The implementation of the EU-MDR (MDR) demanded manufacturers to review all their technical documentation, including former biological safety assessments made for legacy devices. Do you know how to ensure compliance and a smooth continuation of the device's availability on the market regarding biocompatibility requirements?
Biocompatibility under MDD x MDR
Despite many significant changes in several aspects of the requirements for placing medical devices in the market, MDR did not bring a big shift regarding the expectation for biocompatibility assessments. However, the new regulation introduced new classification rules that can result in more rigorous biocompatibility requirements for certain devices, especially those that come into direct or prolonged contact with the human body. In addition, devices that fall into the new class I reusable (Ir), inexistent under MDD, will require verification regarding their performance and safety after the recommended number of reuses.
Requisite 10.4.1 of chapter II of Annex I from the MDR, which discuss the use of carcinogenic, mutagenic, or toxic to reproduction (CMR) substances and chemicals with endocrine-disrupting properties (ED), is often seen like a new requirement related to the biological safety of the devices. However, it was somehow already considered in the previous directive. While the specific term CMR was not used in the MDD, it encompassed the principles of assessing and mitigating risks associated with hazardous substances, including those classified as carcinogenic, mutagenic, or toxic to reproduction. Requisites are similar in essence, but there are some differences due to the stricter and more comprehensive nature of the MDR and, as a consequence, a bigger commitment from Notify Bodies, which did not tend to pay attention to this topic before.
Neither MDD nor MDR present any specific guidance on how to perform the biological assessment, as for that manufacturers can always rely on the ISO 10993 series (Biological evaluation of medical devices). Therefore, regarding biocompatibility, the key is to keep the documentation up to date with the current versions of the series, particularly to Part 1 – Evaluation and testing within a risk management process.
How to deal with legacy devices
The first concern manufacturers should have been if their legacy device had its classification changed under MDR or according to ISO 10993-1 table A.1, especially regarding the nature and duration of contact with the human body, which could lead to additional biological safety endpoints to be assessed. Next, manufacturers should evaluate if CMR 1A/1B or ED are present, and in which percent, in case of legacy devices that:
- are invasive and come into direct contact with the human body,
- (re)administer medicines, body liquids or other substances, including gases, to/from the body, or
- transport or store such medicines, body fluids or substances, including gases, to be (re)administered to the body.
If any of those substances are present in a concentration that is above 0,1 % weight by weight (w/w), the manufacturer should perform a risk assessment considering factors such as the exposure level, duration of contact with the body, intended use of the device, potential routes of exposure (e.g., skin contact, inhalation, ingestion), and the change of raw material. Wherever feasible, manufacturers should consider substituting CMR/ED substances with safer alternatives that have comparable functionality. If substitution is not possible, it is required implementation of measures to mitigate the risks, such as minimizing exposure or using appropriate containment mechanisms, and of a sound rationale, which is a challenge that may require additional testing. In addition, users must be informed in the labeling that the device contains CMR/ED substances above 0.1 % w/w.
Legacy devices usually have a biological safety assessment performed under a previous version of ISO 10993-1 (Biological evaluation of medical devices – Part 1 – Evaluation and testing within a risk management process) and tested in accordance with previous parts of standard as well. The most common mistake manufacturers make is not performing gap assessments to update their biocompatibility reports with the requirements of the current version of the standard, regardless of a resubmission or not. It is completely plausible that a manufacturer keeps tests performed years ago, if there was no relevant change in the device which could affect its biological safety, such as material and manufacturing processing, and it is well-documented via the Quality System, which then can allow a scientific justification. Therefore, it is important to keep in mind that updating the biocompatibility documents does not always lead to new testing (but sometimes, it does!).
Another important point to pay attention to is that MDR requires manufacturers to implement a comprehensive risk management system that considers biocompatibility risks throughout the entire lifecycle of the medical device. In that sense, risk management and biological safety documents should match and feed each other. And latest, MDR places greater emphasis on post-market surveillance and vigilance of medical devices, including monitoring biocompatibility-related issues that may arise after the device is placed on the market. Indeed, legacy devices are expected to have post-market data in place to feed the biocompatibility reports as well.
Concluding remarks
Maintaining the biological safety documentation of legacy devices is not an easy task, as it requires constant update regarding the current regulations, particularly the ISO 10993 series. It is important to double check any time if there is a latest version of the ISO or the harmonized EN ISO, as the newest one of them is considered state of the art and must be followed. In addition, if the device is sold is other markets than the EU, addition documents, such as the FDA’s guidance Use of International Standard ISO 10993-1, "Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process" must be followed as well.
Qserve’s Notified Body-like Review service can help you making your biological safety assessment of legacy devices up to EU-MDR standards. Please do not hesitate to contact us.