By Matthew Jorgensen, PhD, DABT- Senior E&L Expert; Audrey Turley- Senior Biocompatibility Expert; Thor Rollins- Director Toxicology and E&L Consulting
The 566-page Medical Device Regulation (MDR), which replaces the EU’s Medical Device Directive (93/42/EEC) and the Directive on Active Implantable Medical Devices (90/385/EEC), has caused much discussion, training, debate, and stress in the medical device industry since its publication in May 2017. This article briefly examines the current state of the MDR, including deadline extensions announced in the second corrigenda, a strategy to address material information, and what should be included in a gap analysis.
Toward the end of November 2019, the EU Commission published the second corrigendum to the MDR, which brought a huge relief to manufacturers of Class I devices that will be upregulated under the new MDR. The corrigendum allows for devices that are Class I under MDD 90/385/EEC or 93/42/EEC, which have a declaration of conformity prior to May 26, 2020, to remain on the market until 26 May 2024 before filing under the new MDR. Another significant allowance under the second corrigendum is that devices previously on the market prior to 26 May 2020 may continue on the market until 26 May 2025; however, an earlier submission may be required based on when the current CE mark expires. For example, if the CE mark expires between 26 May 2020 and 26 May 2025, the device will need to be submitted for a CE mark under the new MDR at the time of CE expiry.
Material information for medical devices is highlighted in the MDR and in the international standard ISO 10993-1: 2018 biological evaluation for medical devices – Part 1: Biological evaluation within a risk management process. Manufacturers are required to gather as much information regarding a device’s materials and processes as possible, and this starts with raw material supplier information. In the MDR, section 10.4 identifies that devices and their constituent materials should not contain substances, which are carcinogenic, mutagenic, or toxic to reproduction (CMR) or substances having endocrine-disrupting properties above 0.1 percent (w/w). If such compounds are used, their use must be justified, and the product label must identify that the compound is present.
The preferred method for addressing CMRs is to obtain certification regarding the CMR content of materials from suppliers which can be difficult to obtain due to protection of intellectual property. This would require a certificate from the supplier indicating that they have reviewed the manufacturing process and materials and compared known compounds to a published list of CMRs (Annex VI of CLP) and that none of the supplied materials contain any of the CMRs above 0.1%. When supplier information is unavailable, the only true way to address the strict requirements of 10.4 is to fully dissolve or digest the device’s materials and conduct a complete chemical analysis. This is a complex endeavor and may not be possible within a reasonable time frame. A final option would be to examine whether any CMRs are in a material or device, which could result in patient exposure. If no CMRs are found above toxicologically concerning levels when a material is extracted under conditions more aggressive than clinical use conditions, then at least patient risk is addressed.
Many manufacturers will be finding themselves looking at previous submission files and wondering whether the data used to support the submission originally is still sufficient today. The best way to go through the necessary thought process to answer that question is to perform a gap analysis. This consists of a review of the previous data with comparison to the current standards and regulatory expectations. Previously, companies could claim that a device was made from commonly known and used materials and the biocompatibility discussion was considered resolved. However, now there is a strong emphasis on the effects of the processing of the medical device. Therefore, outlining the manufacturing process is expected as well.
Material and Process Changes
A surprise to many companies going through the gap analysis process is how many material and process changes have occurred in totality over the lifetime of the device under evaluation. What may have seemed like small modifications with no overall device impact during an individual change can add up to almost a completely new device over many iterations of changes. It is important in the gap analysis to compare the device that was previously assessed to the device currently being submitted. All differences should be identified and discussed as to why certain changes were made, whether the changed area will contact the patient (either directly or indirectly), and if the previous evaluation still supports the device in its current state.
Seldom in the history of the regulatory evaluation of medical devices have we seen as significant of impact as we have with the convergence of the release of the Medical Device Regulation. This timing has forced medical device manufactures to evaluate not just new devices that they intended to introduce to the European market but all devices that are currently sold with a CE mark. The necessity to perform gap analysis to current standards necessitates considerable effort. Regulation knowledge and skill, cooperation with your notified body, and keeping up to date on latest trends are the new norm under the MDR world in which we find ourselves.
This article was written by Audrey Turley, BS; Thor Rollins, BS; Matthew Jorgensen, PhD, DABT, of Nelson Laboratories, Salt Lake City, UT. For more information, visit www.nelsonlabs.com.
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