is these markets are required as part of the portfolio. There is an additional cost for this service will allow less audit pressure and ease market access routes”

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Learning Outcomes: Recap

 Quality Management Systems are essential for the IVD industry  How a QMS is used is highly dependent on the organisation, but based on ISO13485 requirements  An effective QMS can add real value  MDSAP is a useful addition to the process if applicable to your product portfolio

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Acknowledgements Mauricio Suppo - Qarad

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Lecture 5 Technical Documentation What is it? How should it be compiled? How to write a DoC

Wednesday 19 th April 2023

Ben Jacoby, Cambridge RA Ltd. bjacoby@cambridge-ra.com

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Scope

Directive 98/79/EC on in vitro diagnostic medical devices

Regulation (EU) 2017/746 on in vitro diagnostic medical devices

IVD Regulation, abbreviated ‘IVDR’

IVD Directive, abbreviated ‘IVDD’

The focus is on European legislation:

More emphasis on IVDR than IVDD

details omitted for For general awareness only, brevity

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Learning Outcomes / agenda

General introduction

Technical documenation

UK Brexit

How should it be compiled?

How to write a DoC

What is it?

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General introduction

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Increased regulatory scrutiny under IVDR

IVD directive ~15% of IVD’s require intervention of notified body

IVDR ~85% of IVD’s require intervention of notified body (All except Class A)

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Review of technical documentation under IVDD

Annex II Most technical files reviewed by NB

Non-Annex II Few if any technical files reviewed by NB

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Notified body expertise under IVDD

Annex II NB’s generally familiar with these products

Non-Annex II NB’s mostly unfamiliar with these products which are self certified by the manufacturer

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Notified bodies under IVDD = 19

‘

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Notified bodies under IVDR = 10 (As of March 2023)

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Some potential transition issues (IVDD to IVDR)

Impact on legacy devices especially re-classification Conversion to IVDR •How far should technical documentation follow the exact order and structure of Annexes II and III? Conformity with IVDR general safety and performance requirements rather than IVDD essential requirements Number of technical files which might need revision Availability and resources of notified bodies Additional clinical evidence which might be required Impact of common specifications, implementing acts, updated guidance Resources required to maintain technical documentation

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Technical documentation

What is it?

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Technical documentation IVDR (Article 10)

1.’When placing their devices on the market or putting them into service, manufacturers shall ensure that they have been designed and manufactured in accordance with the requirements of this Regulation.’ 4. ‘Manufacturers shall draw up and keep up to date the technical documentation for those devices. The technical documentation shall be such as to allow the conformity of the device with the requirements of this Regulation to be assessed. The technical documentation shall include the elements set out in Annexes II and III.’

Article 10 ‘General obligations of manufacturers’ * Highlighting added to draw attention to this need.

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Technical documentation

How should it be compiled?

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How should it be compiled?

‘The technical documentation and, if applicable, the summary thereof to be drawn up by the manufacturer shall be presented in a clear, organised, readily searchable and unambiguous manner* and shall include in particular the elements listed in this Annex.’ (IVDR Annexes II and III)

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The IVDD has no fixed format for technical documentation. By contrast IVDR Annexes II and III are quite prescriptive. This should drive more consistency around the content of technical documentation for example both within and between different manufacturers. Format of technical documentation

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Some notified bodies have their own guidance for IVDR, e.g.:

bit.ly/3sHnXip

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Team NB Position Paper

Best Practice Guidance for the Submission of Technical Documentation under Annex II and III of In Vitro Diagnostic Medical Devices Regulation (EU) 2017/746

27 th February 2023

https://www.team-nb.org/team-nb-pp-best-practice-guidance-for-the submission-of-technical-documentation-under-annex-ii-and-iii-of-in-vitro diagnostic-medical-devices-regulation/

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Best Practice Guidance for the Submission of Technical Documentation under Annex II and III f In Vitro Diagnostic Medical Devices Regulation (EU) 2017/746 27 th February 2023

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Team NB Position Paper

Information to be supplied by the manufacturer – a collaborative notified body approach. • The following slides include selected text from the Position Paper within ‘quotation marks’. Some text is highlighted in yellow to show particular emphasis. https://www.team-nb.org/team-nb-pp-best-practice-guidance-for-the-submission-of technical-documentation-under-annex-ii-and-iii-of-in-vitro-diagnostic-medical-devices regulation/

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IVDR Annex II, main headings

● 1. DEVICE DESCRIPTION AND SPECIFICATION, INCLUDING

VARIANTS AND ACCESSORIES 1.1. Device description and specification - ‘The Basic UDI-DI must be consistent throughout the technical documentation - For devices grouped under one basic UDI-DI number please describe the differences to demonstrate how these falls under the same group.’

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How to write technical documentation

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IVDR Annex II, main headings

● 1. DEVICE DESCRIPTION AND SPECIFICATION, INCLUDING VARIANTS AND ACCESSORIES 1.1. Device description and specification - ‘The intended user and use environment should be clearly described within the technical documentation. - The intended use, user, target population and clinical condition / physiological state must be supported by the results of the clinical performance evaluation. - ’

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IVDR Annex II, main headings

1.2. Reference to previous and similar generations of the device

‘All submissions should be accompanied by a market history ...’

If the device is new and has never been marketed by the manufacturer anywhere in the world, state this explicitly.’

Provide an overview of identified similar devices available on the EU or international markets ... Provide a comparison of the key specifications.’

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IVDR Annex II, main headings

● 2. INFORMATION TO BE SUPPLIED BY THE MANUFACTURER ‘Provide the label or labels on the IVD for all variants; this includes … sales packaging labelling or transport packaging labelling, in the final approved version.’

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IVDR Annex II, main headings

● 2. INFORMATION TO BE SUPPLIED BY THE MANUFACTURER ‘Manufacturers must ensure that the information within the IFUs, especially related to intended purpose, indications, contra-indications, and other safety related information, warnings is aligned with similar information from other sections such as risk management, performance evaluation, usability etc.’

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IVDR Annex II, main headings

● 2. INFORMATION TO BE SUPPLIED BY THE MANUFACTURER ‘Manufacturers’ ‘If a safety data sheet (SDS) is provided for the device, the SDS is part of the Technical Documentation …’ ‘Note that instructions for obtaining the SDS shall be included on the label or instruction for use’

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IVDR Annex II, main headings

● 2. INFORMATION TO BE SUPPLIED BY THE MANUFACTURER

‘Only marketing literature that mention that the device fulfils the requirements of CE marking or includes the CE mark itself is required to be provided.’ ‘Claims made in the marketing literature must be consistent with the IFU and consistently displayed in the submitted technical documentation.’

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IVDR Annex II, main headings

3. DESIGN AND MANUFACTURING INFORMATION – 3.1. Design information – ‘Where the device uses software … provide a description of the data interpretation methodology i.e., analysis algorithm’ – For devices containing raw materials

of human, animal or microbial origin, a Certificate of Analysis (CoA) must be submitted

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IVDR Annex II, main headings

3.2. Manufacturing information

Incoming inspection of critical raw materials/active ingredients Specifications and final concentrations/quantities of critical raw materials/active ingredients (subcomponents for instruments) in the finished device In-process QC Final release QC, with the CoA.’

Provide detailed information on:

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IVDR Annex II, 3.2. Manufacturing information

In case of sub-contracted (outsourced) processes:

‘For critical component suppliers (e.g., outsourced manufacturing of sterile device) overview of manufacturing processes and corresponding control measures (e.g., references to verification and validation activities, copy of the certificate shall be included).’

‘For non-critical component suppliers (e.g., bulk) identification of supplier only.’

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IVDR Annex II, 3.2. Sites and subcontractors

‘The manufacturer shall provide …: Site and local manufacturer details … Site with design responsibility Site(s) performing production, assembly, final product testing, and packaging of the finished device … Where a service or production is outsourced provide the name and address of the critical subcontractors or suppliers (as per Commission Recommendation 2013/473/EU) ... Copies of critical subcontractor and suppliers ISO 13485 certificates …'

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IVDR Annex II, 3.2. Sites and subcontractors

‘For critical suppliers and /or subcontractors satisfactory evidence that the purchase critical products or service meet the specified requirements shall be shown (e.g., EN ISO 13485 certificate, records of supplier audits, 100 % incoming inspection or any other control)’

‘… the notified body will then assess if an audit at the premises of the critical supplier and/or subcontractor is necessary. Relying on solely the supplier certification may not be considered sufficient.’

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