Zachary Remillard and Sandi Schaible , WuXi AppTec09.01.22
Regulatory agencies worldwide are adopting a risk-based approach to preclinical medical device safety testing. The U.S. FDA, EU MDR, and Japan's MLHW are three regulatory bodies that expect biological evaluations to include materials characterization information, toxicological risk assessment, and biocompatibility testing.
The ISO 10993 family of standards is the predominant framework upon which the risk-based approach is built. Specifically, ISO 10993-18:2020 provides guidance on chemical characterization information for medical device evaluations. The data generated during testing estimate patient exposure to chemicals contained within medical devices and is the basis for a toxicological risk assessment (TRA). Chemical characterization can include all chemical constituents or target a single compound of concern, but the data are derived from extractables/leachables (E/L) testing.
The bottom line is unknown chemicals are unacceptable, and experts monitoring regulatory expectations and making quick adjustments are critical. Manufacturers that attempt to cut corners will suffer elongated timelines and bloated budgets searching for testing partners who can meet the threshold of a complete risk assessment. Following are three recent real-world examples of device manufacturers who made that mistake.
A few months later, when the report was complete, the biocompatibility expert reviewed test results with an accomplished toxicology consultant. The toxicologist said the product was unlikely to achieve U.S. regulatory success based on the report’s poor quality and several reported “unknown chemicals.” The expert was surprised at the consultant’s advice, having successfully achieved regulatory approval in the past. However, the expert’s team had never submitted to the FDA and it did not fully understand the agency’s requirements. That’s why the company turned to its trusted lab testing partner to handle everything.
Faced with a fast-approaching deadline and mounting internal pressure, the expert trusted the consultant’s advice and quickly scrapped plans to submit the data. The team then worked frantically to secure the services of another testing laboratory, taking care to fully vet the laboratory and understand its timelines, its track record with FDA submissions, and its approach to complete chemical characterization.
The expert rushed sample devices to the new laboratory and nervously kept tabs on the testing status. The first lab’s failure combined with mounting internal pressure meant jobs were on the line. After a few months, the expert was ecstatic to receive a chemical characterization report with identities assigned to every chemical. This allowed the consultant toxicologist to write a risk assessment without any additional biological testing. The product ultimately received FDA approval, but only after the manufacturer pushed back its marketing schedule and nearly doubled its testing budget.
Lessons learned: The original laboratory conducted general testing according to a standard mass spectrometry database, but it failed to recognize the FDA’s chemical characterization expectations when it included unknown chemicals in the chemistry report. European Notified Bodies in the EU have not traditionally asked for complete chemical characterization data as the EU MDR’s precursor (MDD) did not require it. European manufacturers used to use data from literature reviews to demonstrate risk management, but the heightened focus on advanced chemical analyses has made that approach insufficient. This case study is a cautionary tale of European submissions that fail to meet evolving regulatory standards.
MDR leans heavily on the concept of “state-of-the-art,” or the most recent version of an accepted, published standard. Translation—a risk-based approach that mirrors FDA expectations. While submitting in Europe for MDR approval will be different from submitting to the FDA or MLHW (Japan), they all have evolving expectations. Working with a testing partner that understands global regulatory expectations can save companies precious time and money.
The first testing lab the manager approached quit the project after a short time, citing an unrealistic timeline and an impossible program budget. The second lab the manager approached insisted that testing the device would take a full year. When questioned about testing the lead, laboratory staff claimed it was unnecessary and regulatory approval could be achieved without doing so. The biocompatibility manager left the initial meeting feeling skeptical about the lab’s ability to meet the timeline and dreading the results from this second battery of testing. Despite their misgivings, the manager stubbornly proceeded with their testing program.
As internal pressure mounted and the submission deadline loomed, the manager was determined to communicate with the lab—regularly checking on testing status and a projected completion date.
Repeated calls to the laboratory often went unanswered, creating extended periods of complete silence on the program’s status. After finally reaching lab staff, the manager was told the lab would happily abandon the program if the repeated calls persisted. Nine months later, testing continued but the manager was forced to engage a third lab to conduct testing another component of the device.
Splitting biocompatibility testing between two laboratories brings additional scrutiny, but the manager felt he had little choice but to approach a proven and professional lab to finish the work. This lab also implemented a strategy to mitigate regulatory concerns in case questions arose from splitting the work. Today, all testing is on track to meet the October deadline but after three years of stops and starts, the program’s cost has grown to several times the initially budgeted amount.
Lessons learned: Throwing good money after bad when labs prove they cannot meet deadlines or provide professional customer service is a recipe for program failure. This is how budgets get busted, milestones get missed, and people lose their jobs. The timeline is sacrosanct for biological evaluations on medical devices. It is incumbent upon device manufacturers to vet potential lab partners thoroughly and insist upon a track record of success. Laboratories that lack the staff, expertise, or bandwidth to meet basic client needs should be avoided at all costs.
Similarly to the previous failed submission, the QA manager quickly ran into communication problems with lab staff. Calls were unanswered, internal deadlines were unmet and, when interaction did occur, the manager felt disregarded, and the program deprioritized, despite agreeing to specific time-based milestones. Specifically, the manager sought information on how the lab would avoid previous mistakes and achieve the regulatory approval that eluded them. No strategy or plan was ever communicated and when regulators identified questions and concerns with the submission, the lab offered no answers.
Frustrated and left with few alternatives, the QA manager ended the relationship with the previous lab and found a qualified replacement. The manager warily hired the new lab, but only after clear expectations around communication and internal deadlines were established and documented. An extremely tight timeline meant fast-track testing was required, but the new lab happily took on the new client and is currently conducting complete chemical characterization per ISO 10993-1:2018 standard. Unfortunately, it took two failed submissions and more than double the initial budget to get this medical device on track toward regulatory approval.
Lessons learned: The true measure of a lab testing partner is how it responds during times of crisis. When regulators have questions, does the lab support the QA or biocompatibility manager? Does it explain clearly where problems lie and map out a strategy to mitigate regulatory concerns? Does it understand the current regulatory expectations and have the expertise to meet them? Manufacturers must be confident their testing partners will support them in good times and bad.
Regulatory bodies worldwide are elevating their requirements as they learn more about the devices they see and their expectations evolve. Complete chemical characterization is one such requirement that will continue to derail device submissions until everyone recognizes it as the new normal.
Zachary Remillard is a chemistry operations manager at WuXi AppTec Medical Device Testing and has been in the medical device testing industry for five years. He earned a bachelor of arts degree in chemistry from Williams College, with a concentration in biochemistry and molecular biology.
Sandi Schaible is the senior director of analytical chemistry and regulatory toxicology at WuXi AppTec Medical Device Testing, specializing in extractables and leachables studies. She is a U.S. delegate and international delegate for TC194, WG14 (ISO 10993 part 18 in chemical characterization), and also a U.S. delegate for ISO 10993 part 13 and the particulates committee (TIR42).
The ISO 10993 family of standards is the predominant framework upon which the risk-based approach is built. Specifically, ISO 10993-18:2020 provides guidance on chemical characterization information for medical device evaluations. The data generated during testing estimate patient exposure to chemicals contained within medical devices and is the basis for a toxicological risk assessment (TRA). Chemical characterization can include all chemical constituents or target a single compound of concern, but the data are derived from extractables/leachables (E/L) testing.
The bottom line is unknown chemicals are unacceptable, and experts monitoring regulatory expectations and making quick adjustments are critical. Manufacturers that attempt to cut corners will suffer elongated timelines and bloated budgets searching for testing partners who can meet the threshold of a complete risk assessment. Following are three recent real-world examples of device manufacturers who made that mistake.
Submissions Must Reflect Evolving Regulatory Expectations
Case Study 1: A European manufacturer with a limited duration blood contacting medical device approached its regular E/L testing partner for support for its IDE application. The manufacturer had spent considerable time and money on a marketing campaign to launch the new product, its first in the U.S. market. Timelines were tight but the laboratory promised quick results for a competitive price. The manufacturer’s biocompatibility expert had successfully worked with this laboratory many times before on submissions for EU MDD approval and felt good about using a trusted partner for its FDA submission. The expert sent devices for testing and eagerly awaited the final report.A few months later, when the report was complete, the biocompatibility expert reviewed test results with an accomplished toxicology consultant. The toxicologist said the product was unlikely to achieve U.S. regulatory success based on the report’s poor quality and several reported “unknown chemicals.” The expert was surprised at the consultant’s advice, having successfully achieved regulatory approval in the past. However, the expert’s team had never submitted to the FDA and it did not fully understand the agency’s requirements. That’s why the company turned to its trusted lab testing partner to handle everything.
Faced with a fast-approaching deadline and mounting internal pressure, the expert trusted the consultant’s advice and quickly scrapped plans to submit the data. The team then worked frantically to secure the services of another testing laboratory, taking care to fully vet the laboratory and understand its timelines, its track record with FDA submissions, and its approach to complete chemical characterization.
The expert rushed sample devices to the new laboratory and nervously kept tabs on the testing status. The first lab’s failure combined with mounting internal pressure meant jobs were on the line. After a few months, the expert was ecstatic to receive a chemical characterization report with identities assigned to every chemical. This allowed the consultant toxicologist to write a risk assessment without any additional biological testing. The product ultimately received FDA approval, but only after the manufacturer pushed back its marketing schedule and nearly doubled its testing budget.
Lessons learned: The original laboratory conducted general testing according to a standard mass spectrometry database, but it failed to recognize the FDA’s chemical characterization expectations when it included unknown chemicals in the chemistry report. European Notified Bodies in the EU have not traditionally asked for complete chemical characterization data as the EU MDR’s precursor (MDD) did not require it. European manufacturers used to use data from literature reviews to demonstrate risk management, but the heightened focus on advanced chemical analyses has made that approach insufficient. This case study is a cautionary tale of European submissions that fail to meet evolving regulatory standards.
MDR leans heavily on the concept of “state-of-the-art,” or the most recent version of an accepted, published standard. Translation—a risk-based approach that mirrors FDA expectations. While submitting in Europe for MDR approval will be different from submitting to the FDA or MLHW (Japan), they all have evolving expectations. Working with a testing partner that understands global regulatory expectations can save companies precious time and money.
Select Testing Partners Wisely and Keep Them Accountable
Case Study 2: The FDA rejected a Chinese device manufacturer’s long-term cardiac implant after more than three years of testing with multiple laboratory partners. The regulatory agency found fault with the solvent selection and analytical techniques used in testing. Needless to say, the program’s biocompatibility manager was exasperated and his bosses were apoplectic that the program took so long and cost so much with few positive results to show. It was a career-defining opportunity for the manager and, thus far, the program was in ruins.The first testing lab the manager approached quit the project after a short time, citing an unrealistic timeline and an impossible program budget. The second lab the manager approached insisted that testing the device would take a full year. When questioned about testing the lead, laboratory staff claimed it was unnecessary and regulatory approval could be achieved without doing so. The biocompatibility manager left the initial meeting feeling skeptical about the lab’s ability to meet the timeline and dreading the results from this second battery of testing. Despite their misgivings, the manager stubbornly proceeded with their testing program.
As internal pressure mounted and the submission deadline loomed, the manager was determined to communicate with the lab—regularly checking on testing status and a projected completion date.
Repeated calls to the laboratory often went unanswered, creating extended periods of complete silence on the program’s status. After finally reaching lab staff, the manager was told the lab would happily abandon the program if the repeated calls persisted. Nine months later, testing continued but the manager was forced to engage a third lab to conduct testing another component of the device.
Splitting biocompatibility testing between two laboratories brings additional scrutiny, but the manager felt he had little choice but to approach a proven and professional lab to finish the work. This lab also implemented a strategy to mitigate regulatory concerns in case questions arose from splitting the work. Today, all testing is on track to meet the October deadline but after three years of stops and starts, the program’s cost has grown to several times the initially budgeted amount.
Lessons learned: Throwing good money after bad when labs prove they cannot meet deadlines or provide professional customer service is a recipe for program failure. This is how budgets get busted, milestones get missed, and people lose their jobs. The timeline is sacrosanct for biological evaluations on medical devices. It is incumbent upon device manufacturers to vet potential lab partners thoroughly and insist upon a track record of success. Laboratories that lack the staff, expertise, or bandwidth to meet basic client needs should be avoided at all costs.
Know When to Pull the Plug on Substandard Lab Partners
Case Study 3: The FDA rejected a medical device submission due to the presence of “unknown” chemical compounds in the final report. The quality assurance (QA) manager overseeing the testing program for this device contacted a laboratory to conduct a routine biological evaluation almost a year before the FDA submission. The QA manager was hesitant to use the lab on this project after a previous device on which it performed chemical characterization also failed to achieve regulatory approval. The manager proposed finding a new partner to conduct the testing, but was overruled by upper management, citing the looming deadline and budgetary implications of searching for another partner.Similarly to the previous failed submission, the QA manager quickly ran into communication problems with lab staff. Calls were unanswered, internal deadlines were unmet and, when interaction did occur, the manager felt disregarded, and the program deprioritized, despite agreeing to specific time-based milestones. Specifically, the manager sought information on how the lab would avoid previous mistakes and achieve the regulatory approval that eluded them. No strategy or plan was ever communicated and when regulators identified questions and concerns with the submission, the lab offered no answers.
Frustrated and left with few alternatives, the QA manager ended the relationship with the previous lab and found a qualified replacement. The manager warily hired the new lab, but only after clear expectations around communication and internal deadlines were established and documented. An extremely tight timeline meant fast-track testing was required, but the new lab happily took on the new client and is currently conducting complete chemical characterization per ISO 10993-1:2018 standard. Unfortunately, it took two failed submissions and more than double the initial budget to get this medical device on track toward regulatory approval.
Lessons learned: The true measure of a lab testing partner is how it responds during times of crisis. When regulators have questions, does the lab support the QA or biocompatibility manager? Does it explain clearly where problems lie and map out a strategy to mitigate regulatory concerns? Does it understand the current regulatory expectations and have the expertise to meet them? Manufacturers must be confident their testing partners will support them in good times and bad.
Regulatory bodies worldwide are elevating their requirements as they learn more about the devices they see and their expectations evolve. Complete chemical characterization is one such requirement that will continue to derail device submissions until everyone recognizes it as the new normal.
A Final Word on Risk-Based Approach
All the manufacturers in the case studies approached their final lab testing partner with an emergency. The failure to adequately prepare on the front end—including when selecting a vendor—cost them precious time and resources. Despite an industry-wide shift toward complete chemical characterization and toxicological risk assessment, medical device submissions are not the same worldwide. It behooves manufacturers to spend whatever time they need to find partners that can confidently execute a complete safety evaluation and have the requisite geographic and regulatory knowledge to get their device across the finish line.Zachary Remillard is a chemistry operations manager at WuXi AppTec Medical Device Testing and has been in the medical device testing industry for five years. He earned a bachelor of arts degree in chemistry from Williams College, with a concentration in biochemistry and molecular biology.
Sandi Schaible is the senior director of analytical chemistry and regulatory toxicology at WuXi AppTec Medical Device Testing, specializing in extractables and leachables studies. She is a U.S. delegate and international delegate for TC194, WG14 (ISO 10993 part 18 in chemical characterization), and also a U.S. delegate for ISO 10993 part 13 and the particulates committee (TIR42).
