ISO 10993-18:2020’s new challenges for manufacturers submitting in the EU

Mark Cabonce, principal toxicologist, Sandi Schaible, senior director of analytical chemistry and regulatory toxicology, and Dr Sherry Parker, senior director of regulatory toxicology, WuXi AppTec advise how medical device manufacturers can best navigate the recent updates of ISO 10993-18:2020.

The International Organisation for Standardisation (ISO) significantly updated the standard for chemical characterisation when it revised 10993-18:2020 — Chemical characterisation of medical device materials within a risk management process. The revision built a framework for identifying and quantifying medical device materials and constituents in concentrations that could potentially cause toxicological concern. Two primary components introduced in the standard are the analytical evaluation threshold (AET) and intensified extraction requirements. Both components have contributed to a massive increase in the amount of testing each medical device undergoes to support safety.

Given the broad and fundamental changes inherent in ISO 10993-18:2020, regulatory bodies in the US and the EU have taken a stepwise approach to recognise, adopt, and implement the standard. The US Food and Drug Administration (FDA) partially recognised 10993-18:2020 in July 2020 but stopped short of full recognition. Still, FDA regulators expect manufacturers submitting products for use in the US to address the requirements of the standard.

In the EU, the process is more nuanced. In May 2021, the Medical Device Regulation (MDR) replaced the Medical Device Directive (MDD) as a new, more comprehensive regulatory framework for medical devices in the EU. The regulation framework changed how devices are classified in the EU and introduced stringent requirements that prioritise patient risk.

The MDR accepts the revised ISO 10993-18:2020 as “state of the art”; that is, it is the most recent published version of an accepted standard — and holds manufacturers to the standard. But the EU has yet to harmonise the standard across member states. Yet, what constitutes state-of-the-art analytical chemistry is not explicitly defined in the regulation. The MDR empowers notified bodies (organisations that help shepherd products through regulatory submission) to interpret the meaning of state of the art and work with manufacturers to ensure compliance with standards before submission.

Although potentially confusing, EU regulators did not set out to create a challenging system. The European Council and Parliament implemented the MDR to alleviate subjectivity in the submission process and align Europe with evolving global standards. The byproduct of their efforts is a process that requires solid partnerships and precise time management to achieve regulatory success.

ISO 10993-18:2020’s impact on the EU

Expectations for physical/chemical information introduced in ISO 10993-1:2018 — Evaluation and testing within a risk management process, and now ISO 10993-18:2020 have compelled EU and US regulators to prioritise chemistry. Exaggerated and exhaustive extractions and a low AET can yield hundreds, sometimes thousands, of compounds for toxicologists to assess. The number of chemicals to identify and quantify adds a significant amount of time to submission preparation. It also increases the likelihood of unfavourable or “equivocal” findings (that is, those for which toxicologists deem the level of risk unacceptable, given the available information), which could mean more time for risk mitigation.

Before ISO 10993-18:2020, assuming two months for chemistry studies prior to regulatory submission would have likely been reasonable. Today, regulatory expectations are much higher, and timelines include preliminary chemistry testing, extractables/leachables (E/L) testing, toxicological risk assessment and risk mitigation (if necessary). Although timelines are never absolute, manufacturers are finding submissions today take far longer than before. Budgeting 8–12 months for chemical characterisation, biocompatibility and risk assessments is now a more realistic timeline.

Regulatory backlogs in the EU also contribute to lengthier timelines. Harmonised standards (HAS) consultants assess to what extent European standards comply with relevant EU legislation. Manufacturers are responsible for ensuring their products meet EU safety, health, and environmental protection requirements. To sell products in the EU, manufacturers must conduct a conformity assessment, create a technical file, draw up an EU declaration of conformity (DoC) and affix a ‘CE’ mark to their products. HAS consultants can help manufacturers verify the legal definition of their products and clarify the category into which they fall. All documentation must be contained in a technical dossier and provided during regulatory submission. The process can be lengthy, and there are a limited number of qualified HAS professionals to consult.

Rigorous chemistry is the new normal in the EU, so manufacturers should consider adjusting their programme timelines accordingly. The scarcity of regulatory assistance is also real. Manufacturers with risk management strategies and timelines responsive to the EU’s regulatory environment and ISO 10993-18’s chemistry requirements will be positioned well for success.

Working with notified bodies

Notified bodies help verify a medical device’s design and quality. They assist with interpreting regulatory guidance and, as noted above, ensure manufacturers adhere to state-of-the-art standards. Notified bodies also provide a window into expectations for their conformity assessment — they can even supply a checklist of factors to consider based on the product and classification. The questions they ask and the data they request will likely reflect the rigour inherent in MDR and ISO 10993-18:2020, making notified bodies valuable members of the manufacturer’s submission strategy team.

When working with notified bodies, the bottom line is to secure one as soon as possible. It does not matter where a manufacturer’s product is in the submission process; the key is to get in the queue. To ensure compliance, notified bodies now recommend manufacturers file applications at least 18 months before a product’s MDD expiration date.

Each notified body has a portfolio of clients, and once capacity is reached, manufacturers are out of luck until new notified bodies are accredited. The EU offers guidance documents, FAQs and transition plans on its website for manufacturers that have questions while waiting for access to a notified body.

Preparing for submission post-MDR

Added transparency in the submission process is anticipated in the EU, but for now, notified bodies and manufacturers are navigating the new guidance together. As notified bodies receive more submissions, they will start to ask more detailed questions. And, as they gain exposure to MDR feedback, notified bodies can prepare their partners more thoroughly. And as manufacturers go through the process, they will gain valuable experience that will serve them well in the future. All these factors will help set better expectations and create a smoother process for future submissions.

For now, using data that isn’t state-of-the-art could cause serious problems with a manufacturer’s submission. Regulators understand that standards are updated periodically and inconsistently, but manufacturers who submit a device with outdated data can expect a regulatory inquiry and a request for justification. In these instances, EU regulators can ask for a “hard pause”. A hard pause is not necessarily a request for retesting; it just means regulators want additional time to consider the data and supporting evidence for a device’s safety claims.

Any manufacturer submitting a device with outdated data should proactively conduct a gap analysis to identify weak areas of its submission. Internal teams or laboratory partners can conduct gap analyses, but they should include representation from an organisation’s quality control, regulatory, R&D, finance, product management and procurement departments. 

ISO 10993-18:2020 presents some of the biggest challenges manufacturers face. Due to materials characterisation requirements, manufacturers need to disclose whether any carcinogens, mutagens, reproductive toxicants or endocrine disrupters (CMRs) are present in their devices in amounts ≥0.1% w/w. This applies to most devices, regardless of contact duration or risk class. For many manufacturers, materials characterisation compliant with ISO 10993-18 will be the best approach for addressing CMRs. 

Streamlining EU submissions

Some manufacturers have found success by gaining FDA approval for their devices before submitting them for review in the EU. Regulatory bodies differ, and expectations can be subjective, but in some instances, receiving a green light from the FDA has effectively demonstrated device competency and data validity en route to regulatory approval.

The primary recommendation for manufacturers submitting in the EU is to overcommunicate. Be prepared to communicate with notified bodies and laboratory partners consistently. Overcommunication ensures clarity among partners and protects programme timelines.

It is also critical for manufacturers to take advantage of whatever opportunity they have with notified bodies. As mentioned, these consultants are in short supply, and there is little evidence to suggest that trend will change any time soon. A manufacturer’s relationship with a notified body could mean the difference between regulatory success or failure for its medical device.

Finally, building a solid relationship with a laboratory partner supports safety. A suitable laboratory partner can help manufacturers gather reliable data and avoid potential pitfalls. More than that, a partner with experience navigating the nuanced regulatory environment in the EU can provide crucial guidance, help set expectations and avoid uncertainty. Without this relationship, manufacturers could be putting their products and patients at risk.

The final word

Submitting a medical device for regulatory approval in the EU is no easy feat. Regulatory delays and confusing submission pathways persist despite the extra year to prepare for the MDR rollout. Fortunately, manufacturers do not have to navigate the landscape alone. Experienced laboratory partners can help clarify MDR, guide manufacturers through the EU’s unique regulatory system and, ultimately, provide the safest products possible to EU patients.