by Giuliana Miglierini
As the term to apply for the certification of medical devices and in vitro diagnostics according to regulation 607/2023 approaches (24 May 2024), new data have been published by the European Commission on the current status of the procedures. The critical goal for all the stakeholders involved in reaching compliance with the new rules in time is to avoid the risk of seeing many products excluded from the market.
The last release of the Notified Bodies Survey on certifications and applications run under the DG SANTE’ Framework contract reports data from notified bodies (NBs) designated under MDR/ IVDR until 30 June 2023.
The Medical Devices Coordination Group (MDCG) also updated its position paper “Notice to manufacturers and notified bodies to ensure timely compliance with MDR and IVDR requirements”.
The Notified Bodies Survey on certifications and applications
The Notified Bodies Survey was launched by the European Commission in December 2022 and will close in December 2025. All the 39 notified bodies included in its last release responded to the survey. The majority of them (29) are designated only under the MDR, 9 both under the MDR and IVDR and just 1 only under the IVDR.
Data for medical devices show that there are currently 22.793 total valid certificates referred to Directive 93/42/EEC (MDD) or Directive 90/385/EEC (AIMDD, on active implantable devices). The great majority of them (17.045) will expire during 2024. As for 30 June 2023, there were 13.177 applications filed to comply to the new MDR (+22% compared to October 2022), and 3.899 issued certificates (+32%).
The great part of both applications and certificates refer to devices that need to meet requirements listed in Annex IX (classes I&III and II). Many of the applications and certificates refer to the Quality Management System (QMS, 9.071 and 2.682 respectively), while product ap-plications and certificates were respectively 4.106 and 1.217. A small part of the applications (388) refers to devices incorporating a medicinal substance, thus requiring the activation of the consultation procedure with pharma regulatory authorities (57 issued certificates). The survey also indicates it takes a mean of one to three months to reach signature of the written agreement for applications filed for changes of already MDR issued certificates.
The main reasons for the refusal of the certification include the fact the application is outside the scope of the NB’s designation (47%) or is incomplete (27%). To this instance, the percentage of submissions with a completeness rate > 50% is still low (21% in June 2023, vs 31% in October 2022). The survey also indicates it takes a longer time to obtain MDR QMS + product certificates (13-18 months for 40% of NBs), compared to just the QMS certificate (6-12 months for 45% of NBs).
As for products with no intended medical purpose that fall under the scope of the MDR, the collected data show an increase of the requests to sign a written agreement for a conformity assessment procedure of an Annex XVI product. This trend is expected to continue further in 2024, as well as the estimated transit of MDD certificates for Annex XVI products to the MDR without maintaining the medical purpose for the covered devices.
As for certification applications in accordance with Annex VII section 4.3 of MDR (Application review and contract), the survey reports a total of 15.530 applications and 9.422 signed written agreements (+28% vs the results of the survey closed on 31 March 2023).
The situation for vitro diagnostics
The survey run in October 2022 showed a total of 1.551 valid IVDD certificates. In this case too, the great part of certificates will expire in 2024 (482) and 2025 (866).
The trend of applications and certificates is similar to that of medical devices, with a total of 1.155 applications received as for June 2023 (+22% compared to March 2023) and 500 granted certificates (+51%). Again, the great majority refers to products following Annex IX requirements.
As for class D devices (i.e. IVDs aimed to detect or exposed to transmissible agents which are life-threatening or have a high risk of propagation), the survey reports a total of 231 applications received by June 2023, and 62 certificates. Incomplete applications are again the main reason for refusal of certification. Times required to reach certification are also similar to those seen for medical devices.
MDCG’s amendments to the Notice to NBs and manufacturers
Revision 1 of the MDCG position paper 2022-11 is focused on the new section which calls notified bodies to streamline the certification process, and on the revision of the one referred to manufacturers to submit applications without delay.
The MDCG’s document adds further details to the above seen data from the survey. According to the Coordination Group, the actions taken to facilitate the transition and improve NBs’ capacity (MDCG 2022-14, e.g. use of hybrid audits, deferral of re-assessment of notified bodies, etc.) are showing good results.
Despite the increased number of notified bodies designated under the MDR and the IVDR (40 and 12, respectively), the MDCG highlights that data from the survey indicates limited progress for both the applications and certifications. “This shows that manufacturers tend to transfer at different times devices to be included in the same certificate. Whilst this approach is understandable, it might create issues in planning and in the capacity of notified bodies”, wrote the Coordination Group, also underlining the more worrisome situation for IVDs.
On this basis, the MDCG calls the manufacturers “to make the best possible use of the additional time provided by the amendments of the MDR and IVDR by submitting applications for conformity assessment in good time”.
The position paper also comments on the need to file complete and high-quality applications, so to avoid undue delays in the certification process, possibly before the end of 2023 as strongly recommended by notified bodies.
Manufacturers are also expected to regularly provide data on their devices, to increase transparency, improve the exchange of information on specific medical devices and support institutions and Member States in preparing for changes to product ranges.
As for notified bodies, the MDCG asks them to make the certification process more efficient, transparent, and predictable. Streamlined procedures should be the main objective, together with the need to operate in accordance with consistent, fair, and reasonable terms and conditions.
The position paper highlights the importance for notified bodies to provide regulatory guidance and technical information to manufacturers on how to apply for the conformity assessment procedure, so to avoid any issue and delay with the application and certification process.
The MDCG also recalls the importance to support small and medium size companies, and to organise structured dialogues with manufacturers as a part of the normal pre-application and conformity assessment activities. Notified bodies are also expected to regularly provide data on the progress made as for certification, capacity, and timelines for conformity assessment. To this instance, the tool suggested by the position paper would see the activation of a publicly available, common website.
Reactions to the proposed ban of PFAS
by Giuliana Miglierini
A proposal to ban around 10,000 per- and polyfluoroalkyl substances (PFAS) was submitted in January 2023 to the European Chemicals Agency (ECHA) by authorities of Germany, Denmark, the Netherlands, Norway, and Sweden. The proposal was published on ECHA website on 7 February 2023.
The focus is the so-called “forever chemicals”, i.e. very high persistence PFAS typically characterised by bioaccumulation (also in plants), great mobility and a long range transport potential, and potential endocrine activity.
“This landmark proposal by the five authorities supports the ambitions of the EU’s Chemicals Strategy and the Zero Pollution action plan. While the evaluation of such a broad proposal with thousands of substances, and many uses, will be challenging, we are ready.”, said Peter van der Zandt, ECHA’s Director for Risk Assessment.
The proposal was open to public consultation on 22 March 2023, giving rise to the collection of 5,600 comments. Opinions will be issued by ECHA’s scientific committees for Risk Assessment (RAC) and for Socio-Economic Analysis (SEAC), to be then forwarded to the EU Commission for final decision.
The current role of PFAS
PFAS are characterised by the presence of alkyl groups in which many or all the hydrogen atoms have been replaced with fluorine. The main carbon chain of these substances may have different lengths, from small molecules to long chain PFAS and polymers, and may carry a very wide variety of other functional groups. The strength of the carbon-fluorine bond is the root cause of PFAS persistence, leading to these substances remaining in the environment for decades to centuries.
Per- and polyfluoroalkyl substances are currently used in many different industrial sectors, thanks to their useful technical properties. Among others, PFAS can be used to repel water, oil and dirt from surfaces, and is characterised by a high durability under extreme conditions of temperature, pressure, radiation, and chemicals. PFAS also present electrical and thermal insulation properties.
The main features of the restriction proposal
According to the authorities that submitted the proposal, around 4.4 million tons of PFAS would end up in the environment over the next 30 years in the case of no action. Ban would refer to manufacture, placing on the market and use as such, as constituent in other substances or in mixture as well as in articles.
Two options for restriction have been considered, a full ban or specific derogations for certain industries, based on the analyses of alternatives, efforts put in place for switching to them, and socio-economic considerations. The ban would be effective above a set concentration limit; a transition period of 18 months should occur between final adoption and entry into force. Use-specific, time-limited derogation might refer, for example, to a 5-year period in the case of food contact materials for industrial food and feed production (as alternatives are already under development, but are not yet available to entry into force), or to a 12 years for implantable medical devices (for which identification, development and certification of alternatives is still needed).
During the public consultation phase, comments were received from more than 4,400 organisations, companies and individuals, to be reviewed by both the RAC and SEAC committees and the five proposing countries. Sweden, Germany and Japan are the countries that contributed the higher number of comments, well in advance of Belgium, China, Italy and the US. Companies provided more than the half of the comments (58,7%), followed by individuals (27,3%), and industrial or trade associations (9,8%). The full list of entities participating to the consultation is available at the consultation webpage.
EFPIA response to ECHA’s consultation
The European Federation of Pharmaceutical Industries and Associations (EFPIA) contributed to the consultation with a detailed document. Another joint ISPE-EFPIA document particularly addressed the use of fluoropolymers and fluoroelastomers in medicinal product manufacturing facilities.
“While we support the need to restrict certain PFAS, we need to find the right approach to ensure the continued manufacturing and availability of medicines in Europe. A total ban would see medicines’ manufacturing in the EU grind to a halt in under three years. It would also jeopardise the production of all pharmaceutical substances in Europe and would conflict with the EU’s strategy of reducing dependency on nations outside of the EEA in the event of shortages or pandemics.”, said EFPIA’s director general, Nathalie Moll.
EFPIA’s consultation documents highlights the many different uses of PFAS in the pharmaceutical industry, ranging from active pharmaceutical ingredients (API) falling within the definition of PFAS used in the proposal, to building blocks and raw materials used within chemical synthesis of PFAS and non-PFAS medicines. Other reagents and equipment might also fall within the scope of the ban, as well as packaging materials or combination products such as pre-filled syringes. The ban would also affect the manufacturing process, where PFAS materials are used in a wide variety of applications.
It might thus result in the disappearance from the market of a large number of important medicines, warns EFPIA, due to the unavailability of replacement materials, and the time required to obtain regulatory re-approval of alternatives. The supply chain of pharmaceuticals would be also impacted at many stages, thus possibly exacerbating shortages.
In its analysis, EFPIA highlights how some PFAS are considered of low concern by the OECD, and in particular “those used in actual medicines have no or low identified risk through medicines risk benefit or environmental risk assessments”.
A patient access impact analysis was also jointly developed by the involved industrial associations (AESGP, EFCG, EFPIA, Medicines for Europe and Vaccines Europe), showing that the current proposal would lead to at least 47,677 global marketing authorisations being affected by the ban. More than 600 medicines from the WHO Essential Medicines List would be at risk; restrictions would greatly impact also the European Member State’s “Critical Medicines lists”.
EFPIA submitted also a socio-economic assessment of the proposal, according to which a broad restriction of PFAS used in the production of human medicines would have disproportionate negative impacts on the European economy and society. “Without additional derogations, the entire pharmaceutical industry would no longer be able to manufacture active pharmaceutical ingredients (APIs) (whether classified as PFAS or non-PFAS APIs) or associated medicinal products in the EEA”, writes EFPIA, resulting in APIs production to necessarily move out of the European Economic Area.
The position of the medical device sector
MedTech Europe also published a position paper on the PFAS restriction proposal and called for “a realistic transition pathway to non-PFAS alternatives that are both reliable and feasible for medical technologies (including their manufacturing and supply chain) to avoid shortages of medical technologies for patients and practitioners”.
The position paper presents many PFAS use cases in the field of medical devices, together with the criticalities posed by the proposed transition. In particular, broad derogations should be considered to allow sufficient time to first “identify all PFAS uses in medical technologies and to subsequently move to alternatives where these are proven to be technically viable, available besides in conformity with the sector-specific MD and IVD Regulations so as fit for the intended purpose”. In this case too, the need to manage complex supply chains would require a realistic timeline in order to address dependencies, and long development timelines and steps to ensure compliance with the sectorial legislation.