Medical device biological safety evaluations have advanced significantly over the last ten years, and regulatory requirements are quickly evolving as well. Turnkey evaluation of testing requirements has progressed into a more device-specific evaluation of risks. It is essential for manufacturers to consider how the changes put in place by ISO 10993-18 will impact their product’s testing needs and any historical compliance of chemical characterization studies.
Complying with the new standard requires a variety of highly sensitive and selective analytical equipment, robust databases and, above all, the expertise to sift through data and identify all chemical constituents. Manufacturers are reevaluating their products to ensure past testing strategies still hold up to current regulatory expectations. To understand how the industry got to this point and forecast where it is headed, we need to start from the beginning.
E/L Gains Momentum
When E/L testing first gained a foothold with medical devices in the early 2000s, methods were focused on qualitative measures. Testing did not generally attempt to quantify the amount of specific chemical constituents present but rather verify major materials present and evaluate total extractable residue.
As certain products were facing public litigation, such as pelvic mesh and breast implants, renewed scrutiny around the risks presented by implantable devices quickly caused the expectations for chemical characterization to be more rigorous, selective and quantitative.
As the decade progressed, even more analytically selective and sensitive techniques emerged, and chemical characterization requirements tightened. Regulators responded with an increased focus on testing device materials and a growing interest in customizing testing to better suit medical devices. In 2016, the US FDA Draft Guidance on ISO 10993-1 reaffirmed the value of chemical characterization when evaluating medical devices.
Recent E/L Testing Trends
Expectations grew along with advanced test methods and equipment that could accommodate increasing regulatory requirements. The 2016 US FDA guidance on the use of ISO 10993-1 required two to three solvents per instrumentand three replicates, thus increasing the investment that companies made during biological safety evaluations.
Around 2017, regulatory agencies began requiring exhaustive extractions (that is, multiple extractions on the same device) for permanent implants. Then in 2018, regulators published a revised version of ISO 10993-1, putting new guidance in place. Specifically, it made chemical characterization and the subsequent risk assessment fundamental components in assessing device safety.
This expectation meant submissions must examine chemistry information and risk assessment to drive their biocompatibility test strategy, and manufacturers must provide justification to support final submissions. Additionally, reviewers examined the training and qualifications of the expert personnel performing these tests.
Internally, the U.S. FDA showed increasing alignment around chemical characterization and toxicological risk assessments, asking how those play into evaluating a device’s biological safety. By 2019, reviewers began requiring exhaustive extraction on prolonged devices as well as permanent devices, which extended the timeline needed to perform testing and increased associated costs.
E/L Testing Today & Going Forward
The publication of ISO 10993-18:2020 marked a significant milestone for the medical device industry. The 2020 revision continued to push expectations and the subsequent approach forward.
This revision provided increased guidance for tailoring chemical characterization to each device by establishing thresholds based on device size, duration and type of patient contact, and the target patient population. For example, reviewers began expecting confidence intervals for identification and implemented the analytical evaluation threshold (AET) as a common baseline for chemistry studies. The AET is essential to achieving an accurate risk assessment. It also helps avoid regulatory scrutiny by requiring qualified chemists to work alongside toxicologists.
The methodologies that laboratories employ today are evolving rapidly, perhaps even faster than the standards themselves. Thus, the concept of “state-of-the-art” procedures is gaining attention as regulators’ expectations grow in tandem with the industry’s capabilities. This is evident with the September 2020 release of International Standard ISO 10993-1, “Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process.” As we near the upcoming publication of ISO 10993-17, toxicological risk assessments are positioned next to advance the practices in place. Still, manufacturers may find these latest regulations challenging to keep up to date with the continuously evolving regulatory landscape.
Keeping Up with Chemistry
If you have not conducted E/L testing in recent years, it may be time to consider retesting to satisfy the evolved science and regulations. For many products, testing conducted prior to the publication of ISO 10993-18:2020 may need reevaluation according to the new guidance.
Given the new role that chemical characterization has taken in testing and the new expectations to identify biological concerns, it is critical to consider E/L testing as an essential ingredient in preparing a successful medical device submission. Looking to dive further into the details? Check out a detailed recap about ISO 10993 in “Planning and Predicting for ISO 10993: Part 18 & Part 17.“
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WuXi AppTec provides a broad portfolio of R&D and manufacturing services that enable companies in the pharmaceutical, biotech and medical device industries worldwide to advance discoveries and deliver groundbreaking treatments to patients. As an innovation-driven and customer-focused company, WuXi AppTec helps our partners improve the productivity of advancing healthcare products through cost-effective and efficient, socially responsible and sustainable solutions – and has received ESG (Environment, Social and Governance) A Ratings from Morgan Stanley Capital International since 2019. With industry-leading capabilities such as R&D and manufacturing for small molecule drugs, cell and gene therapies, and testing for medical devices, WuXi AppTec’s open-access platform is enabling more than 4,200 collaborators from over 30 countries to improve the health of those in need – and to realize our vision that “every drug can be made and every disease can be treated.”
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Only about a fourth of medical device companies plan to be fully compliant with the European Union’s new Medical Device Regulation when it goes into effect on May 26, 2020, according to a new survey from the Regulatory Affairs Professionals Society (RAPS) and KPMG.
The survey — which closed in late June and was released yesterday — included 230 responses from medical device organizations with a wide range of sizes, mostly from the E.U. and North America. Only 27% (28% among companies with more than $1 billion in annual revenue) plan to declare full MDR compliance in May.
Nearly half, 46%, plan to leverage the MDR’s transitional provisions to continue selling in the E.U. through 2024 while working on their compliance programs — a move that will create additional work to recertify products and manage inventory.
More than a third of respondents said they planned to spend more the $5 million to achieve compliance.
“Without adequate planning and budgeting, E.U. MDR compliance efforts could lead to strained resourcing, employee resistance, insufficient training, and communication failures across the organization – causing barriers to get EU MDR compliant products to the market. Companies should also start considering the operating model changes to support EU MDR sustainability,” Rajesh Misra, an advisory principal in KPMG’s healthcare & life sciences practice, said in a news release.
More than a third of organizations described the lack of notified bodies as a significant barrier to complying with the MDR. As of August 2019, there were only four notified bodies designated and no more than 10 to 12 designations expected by end of the year, according to RAPS.
“The low number of notified bodies designated so far is making medical device companies particularly apprehensive because they perform a necessary part of the European device approval process,” said RAPS executive director Paul Brooks. “If there are too few notified bodies or their capacity to assess devices under EU MDR is inadequate to meet the demand, it will create bottlenecks that could result in product shortages, including for critically important and high-risk devices patients depend on.”
Device manufacturers should not underestimate MDR deadline strictness, said Sandi Schaible, senior director of analytical chemistry and regulatory toxicology at WuXi Medical Device Testing.
“At this point, it’s not likely that Europe will grant an extension on MDR. If they do, it may not happen until the 11th hour, so don’t count on it,” Schaible said in a statement shared with Medical Design & Outsourcing.
Companies just beginning to prepare for MDR need to work carefully to prioritize product lines, according to Schaible. “Focus on products that have the highest market demand and ROI. And if you’re going to work with a lab testing partner, be transparent. Being forthcoming with details and giving lab partners visibility to forecasts, intervals, and timelines will set you up for success.”
Other RAPS/KPMG survey findings included:
- 66% of organizations surveyed have yet to develop a strategy to sustain their MDR compliance;
- 58% say that they’ve made some progress toward implementation of changes to their Quality Management Systems (QMS), buy have yet to implement the changes;
- Nearly 48% don’t have a strategy developed for EUDAMED, an E.U. database collecting medical device information.
Anyone involved in medical device development and manufacturing has undoubtedly heard of the regulatory changes happening in the EU beginning May 2020, lest they have been living under the proverbial rock. So much has been written and discussed, in fact, that it can become almost as overwhelming to keep up with as the modifications brought on by the new regulations themselves. Admittedly, we’ve devoted more space to covering the topic in our sister publication, Medical Product Outsourcing (MPO), since the regulations impact the entire industry and aren’t unique to the orthopedic space.
Still, we’ve tried to keep it top of mind in ODT as well; most recently, it was discussed in Dawn Lissy’s Best Practices column. Her contribution in this issue serves as a type of “Part 2” on the topic, which continues on the theme from the last issue. In that column, Lissy brought up many of the potential problems with the rollout of the MDR in the EU. On its own, the changeover would be substantial. But given the implications of the impending Brexit and its resulting impact on notified bodies (NB) able to serve the EU (i.e., those located in the UK will not be qualified to be an NB for MDR unless they establish a location in one of the EU member states), it could lead to disaster. Lissy also highlighted the backlog of companies trying to maintain their CE mark status for products currently in the European market, since there aren’t very many NBs qualified to the new regulation. The continuation of the discussion in this issue puts a positive spin on the topic with a look at how the regulatory changes could lead to a shift in product launch strategies, which may see medical devices introduced in the U.S. first (in contrast to the industry’s often-used tactic of an EU-first approach).
For those seeking additional information, however, one only needs to review several of the articles that ran in MPO recently. For example, in the last issue (September), Peter Rose, managing director—Europe of Maetrics, provided clarification of the modifications for certain Class I products that could impact device manufacturers previously exempt from the prior regulatory system the EU had in place.
Due to an “up-classification” of certain Class I devices, manufacturers find they require the service of an NB for perhaps the first time. This is creating confusion among these companies, some of whom are not even aware their devices have had their classification change under MDR. If your company sells Class I devices previously exempt under the Medical Device Directive (MDD) in the EU, you may want to read this article to determine if you will need to seek out an NB before the deadline (if you are still interested in selling into the EU, that is). Find the article here: http://bit.ly/odt191011.
In that same issue, MedWorld Advisors’ Florence Joffroy-Black and Dave Sheppard pose several scenarios for device manufacturers currently selling into the EU. They provide the potential positives and negatives of either recertifying all products currently sold into the sector, using the opportunity to perform “portfolio management” on current offerings, or delaying action in favor of recertifying to MDD requirements. Companies unsure of what action to take or whether they are interested in continuing to sell their full product line in the EU should review this article. It can be found here: http://bit.ly/odt191012.
Representatives from WuXi AppTec authored two articles in subsequent issues of MPO—June and July/August—which focus on testing implications associated with MDR. The June column presents a deep dive on the impact the MDR has on ISO packaging standards, specifically regarding testing and validation. It also offers a series of questions device manufacturers should be asking of testing partners who will be handling products headed to Europe. The more recent column is a less narrow look at MDR; rather, it provides insights on a variety of items companies need to keep in mind regarding device testing, their outsourcing partners, and the MDR. You can find June’s column here—http://bit.ly/odt191013—and the one from July/August here— http://bit.ly/odt191014.
Hopefully, all of this worry is for naught and the EU recognizes the disarray caused by the regulatory rollout given the timing with Brexit and the issues involving available NBs. As such, a delay in implementation would avoid the potential device shortages some are predicting will occur if the timeline isn’t altered. In fact, according to an article from Aug. 2 on the Regulatory Affairs Professionals Society website (http://bit.ly/odt191015), the U.S. has raised “serious concerns” regarding the regulatory changeover. The letter to the Word Trade Organization urges the EU delay implementation by three years.
Whether the sector takes that advice or not could significantly impact how bumpy a ride this is.