Earlier this month, Rania Gerges, a Qserve Consultant and a QMS
expert presented “Beyond MDSAP and ISO 13485: The Impact of the New EU
Regulations on Audits”, in the International Track at the MedCon conference in
Cincinnati, OH. Rania focused her talk on how the MDR impacts the design and
development cycle. This blog summarizes the main points of her talk.
The new Medical Device Regulation (MDR, EU 2017/745) has introduced
a number of new and significantly updated processes that must be integrated in a
manufactures’ Quality Management System (QMS) if they currently or intend to
sell medical devices in the EU. These processes go beyond the current
requirements for ISO 13485:2016 and the Medical Device Single Audit Program (MDSAP).
The table below provides a high-level comparison between the ISO 13485:2016 and
the corresponding MDR requirements.
ISO
13485:2016
|
MDR
|
4.2 Documentation requirements
|
§
Technical Documentation – Annex
II, III
§
Strategy for Regulatory
Compliance – Article 10, Annex IX
§
Administrative Provisions – Annex
IX
|
5. Management responsibility
|
§ Person Responsible for Regulatory Compliance – Article 15
|
7.3 Design and development
|
§
Strategy for Regulatory
Compliance – Article 10, Annex IX
§
Use of Harmonized Standards –
Article 8
§
Common Specifications – Article 9
§
General Safety and Performance
Requirements (GSPR) – Annex I
§
Clinical Evaluation – Article 61,
Annex XIV Part A
§
Clinical Investigation – Article 62-82, Annex XV
|
7.5.8 Identification
7.5.9 Traceability
|
§ Importers and Distributors Obligations – Article 13, 14
§ Identification within the Supply Chain – Article 25
§ UDI System – Article
27, ANNEX VI Part C
§ Registration of Devices and Economic Operators – ANNEX VI Part A
|
8. Measurement, analysis and
improvement
|
§
Post Market Surveillance –
Article 83-86, Annex III
§
Vigilance and Trend Reporting –
Article 87-89
§
Post Market Clinical Follow-up – Annex XIV Part B
|
The basis for the new QMS requirements
is laid down in Article 10 (General obligations of manufacturers) and Chapter
1: Quality Management System of ANNEX IX of the MDR. However, additional QMS
requirements are scattered throughout the MDR articles and annexes. The MDR introduces
additional requirements that go beyond Article 10, ISO 13485:2016 and the
MDSAP. These requirements must be thoroughly reviewed to understand their
interdependence and impact on key QMS processes.
A typical design and development
process cycle includes a number of sequential design stages or phases as laid
down by ISO 13485 or 21 CFR 820.30. These phases typically include Design and Development
Planning, Inputs, Outputs, Verification and Validation, Commercialization,
Post-Market and Design Changes. The MDR does not require any changes to the
current design control structure with regard to having stages or phases.
However, it is expected that the revised requirements in the MDR will be
integrated in the design control cycle initiated during planning and carried
throughout the design cycle, including the post market phase.
MDR Annex IX, 2.2 (c) states that “the
procedures and techniques for monitoring, verifying, validating and controlling
the design of the devices and the corresponding documentation as well as the
data and records arising from those procedures and techniques shall
specifically cover: the strategy for regulatory compliance,
including processes for identification of relevant legal requirements,
qualification, classification, handling of equivalence, choice of and
compliance with conformity assessment procedures”. Based on this requirement, the
design and development process must not only consider the markets in which the
device will be launched, compliance to industry and device specific regulations,
and device classification, but also all the aspects needed to address the
strategy for regulatory compliance. That being, device classification, as
modified by Annex VIII of the MDR, and handling of equivalence, based on
requirements in Part A of Annex XIV. These aspects will have regulatory
implications and may also impact the product launch timelines.
Annex IX, 2.2(c) requires that “identification of applicable General Safety
and Performance Requirements (GSPR) and solutions to fulfil those
requirements, taking applicable Common
Specifications and, where opted for, harmonized
standards or other adequate solutions into account” to be covered as part
of the design and development process. Many manufacturers fill out the
Essential Requirements Checklist (Annex I) of the Medical Device Directive
(MDD) just before technical file submission to apply for CE mark. This practice
will change since Annex I (GSPRs) of the MDR has both significantly updated and
completely new requirements that were not part of the MDD. The GSPRs along with
the applicable Common Specifications and Harmonized Standards will impose new
device requirements and specifications that must be addressed as part of the
design and development inputs, outputs, verification and validations phases,
not simply compiled for CE mark submission. To reference only a few of the
significantly updated requirements in Annex I of the MDR, refer to GSPR 10.4 (Hazardous
substances: CMR: carcinogenic, mutagenic or toxic to reproduction , endocrine
disrupting substances), GSPR 12 (Devices incorporating a substance considered
to be a medicinal product and devices that are composed of substances or of
combinations of substances that are absorbed by or locally dispersed in the
human body), GSPR 17 (Electronic Programable Systems), GSPR 22 (Devices
intended for use by lay persons) and GSPR 23 ( Label and instructions for use).
The clinical evaluation process laid
down in the MEDDEV 2.7/1 Rev. 4, : A
guide for manufacturers and notified bodies under directives 93/42/EEC and
90/385/EEC (published in June of 2016) requires the clinical evaluation process
to begin during the development of a medical device. Premarket research and
development are to be guided by clinical evaluation and risk management to define
needs regarding clinical safety and clinical performance of the device. The
process requires the manufacturer to evaluate if there are clinical data available,
determine equivalence, define gaps in data for the device under evaluation, and
determine whether clinical investigations are necessary to fill those gaps. Annex
IX 2.2(c) of the MDR, requires that “the clinical
evaluation, pursuant to Article 61 and Annex XIV, including post-market clinical follow-up,” be
covered in the design and development process. From a documentation standpoint,
the MDR adopts similar requirements of the MEDDEV 2.7/1 Rev. 4 with more specific
contents to be included as part of the Clinical Evaluation Plan (CEP) and
Clinical Evaluation Report (CER). In addition, requirements for biological
equivalence mandate that materials used have similar release characteristics of
substances, including degradation products and leachables. The MDR also
introduces two new terms as part of the clinical evaluation documentation the “Clinical
Development Plan” (CDP) and the “Summary of Safety and Clinical Performance”
(SSCP). The SSCP is only applicable for Class III and implantable devices. Therefore,
the design and development process must consider the handling of equivalence, potential
needs for clinical investigation, as well as, planning and creation of the clinical
evaluation documentation. The planning, gathering of pertinent data, and
evaluation of data must take place throughout the design and development cycle and
in the post market phases.
Another process that is interdependent
to the design and development is Post
Market Surveillance (PMS). PMS is not a new concept, but the MDR provides a
clear definition for it in Article 2(60) and detailed requirements to be met in
Article 83-86 and Annex III. Under the MDD and ISO 14971: Medical devices -- Application of risk management to medical devices,
the planning for the Post Market Surveillance might be initiated after the
device is placed on the market. Now as part of the MDR (Annex III), PMS now
part of the technical documentation. Therefore, prior to receiving the CE mark
and placing the device on the market under the MDR, manufacturer must create
and plan the PMS including Post Market Clinical Follow-up (PMCF) activities
documented in a PMS and PMCF plan to be executed once the device is placed on
the market.
What does an MDR compliant design
and development process look like? The table below summarizes the discussion
above and gives additional design records that must be generated during the
design development phases.
Design
Phase
|
Design
and development records required by MDR
|
Planning
|
§
Strategy for Regulatory
Compliance
§
Clinical Development Plan (CDP)
§
Clinical Evaluation Plan (CEP)
|
Inputs
|
§
Applicable General Safety and Performance Requirements (GSPRs)
§ Applicable Common Specifications
§ Applicable Harmonized Standards
|
Outputs
|
§
Specifications, procedures and
techniques to conform to GSPRs
§
Labelling (label, sterile
packaging label, implant card, IFU, website contents, etc.)
|
Verification and Validation
|
§ Design Verifications, Validations or other methods demonstrating
conformity to GSPRs
- Clinical
Evaluation Report (CER)
- Clinical
Investigations, as applicable
- SSCP
(Class III and Implantable only)
|
Post Market
|
- PMS Plan
- PMS Report (Class I only)
- Periodic Safety Update Report (PSUR)
- PMCF Plan
- PMCF Evaluation Report
|
Two common questions manufacturers
typically ask: the first question being whether the technical documentation for
legacy devices needs to be remediated. The answer is: Yes. The assumption is that
manufacturers start with a blank page and document all the objective evidence
to fulfill the requirements of Annex II and III to comply with the applicable General Safety and Performance Requirements (GSPRs). The second question is whether design control records such as the
design history file (DHF) also need to be remediated. The answer is: Most
likely, yes. During the remediation of the technical documentation and
addressing the additional requirements of the GSPRs, it is likely the there
will be new design inputs and subsequent outputs, validation and verification
records, as applicable. Thus, impacting design records, and therefore must be
captured as part of design changes to existing DHFs. In a best-case scenario,
if the significantly revised or new GSPRs do not impose additional requirements
to the device under remediation, the labeling (labels, IFUs) will certainly be
updated as a result of GSPR 23.