Article 117 of the Medical Devices Regulation (MDR) is of high impact to market authorisation holders who manufacture and supply medicinal products with integral administration devices that are prefilled and non-reusable (called DDCs, such as prefilled syringes, prefilled pens, inhalers and pumps). The Article requires companies to seek the opinion of a Notified Body regarding the conformity of the device component of the product.

Industry has significant concerns that with the MDR transition period ending in less than 4 months, the required clarity is not in place for on-market DDCs to enable lifecycle changes to the device constituent part, to be made in a predictable and efficient manner. A pragmatic solution is necessary to provide the requisite clarity to avert potential for disruption in the supply of DDCs that European patients rely on every day. The importance of this has been further magnified by the COVID-19 pandemic, as patients with underlying health conditions are the most vulnerable to succumbing to the worst effects of COVID-19. Maintaining patients’ health in as a good a state as possible is vital for those individual patients, as well as vital in minimising the potential additional burden on the European healthcare system.

Changes to the device constituent part of integral DDCs are currently managed via EU classification guidance on variations (EC 1234/2008, 24^th November 2008) and whilst it is not ideally suited to DDCs, this guidance has been demonstrated to be effective. Therefore, continuing with the current arrangements until such time as the variation framework for medicinal products can be updated, does not present undue risk in terms of patient safety. With this is mind, EFPIA took the step of writing to the European Commission highlighting these concerns, and recommended the following three actions be taken:

Recognising that single integral DDCs are regulated as medicinal products, EFPIA proposes a risk-based approach, and the determination of a device related change categorised as ‘substantial’ in nature[3] being one that is shown to affect either performance or safety characteristics, and the DDC no longer remaining within the approved product specification(s) described in the MAA. Based on a position that all changes to DDCs are managed by Market Authorisation Holders (MAHs) within a quality system (aligned with ICH Q10 Pharmaceutical Quality System), that requires a risk-based assessment with specific consideration to the device constituent part of the DDC by suitably qualified device experts. Those changes that are determined as requiring less extensive regulatory oversight prior to implementation are documented internally. Changes that are determined to be more significant in nature are submitted to the EMA or a National Competent Authority. This approach is commensurate with the EU classification guidance on variations and change management for active substance and finished product of medicinal products.

MDR Article 117 is silent on the expectations of life-cycle management of DDCs. Since Article 117 amends Directive 2001/83/EC, and single integral DDCs are regulated as medicinal products, all changes for these products, including those for the device constituent part must legally comply with the EU classification guidance on variations and this interpretation was confirmed by the EMA during the recent EMA webinar. However, it is acknowledged that certain changes to the device constituent part of a DDC may be so extensive, that a Notified Body opinion may be required as part of lifecycle management and MAA variation. That’s where the uncertainly lies for MAH’s and specifically what the threshold or trigger would be such that the change requires the MAH to seek a Notified Body opinion.

Divergent interpretations of ‘substantial changes’

EFPIA was encouraged to hear during the open dialogue at the recent EMA webinar, a commitment made by regulatory stakeholders towards a more harmonised approach to the implementation of the new provisions of Article 117. EFPIA certainly consider this an important step forward towards reaching regulatory alignment, given some divergent views voiced during the webinar itself, specifically concerning the interpretation of so called ‘substantial changes’ to the device component. EFPIA views the goal in the EU Pharmaceutical Strategy to address challenges relating to the interplay of medicines and medical devices through its flagship initiatives on regulatory efficiency by 2022, as highly significant to providing the regulatory alignment required for DDCs.

A recent position paper[4] issued by TEAM-NB (European Association for Notified Bodies) describes an approach on how to determine a ‘substantial change’ to the device constituent part of a DDC that is aligned with how a ‘significant change’ for a medical device is determined. This approach is not aligned with the legislative framework defined for medicinal products under which DDCs are currently regulated.

In our view, a ‘substantial change’ to the device constituent part of a DDC cannot be considered as equivalent to a ‘significant change’ to a stand-alone, CE-marked, medical device regulated within a medical device quality management system.

TEAM-NB has taken the position that a device related change of a DDC is substantial if it has the potential to impact safety or performance against relevant General Safety & Performance Requirements. The assessment is not based on the impact to the terms of a marketing authorisation dossier for the authorised drug-device combination medicinal product. Nor does it consider that evidence or data could be gathered that demonstrates no impact to overall safety or performance as a result of the change, and therefore potentially require minimal regulatory oversight (i.e. notification only) prior to implementation, which should in turn not require a Notified Body assessment of the change. If post change, safety and performance remain within prior approved specifications for critical quality attributes, the change is considered non-substantial and therefore would not require a Notified Body review.   

With this interpretation, we believe there is a risk that Notified Bodies will become routinely involved with technical changes that are deemed minor, and that do not otherwise require prior approval from EMA or National Competent Authorities.

Although TEAM-NB states that “This position paper is not intended to supersede the variation regulation (EC 1234/2008) and MAH’s must continue to apply the variation regulations as required, rather this position paper is to support MAH’s in determining if a NBOp [Notified Body opinion] is required as part of a variation/extension application”, there is significant concern it does not align with an ICH Q10 based quality system or  the current variation regulation and overall approach within. Furthermore, industry views the paper as a high risk if translated into a formal Commission or EMA guidance ending up setting a new regulatory framework with requirements not proportionated to the regulatory flexibility being considered for management of changes for medicinal products overall and desired goals of ensuring public health protection[5].

Industry is highly concerned with the additional regulatory burden and timelines this would impose on the significant volume of marketed DDCs that would have very limited or no benefit in terms of enhanced patient safety, particularly when considering these are predominantly well-established products such as prefilled syringes, prefilled pens, inhalers and pumps.

For EFPIA, this represents an urgent matter to be quickly addressed, given the very limited time left until the application deadline for the Medical Device Regulation. Following submission of the letter in early February, an acknowledgement from the European Commission has been received with an ambition to respond within a few weeks, so EFPIA remains optimistic that this remains high on the European Commission’s agenda and are committed to progressing this topic.

[1] https://ec.europa.eu/health/human-use/strategy_en

[2] Team NB Position paper for the interpretation of device related changes in relation to a Notified

Body Opinion as required under Article 117 of Medical Device Regulation (EU)2017/745, Dec 23, 2020

[3] EFPIA Position Paper on Approach to Substantial Design Change of the Integral Medical Device Constituent Part Under Article 117: A Risk Based Approach, December 2019. https://www.efpia.eu/media/413384/ebe-efpia_position-paper_-significant-design-changes.pdf

[4] Team NB Position paper for the interpretation of device related changes in relation to a Notified

Body Opinion as required under Article 117 of Medical Device Regulation (EU)2017/745, Dec 23, 2020

[5] Ensuring public health protection in accordance with Chapter Article 1 of COMMISSION REGULATION (EC) No 1234/2008 of 24 November 2008