Medical Device Regulations

By Ka-Mei Au

Rob Higgins is a Senior Regulatory Affairs Manager at the Medicines and Healthcare products Regulatory Agency (MHRA) and has worked there for over 30 years. Rob has experience working in medical device legislation, reviewing clinical investigations, and monitoring Notified Bodies. His main responsibilities now include conducting inspections on medical device manufacturers, the assessment of UK Approved Bodies, and being involved in global harmonisation activities. With his expertise, Rob gave an overview of the recent and upcoming changes in EU and UK medical device regulations, key considerations medical device manufacturers should be aware of, and what inspectors look for in manufacturer inspections.

Background

Rob’s presentation started with an overview of the existing medical device legislation in the UK which was implemented in 2002. This was based on three EU Directives: Medical Devices Directive (MDD), Active Implantable Medical Devices Directive (AIMDD) and In Vitro Diagnostic Medical Devices Directive (IVDD) (see Figure 1). These will remain active in Great Britain until new regulations are implemented in 2023.

EU MDR and EU IVDR

There are two new EU medical device regulations which are replacing the existing directives in EU Member States: • EU Medical Devices Regulation (MDR) – applies from 26 May 2021 • EU In Vitro Diagnostic Medical Devices Regulation (IVDR) – applies from 26 May 2022

Figure 1. The EU medical device regulations replacing the current EU directives

The implementation of these new regulations will result in the following changes: • Updated medical device definitions and classification (see Figure 2) • A stronger post marketing surveillance system • The requirement for a person responsible for regulatory compliance – similar to a qualified person responsible for pharmacovigilance (QPPV)

• Unique device identification (UDI) for devices • New requirements for medical device importers and distributers

Specific changes implemented by the MDR:

• Includes devices incorporating non-viable human tissues/cells

• Includes products similar to medical devices but have an aesthetic purpose e.g. plano contact lenses, dermal fillers

• Reclassification of many medical devices to higher risk classes

• New classification for reusable surgical devices will require Notified Body oversight • Most companies will need to update clinical data, technical documentation and labelling • Summary of Safety and Clinical Performances is required for implantable devices and Class III devices

Specific changes implemented by the IVDR:

• Expanded definition of in vitro diagnostic devices e.g. companion diagnostic tools, software etc. (previously there was no detail on software) • New classification requires increased scrutiny by Notified Bodies – previously only 10% of in vitro diagnostic devices required approval by a Notified Body. Under this new regulation, 80-90% of these devices will require approval

• More detailed information will be required concerning the analytical and clinical performance of a device

• Sufficient demonstration of clinical benefits and safety will be required

• Summary of Safety and Clinical Performance for

Class C and D devices will be needed

UK medical device regulations

Since these new EU regulations did not take effect during the Brexit transition period, they were not EU law automatically retained by the EU Withdrawal Agreement Act and, therefore, will not automatically apply in Great Britain.

From January 2021, the MHRA have been working to develop a new domestic regulatory framework for medical devices. International standards, best practice and global harmonisation are being taken into consideration. A consultation on the future regulation of medical devices in the UK was opened by the MHRA on 16 September 2021, which invited members of the public and those in the industry to share their views on the matter.1 The MHRA also held two webinars in October 2021 to provide people with more background knowledge. The consultation closed on 25 November 2021.

Registration of medical devices in GB

Previously, medical device manufacturers only had to register in one EU Member State but now, if manufacturers want to sell into GB, the device must be registered first in GB. To register a medical device with the MHRA, it must conform to the UK MDR 2002, the EU MDR (until 30 June 2023), or the EU IVDR (until 30 June 2023).

UK Responsible Person

If manufacturers based outside of the UK wish to place a device on the GB market, the product must be registered with the MHRA beforehand. The manufacturer should therefore appoint a UK Responsible Person (UK RP), who is established in the UK, to do this. This requirement has been implemented since 01 January 2021.

Figure 3. Registration dates for different medical devices in GB

CE and UKCA marking in Great Britain (GB)

CE marking is still valid in the UK until 30 June 2023. The UK Conformity Assessed (UKCA) marking is a new marking for UK goods being placed on the market in GB and will replace the CE marking. UKCA marking is now valid for medical devices marketed in GB and will become mandatory from 01 July 2023. A UK Approved Body, which replaces UK Notified Bodies, must be used to obtain the UKCA mark. They cannot conduct conformity assessments for the CE mark.

Northern Ireland

The Northern Ireland Protocol, which was agreed upon in October 2019, allows Northern Ireland to follow different rules for placing medical devices on the market: • NI will continue to have access to the EU Single Market and will follow EU legislation • As with the other EU Member States, NI will implement the EU MDR and EU IVDR from 26 May 2021 and 26 May 2022 respectively • CE marking, which will be applied by an EU Notified Body, will still be required for medical devices

Figure 4. Timeline overview of key actions in GB

• If a third-party conformity assessment is required for a device, the UKNI marking can be applied by a UK Notified Body. The UKNI marking does not replace the CE marking and is valid for the NI market only

MHRA market surveillance

The MHRA carries out risk-based market surveillance activities which involves proactive and reactive actions. Their proactive activities involve: • Checking medical devices on the market to ensure compliance • Monitoring the safety of the devices • Ensuring the devices work as intended by the manufacturer and that they deliver the intended benefits

Direct audits and inspections are some of the tools that are used by the MHRA to improve the effectiveness and efficiency of market surveillance. These activities are not intended to undertake the role of a UK Approved Body/ EU Notified Body, but rather to complement the inspections conducted by these Bodies.

MHRA audits/inspections

Rob then talked us through the key issues that are often identified in MHRA inspections of medical device manufacturers. He explained that medical device manufacturers of medium and high risk devices must have certification from a UK Approved/EU Notified Body which also normally includes certification against ISO 13485:2016.

Key elements of ISO 13485 include: • General requirements e.g. document control, technical files

• Management responsibility e.g. management review • Resource management e.g. making sure personnel are all trained; infrastructure of building • Product realisation: where production and testing take place

• Measurement, analysis and improvement e.g. AE investigation, reporting to Regulatory Authorities, internal audits

These key elements were expanded upon:

Management responsibility

• Top management should review the organisation’s quality management system (QMS), at annual intervals

• They should refer to ISO 13485, which lists what should be included in these reviews

• The review of new regulatory requirements is often poorly done. In recent inspections, Rob has noted that many management review meetings have not taken into account the changing requirements imposed by the new EU regulations

• Planning • Customer related processes • Design and development: • Validation is an important step to ensure the product can meet the requirements for its intended use

• This requires clinical or performance evaluation(s) to be carried out: • Can be done with clinical trial evaluations or literature reviews. However, Rob remarked that the latter is looked at less favourably these days • Rob explained how clinical evaluations for the design and development of devices is one of the most poorly done areas. He recalls instances where manufacturers have claimed a device is equivalent to another but is in fact very different and where the literature used in their reviews are not relevant to the devices they are developing • Purchasing: • This area is generally done well as the requirements are quite clear-cut • Purchased products should conform to specified purchase requirements and the purchasing information should describe the product • Verification of purchased product • Product and service provision • Validation of processes: • Processes where the resulting output cannot be verified by subsequent monitoring or measurement should be validated e.g. sterilisation processes should be validated prior to initial use

• Can be costly to validate these processes • Overall, this is done reasonably well • Identification and traceability • Preservation of product: • Includes identification, handling, storage and protection • Manufacturers should have documented procedures for the control of a product with a limited shelf life or those requiring special storage conditions • A common finding in inspections is that the monitoring of their storage conditions is inadequate as fridges and freezers are not monitored properly. Important considerations that should be made such as what measures are in place if a fridge/freezer fails, or if the doors have been left open for too long • Control of monitoring and measuring devices

Measurement, analysis and improvement – monitoring and measurement involves:

• Manufacturers receive feedback including customer complaints/vigilance: • Manufacturers are legally obligated to report SAEs they become aware of to the regulatory authorities

• However, a common finding in inspections is that they do not – possibly for fear of having the authority conduct investigations into the company

• Post marketing surveillance: • This includes literature screening of equivalent products, going through notices from the authorities and collecting proactive feedback from users

• This is also a weak area in inspections – many companies are not proactive enough to do more than handle customer complaints • Suggested that internal audits should be carried out annually to determine whether the QMS conforms to regulations and ensure it is effectively implemented

Resource management involves:

• Competence, awareness and training of staff: • The organisation should: • Determine the competency necessary for personnel performing work which affects product quality • Provide training and evaluate effectiveness of the training • Maintain training records • Rob finds it concerning that organisations do not always send their regulatory staff on courses to understand regulations and quality system standards

• As a result, Rob often finds that the Regulatory Affairs Manager is not up to date on changes in regulations • However, it has been noted that manufacturers are generally good at training the assembly staff and those involved in production • Infrastructure: • Appropriate buildings, workspaces, associated utilities • Process equipment (hardware and software) including their maintenance • Supporting services

• Work environment: • Health cleanliness, clothing of personnel, suitable airflow through facilities • Special work environment conditions and their monitoring • An area of concern is that the fabrics seen in controlled environments are not always suitable

Technical file reviews:

• Technical files are sometimes pulled off site in inspections • This is the biggest area of concern for compliance, even in companies that have been approved by

Notified Bodies

• Main areas of concern in technical file reviews include: • Declaration of conformity • Classification – sometimes this is wrong • Clinical/performance evaluation – can be very poor • Risk management – can be poor • Biological safety evaluation • Electrical safety • Electromagnetic compatibility • Packaging and labelling • Sterilisation validation • Stability studies

1. Consultation on the future regulation of medical devices in the

United Kingdom - GOV.UK (www.gov.uk)

Ka-Mei Au

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