by Giuliana Miglierini
The lack of a suitable capacity of notified bodies (NBs) is one of the main issues still pending after the entry into force of the new Medical Device Regulation (MDR) (EU) 2017/745 and In Vitro Diagnostic Regulation (IVDR) (EU) 2017/746. The Medical Devices Coordination Group (MDCG) discussed some suggestions on how to address the problem within a position paper published in August 2022.
Even if the document does not represent an official guideline, it describes some critical points to be considered by manufacturers and notified bodies in order to face the great challenge of the re-certification of medical devices and in vitro diagnostics according to the new rules. Should this not occur in time, many products may exit the market at the end of the transition period, potentially leading to a supply crisis greatly impacting on the health of patients and the normal functioning of healthcare institutions.
The MDCG position paper answers the request of EU Health ministers advanced during the EPSCO Council meeting on 14 June 2022 to figure out some immediate measures to face the problem. The final goal of the document is to improve the efficiency in the application of the current regulatory framework, with no reduction of requirements to be fulfilled by manufacturers. Waivers from applicable conformity assessments procedures should be considered only in relation to an interest of public health, patient’s safety, or health.
The position paper consists of nineteen points addressing the issue under its different perspectives, the first eleven of which refer to the increase of notified bodies’ capacity. The MDCG calls on all stakeholders to collaborate in order to smoothly implement the suggested actions, a process that will be monitored by the MDCG itself.
How to increase the capacity of NBs
Hybrid audits should be the elective tool notified bodies may use where appropriate to timely and efficiently run conformity assessment. Duplication of activities should be also avoided. To this instance, the suggestion is to “develop a framework for leveraging evidence, or components thereof, from previous assessments” run according to previous Directives. A pre-condition to activate this possibility is that the previous assessment has been judged “valid and properly substantiated also with regard to the MDR/IVDR requirements and the device” by a duly qualified notified body personnel.
A flexible approach may also apply to the combination of audits for legacy devices and actions needed to guarantee their ‘appropriate surveillance’. Combined audits may be used particularly for legacy devices whose application for MDR/IVDR certification is under review by a NB, thus moving the focus more towards the assessment of compliance with the new rules. To this instance, the MDCG also announced the intention to produce a specific guidance on ‘appropriate surveillance’ under Article 110(3) IVDR and to update MDCG 2022-4.
Already existing guidance may also be reviewed to reduce the administrative burden for NBs, and remove limitations related to the scope of documentation not required by MDR/IVDR.
A fundamental piece of the new European infrastructure for medical devices and IVDs is represented by the centralised Eudamed database, which should be timely fed by NBs with all relevant information using machine-to-machine procedures. Double registrations should be avoided as much as possible.
New notified bodies are essential in order to increase capacity. To this instance, the MDCG suggests supporting training, coaching and internship activities for their personnel. The rationalisation of internal administrative procedures is also deemed important.
Time for re-assessment of NBs is undergoing a review by the European Commission, which is expected to result in the publication of new Delegated Acts. The proposal is to move from the current first re-assessment at three years after notification (and then every 4th year) to up to five years after notification, on the basis of a flexible approach. There are currently ten re-assessments planned in 2022, twelve in 2023 and 11 in 2024. According to the MDCG, the new timeframe for re-assessment would allow national designating authorities to free resources to assess new NBs, while existing ones could process higher numbers of first MDR/ IVDR certifications.
Assessment, designation and notification of conformity assessment bodies (including the European Commission) are also called to reduce their timeframes and improve the efficiency of their processes, keeping unaltered the requirements to be met. The possibility to add specific codes to the designation of NBs shall be also explored by the MDCG. The Group is also committed to prioritise some ongoing actions which may impact on NB’s capacity (i.e. revision of section III.6. of MDCG 2019-6 revision 3).
MDCG’s guidance documents should be seen as an aid “to apply the legal requirements in a harmonised way, providing possible solutions endorsed by the MDCG”. Nevertheless, demonstration of the compliance to requirements should always benefit of a certain flexibility. A reasonable time should also be granted to integrate the new guidance in the relevant systems and/ or to apply them, suggests the MDCG.
Suggestions for the manufacturers
Under the perspective of manufacturers of MDs and IVDs, costs to access NBs may play an important role, especially for small-and-medium companies (SMEs). The MDCG position paper recalls NBs to the obligation to make their standard fees publicly available, possibly in a way that might be easily compared. Specific access schemes should be also in place to make available some capacity to SMEs and other first-time applicants for conformity assessment.
Manufacturers should also refer to notice MDCG 2022-11 to ensure timely compliance with MDR requirements. IVDs should not left behind, even if this category of products benefits of one more year for the transition to new rules compered to medical devices.
Structured dialogue is the suggested tool to improve the collaboration between manufacturers and notified bodies along the entire process of conformity assessment aimed at regulatory procedures, should this approach turn to be useful in order to improve the overall efficiency and predictability.
A timely communication to manufacturers by mean of webinars, workshops, targeted feedback and informative sessions is also deemed important in order to allow for a better preparedness, with a particular attention to SMEs and first-time applicants. The MDCG also suggest NBs to develop common guidelines for manufacturers to assist them in the application phase, containing explicative examples of typical non-conformities and details on he preparation and content of technical documentation. National authorities and industry associations are called as well to contribute to the dissemination of relevant information across their stakeholders.
Specific guidance should be issued by the MDCG to support a simpler conformity assessment of some aspects of legacy and orphan devices denoted by a demonstrable track record of safety. The development of a specific definition of “orphan devices” is also planned.
An improved dialogue between NBs and medicines authorities, and cases where expedited review would be possible is also supported in order to speed up consultations on medical devices incorporating an ancillary medicinal substance and companion diagnostics.
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.