Note: On April 17, 2020, the European Parliament adopted the Commission proposal to postpone the Medical Devices Regulation until May 26, 2021, due to COVID-19.
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. To say nothing of the changes in device regulation, the aggressive three-year implementation goal of May 26, 2020 has the industry as a whole — manufacturers, laboratories, and regulators — strategizing diligently as we step into 2020. 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.
The goal for end of Q1 2020 was to have 20 designated notified bodies (NBs) approved under the MDR or the In Vitro Diagnostics Regulation (IVDR). Currently, there are 10 NBs under MDR: three from the Netherlands (BSI, DEKRA, DARE), four from Germany (TÜV Rheinland, TÜV SÜD, MEDCERT, DEKRA), one from Italy (IMQ Itituto), one from the UK (BSI), and one from Norway (DNV GL Presafe). In November 2019, BSI UK was announced as the first NB under IVDR, followed by BSI’s Netherlands location and DEKRA, making the three. Thirteen NBs in total is well short of the goal with three months left. A quick look at the designation process can help maintain a positive outlook though. There are 10 phases for a conformity assessment body (CAB) to go through prior to becoming a designated NB. At the end of 2019, there were about 255 CABs at various stages of the process with more than 150 CABs still in the first five phases. There were reported to be 12 CABs in the ninth phase, giving promise to meeting the goal of 20 designated NBs by end of Q1 2020.
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 May 26, 2020 may continue on the market until May 26, 2025; however, an earlier submission may be required based on when the current CE mark expires. For example, if the CE mark expires between May 26, 2020 and May 26, 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. Because details of plastic material formulation and manufacturing are often trade secrets kept by several levels of upstream suppliers, obtaining this information can be a special challenge.
The primary method for addressing CMRs should be by obtaining certification regarding the CMR content of materials from suppliers, which may be addressed without revealing complete formulation. This would require a certification 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 a certain percent. This option would not require CMR risk labeling of the device. 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 analysis. Digestion and analysis of plastics is a complex endeavor, which may not be possible within a reasonable time frame.
In cases where supplier information is unavailable, and digestion untenable, a final option would be to examine conservatively 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 with a conclusion that “if CMRs are present in the material, they are sequestered and unable to produce patient exposure.”
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. If biocompatibility gap analysis is used as an example, there are likely to have been several ISO 10993 standards that have updated since the last submission. Also, there has been increased focus on obtaining material information and biocompatibility data on devices over the last several years. 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, while gathering material information remains a crucial first step in the biological evaluation of a medical device, outlining the manufacturing process is expected as well.
It naturally follows then that the effects of not only the materials but also the manufacturing process should be assessed for any possible impact to the patient. At a minimum, cytotoxicity, sensitization, and irritation should be evaluated for all medical devices on the market. For prolonged (1–30 day) and long-term (>30 day) contacting devices, chemistry testing in the form of extractables and leachables may be identified in the gap analysis as needed testing. In the past, longer duration contact devices have commonly leveraged their history of clinical use, and many devices on the market have no documented biocompatibility testing data. For these devices, history of safe clinical use provides little support as it is acknowledged that the evaluation process of the past may have been inadequate and there are negative outcomes associated with devices that might not be truly attributable to the device itself.
Material 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. The largest topic for discussion in the gap analysis regarding biocompatibility will definitely occur in the material characterization discussion. In ISO 10993-1:2018, the gathering of physical and chemical information of the device is the only required endpoint for evaluation of all devices.
Physical and chemical information is defined in the standard under 3.17 as “knowledge regarding formulation, manufacturing processes, geometric and physical properties, and type of body contact and clinical use that is used to determine whether any additional biological or material characterization testing is needed.” Interpretation regarding how to meet this requirement is interpreted vastly different around the globe. There are pieces of information from ISO 10993-1:2018 to help provide a good foundation for the justification of an appropriate approach. In Figure 1 in ISO 10993-1:2018, one of the first action items (see Figure 1) identified for a biological evaluation of a medical device is to obtain physical or chemical information, or both. This figure also recommends that we should consider material characterization as outlined in ISO 10993-18. It is important to note that it is still not required to perform this testing; rather, consider whether it will be beneficial to the overall analysis of the device.
This definition helps us understand that to meet this requirement, information is to be gathered, but does not necessarily require testing. 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 and the updating of standards such as ISO 10993. 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, CMR inclusions, and reevaluation of device classifications and regulatory approaches necessitates considerable effort. Regulation knowledge 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, Sr. Biocompatibility Expert; Thor Rollins, Director, Toxicology and E&L Consulting; and Matthew Jorgensen, Chemistry and Materials Scientist, of Nelson Laboratories, Salt Lake City, UT. For more information, visit here .