Since Regulation (EU) 2017/745 of the European Parliament and of the Council on medical devices (EU-MDR) came into force, Swissmedic has adapted its authorisation requirements for medicinal products with an integral medical device component (integral combination products) to the provisions of the EU-MDR.
An application for authorisation of an integral combination product in the EU must prove that the medical device component meets the general safety and performance requirements (GSPRs) according to Annex I of the EU-MDR. According to Article 117 EU-MDR, in the absence of an EC certificate a Notified Body Opinion (NBOp) on the conformity of the integral medical device component must be included where the integrated medical device is a product of class Is, Im, IIa, IIb or III. These requirements are also applied in Switzerland.
Swissmedic requirements regarding an NBOp
The NBOp is an essential element of the authorisation documentation for the assessment of an integral combination product.
The NBOp should therefore be evidence of a robust, complete and unambiguous assessment of the conformity of the medical device component(s) with the applicable GSPRs. Swissmedic bases its assessment of integral combination products in the context of the authorisation procedure on the statements included in the NBOps.
To verify whether the information currently provided in the NBOps is sufficient and appropriate for this purpose, Swissmedic medicinal product authorisation experts together with Swissmedic medical devices surveillance inspectors subjected a sample of ten NBOps to a detailed review. Only the content of and statements in the NBOps were reviewed; there was no review of the technical documentation on the medical device components as these fall within the area of responsibility of the Notified Bodies.
In general, the NBOps showed considerable variation in terms of extent and format. In addition, recurrent content-related deficiencies and critical points were identified.
Frequent critical shortcomings of the NBOps examined:
1. Unclear/incomplete scope of the NBOp with regard to the medical device components assessed
Example:
- Unclear which medical device components of the combination product are covered by the NBOp, for example whether the NBOp for an autoinjector also covers the prefilled syringe and the needle.
2. Codes and classification missing/incorrect
Examples:
- Active devices such as spring-loaded autoinjectors are classified as non-active devices.
- MDS code for sterile products missing.
3. Applicable GSPRs not correctly identified and met
Examples:
- GSPR 14.1 missing (device intended for use in combination with other devices). This is particularly important if not the complete medical device component is part of the NBOp.
- Missing or implausible justifications for the non-applicability of GSPRs.
- Applicable GSPRs inconsistent.
- Conformity confirmed despite obvious data gaps.
4. Superseded standards applied
Examples:
- Application of superseded standards in the areas of risk management, usability, biocompatibility.
5. Insufficient verification and validation data
Examples:
- Missing or incomplete data on biocompatibility, usability, transport validation and aging.
- Data not transferrable to the version of the medical device component that is part of the combination product submitted for authorisation.
6. Gaps in the available data on the medical device component are passed on to the authority for review, even when this is not within the area of responsibility of the authority.
Conclusion:
The ten NBOps in the sample do not completely address the questions on the medical device component(s) that are relevant for the authority. It is not clear from the NBOps evaluated that all applicable GSPRs are met for the complete and final medical device component of the integral combination product throughout the entire life cycle.
The competence of the Notified Bodies is not in question. However, the content of the NBOps reviewed shows shortcomings in terms of completeness and plausibility. They are therefore of limited use in terms of completing and supplementing the review by the authorities.
Swissmedic’s expectations regarding NBOps
Based on this analysis, experience to date with submitted NBOps and in accordance with Article 117 EU-MDR, Swissmedic issues the following fundamental instructions on the key content and expected quality of NBOps for the authorisation assessment.
- Those medical device components which are covered and not covered must be clearly identified and the relation to the combination product must be described.
- Product description and intended use are described.
- Specified classification and codes are correct.
- Full conformity with applicable GSPRs based on data is confirmed.
- Applicable GSPRs are correctly identified.
- Plausible justification for non-applicable GSPRs.
- Applied standards, incl. version, are listed.
- A summary of the reviewed data (a.o., biocompatibility, transport, aging, usability) is available. The data are applicable for the version of the medical device component that is part of the combination product to be authorised.
- Data gaps are identified; recommendations concerning these are limited to the area of responsibility of the authority.
- There is a clear conclusion/statement on conformity of the components assessed with the applicable GSPRs.
- Type, version, date and revisions of and persons responsible for the NBOp are clearly indicated.
It is the responsibility of the applicant for the combination product to ensure that the NBOps plausibly prove the conformity of the medical device components. Applicants submitting the corresponding authorisation applications must critically assess the NBOps before submission.
Unclear and incomplete NBOps may result in delays in authorisation, whereas conclusive NBOps support the authorisation process for combination products, including adherence to timelines.