When the Medical Device Regulation (MDR) replaces the Medical Device Directive (MDD) in 2020, requirements for medical devices in Europe will present greater regulatory hurdles. In addition, ISO 10993-1, created by the International Organization for Standardization (ISO) Committee and mandated by both the FDA and MDR also introduce new requirements for pre-clinical safety device testing. Medical device manufacturers are feverishly working to navigate the changes and develop their preclinical device testing strategies to overcome what's not just a regulatory hurdle, but a business challenge.
OEMs have just over a year until implementation of the new regulation. All medical devices — even legacy products that have been on the market for years — will require submissions that are supplemented with new data and updated evaluations. It is estimated that more than half a million different devices CE marked under the MDD must transition to comply with MDR. With much to be done and a shrinking number of notified bodies, time is of the essence. The best way to try to stay ahead of the curve and avoid costly regulatory delays is through thoughtful planning and partnership.
Requirements: What you Need to Know
The new and updated regulations emphasize the role that complete evaluations with robust supporting data play in ensuring medical device safety. ISO 109931 has increased the importance of materials characterization, physical and/or chemical information, and risk assessment to support safety and steer a test plan to meet biological endpoints. As directed in ISO 10993-1, regulators will be looking for detailed chemical information to support the direction of the biocompatibility test plan, and if sufficient information is not provided, additional testing, like extractables and leachables (E/L) studies, will be required. If extractables testing is conducted, regulators will be looking for extraction conditions that demonstrate a device has been challenged (e.g., use of aggressive solvents representing a wide range of polarities, elevated temperatures, and extended timeframes). The expectation is that all chemicals are identified, so avoiding unknowns in chemistry reports is paramount. If unknown chemicals are listed in a report, be prepared for regulators to require you to complete the identification — a complete materials characterization cannot exist with unknowns.
With increased emphasis on chemical characterization, biocompatibility testing alone cannot be relied on to support device safety. Biocompatibility testing can help identify local and systemic effects of your device in a living system, but it only tells part of the story. Detailed chemistry testing and a toxicological risk assessment are necessary to provide information about chemicals present even at minute levels that could be harmful.
Where to Start
Internal due diligence is necessary throughout the testing and submission process. Fire drills, headaches, and delays can be kept at bay with a planful approach and cross-functional team that is apprised of the regulatory changes and business impact. Your internal team should compile existing data on the materials that make up your devices, including adhesives, additives, colorants, polymers, manufacturing aids and more. Procedures used in the manufacturing and sterilization processes should also be reported. This data will help you and your contract research organization (CRO) evaluate what tests are necessary to verify safety and whether a gap analysis should be performed before testing begins.
Sequence of Testing
There are three phases involved in a complete biological evaluation under ISO 10993-1 and MDR — chemical information and/or chemical characterization, toxicological risk assessment, and biocompatibility testing — ideally in that order. Chemical characterization involves exposing the device to aggressive solvents that identify and quantify expected and unexpected chemical constituents contained within the device — an extractables study. Extractables studies are followed by toxicological risk assessments which use the information found in chemistry reports to establish a margin of safety for each chemical and determine what additional tests are needed to further mitigate any safety concerns. The final stage is biocompatibility testing, which looks at how living cells react to the device.
Historically, device manufacturers have been able to reach successful submission with biocompatibility testing alone, but more often than not, this is no longer the case. Beginning with biocompatibility testing is not a best practice because complete chemical characterization often can meet biocompatibility endpoints, such as genotoxicity or subacute/subchronic toxicity; therefore, using chemistry data and risk assessment to develop a biocompatibility test plan can often save unnecessary use of animals in testing and costly test article.
How to Vet a CRO
Outsourcing testing to an experienced CRO that offers a full range of preclinical device testing services can be instrumental in accelerating the process and getting your devices in front of regulators before others. Refer to the following cheat sheet to help determine who to trust with your testing program.
Q: Do you have the capabilities to conduct chemical characterization, toxicological risk assessments, and biocompatibility testing in-house? Enlisting a CRO that has all three capabilities in-house increases efficiency, allows you to address required endpoints, and helps eliminate information gaps. Watch out: If their answer is no, you may have to resort to piecemealing your testing, which can lead to longer timelines, increased cost, miscommunication between parties, loss of information altogether, and unknown impurities getting missed in your chemical reports.
Q: How often do you report unknowns in your chemistry reports? On average, what percentage of compounds in your reports are unknowns? Demand transparency. Working with a chemistry partner that reports unknowns will be problematic. Watch out: Reporting unknowns may indicate that the CRO does not have the expertise, instrumentation and/or the commitment to perform complete chemical characterization. This may cause regulators to reject your submission or issue requests for additional information (AIs). Unknowns are expensive. On average, repeat testing can cost more than $75,000 and 27 weeks of time.
Q: Are your analytical methods sensitive enough to detect constituents at a level low enough to be properly evaluated in a risk assessment? Analytical method sensitivities illustrate the precision and accuracy of the CRO's equipment and the expertise and experience of their team. Watch out: Extractables reports that include only a small number of reported compounds may indicate that the CRO does not have the instrumentation or expertise necessary to provide complete identification.
Q: What protocol do you follow after testing is complete? Do you provide support after submission? The way a CRO answers this question will speak to their philosophy on customer service. Watch out: If the CRO does not provide follow-up support on the testing that they do, you are on your own if regulators have additional questions or requests. It is in your best interest to select a CRO that will stand by you and their reports.
Q: How do you know your advice is in line with the way regulators are thinking? Staying on top of regulatory changes is one thing — the bigger challenge is understanding how regulations are being interpreted. It's necessary to spend time watching and interacting with regulators to understand, for example, their expectations on how testing is conducted. CROs with international delegation on ISO committees and that collaborate with ISO by writing standards, participating in round robins, or offering other technical expertise may demonstrate a commitment to getting to know what regulators want on a deeper level. Watch out: Find out if they have international delegates on ISO committees — an indication they may not only know the standards, but also the “why” behind the standards. Also, ask if prospective CROs keep a database of regulatory feedback and questions to track how interpretations change and influence expectations. This intel should be used to advise OEMs on how to prevent requests for additional information.
The regulatory deadlines are approaching quickly. Stay ahead of the curve with strategic planning and partnership.
This article was written by Sandi Schaible, Senior Director of Analytical Chemistry and Regulatory Toxicology, WuXi AppTec, Shanghai, China, and a U.S. delegate and international delegate for ISO 10993 part 18 in chemical characterization. For more risk-assessment best practices and guidance on how to handle chemistry report unknowns, download WuXi AppTec's white paper “Unknowns are Unacceptable” here. For more information, click here.