As regulatory guidance evolves, a new expectation around preclinical medical device safety testing is emerging: Unknown chemicals are unacceptable. The new risk-based approach means regulatory bodies expect complete chemical characterization. Testing can include all chemical constituents or target a single compound of concern, but the data are derived from extractables/leachables (E/L) testing.
Manufacturers who fail to recognize this trend often need help reining in elongated timelines and controlling bloated budgets. These manufacturers may look to experienced testing partners to get their programs back on track and usher their products toward regulatory clearance. Here are three real-world stories of device manufacturers forced to find a qualified lab testing partner after their first choice failed to deliver.
Case Study 1: Expectations Have Evolved & Submissions Must Do Likewise
A European manufacturer with a limited duration blood contacting medical device approached a potential testing partner for support with its Investigational Device Exemption (IDE) application. The manufacturer spent significant money and time on a marketing campaign in anticipation of launching the product. Time was tight and expectations were high. The testing partner promised fast results and a competitive price. The manufacturer’s in-house expert had worked with the testing partner on European MDD submissions in the past and felt confident they would deliver on time.
The laboratory conducted general testing but failed to meet the chemical characterization threshold outlined in U.S. FDA guidance. A well-known toxicology consultant advised that the product was unlikely to achieve regulatory success in the U.S. based on the poor-quality chemistry report and the presence of unknown materials. With a looming deadline and mounting internal pressure, the manufacturer was forced to approach a second testing partner to fix the problem.
The new testing partner was able to refine the test plan and identify all compounds. The manufacturer ultimately received a chemical characterization report with no unknowns. The consultant toxicologist confidently wrote a risk assessment that recommended no additional biological testing. The product eventually gained regulatory clearance, but only after the manufacturer extended its marketing schedule and almost doubled its testing budget.
Lesson learned: Different geographies have different rules and expectations about how testing should be conducted. This also applies to how analytical reports and risk assessments should be scrutinized. European Notified Bodies do not always ask for complete chemical characterization data because the EU MDR’s precursor (i.e., MDD) did not require it. These days, the EU MDR mirrors the U.S. FDA’s risk-based approach to chemical characterization. And while submitting in the U.S., European Union, Japan or elsewhere, will always be different, one thing is certain: regulator expectations will always evolve. Working with a testing partner that does not appreciate or understand these differences will cost you time and money.
Case Study 2: Choose Your Partners Wisely
A Chinese manufacturer had its long-term cardiac implant rejected by the U.S. FDA after more than three years of testing with various laboratory partners. The regulator found fault with the solvent selection and the analytical techniques used during testing.
The manufacturer was frustrated and bewildered as to why the process had taken so long and had such few positive developments to show. The first lab partner quit shortly after testing began, claiming it could not meet the agreed-upon deadline. The second company said testing one of the device components would take 52 weeks. When pressed, the laboratory staff claimed testing a component of the device would be unnecessary and that they could achieve regulatory clearance without lead data. Despite internal skepticism, the manufacturer proceeded with its testing program. To no avail.
After nine months of trying to contact the lab testing partner, the manufacturer still had incomplete testing data for its device and no updates. Convinced regulators would require test data from all the components of the device, the manufacturer was forced to engage a third lab partner.
Although an unconventional approach, the third laboratory devised a test plan and risk mitigation strategy that eventually would provide the manufacturer with data to support a successful regulatory submission. The device manufacturer learned the hard way that it can be costly to pick the wrong lab partner. After three years of delays and restarts, the cost of the program has grown to several times the initially budgeted amount.
Lesson learned: Working with laboratories that cannot meet established deadlines or provide professional customer service will only cause headaches for manufacturers. Thoroughly vetting potential lab partners to understand their capacity, capabilities and record of success is critical.
Case Study 3: Know When to Pause the Project & Continue with Trusted Partners
An American manufacturer had its medical device submission rejected by the U.S. FDA, citing unknown chemicals in their chemistry report. The manufacturer used its regular testing partner to conduct the biological evaluation of its new device despite the laboratory failing to gain approval in a previous submission. The manufacturer was unsure about using its regular partner for the new testing, but executives within the organization vetoed searching for a new lab, citing their track record of working together and concerns about the looming deadline.
Communication issues, unprofessional service, missed deadlines and a slapdash approach to the testing strategy plagued the new program. When regulators identified concerns with the submission, the testing partner provided no explanations and no help. Frustrated, the manufacturer engaged a new testing partner.
A very tight timeline meant fast-track testing would be required, and routine communication would be expected. The new laboratory gladly accepted the challenge and is currently conducting chemical characterization per ISO 10993-1:2018. Unfortunately, the manufacturer had to endure two failed submissions, poor customer service and a greatly inflated budget before getting its testing program back on track.
Lesson learned: A quality lab testing partner shows its mettle when times get tough. Partners that step up and provide solutions when hard questions are asked can be incredibly valuable team members. Those that fully understand current regulatory expectations—complete chemical characterization, for example—and have the expertise to meet them, are irreplaceable.
Choosing the Right Laboratory Partner
All three of these examples have a lesson in common: it’s crucial to choose the right partner. The wrong laboratory testing partner can derail a test program and bust its budget, which is why it is so important to vet them thoroughly. Here are some key questions manufacturers can ask to maximize the chances of success.
- How long have you been conducting E/L studies? How many programs have you run?
- Is complete chemical characterization included in the quoted price and timeline?
- Can you commit to elucidation and complete identification of all components?
- What is your on-time delivery record? And, when does the clock start?
- What is your communications strategy when unexpected issues arise?
- Do you provide support after analytical testing concludes? What if regulators have questions?
A Final Word
All three case studies highlight the need for manufacturers to adequately prepare on the front end to avoid unnecessary delays and costs on the back end. It’s also worth remembering that while the move towards complete chemical characterization and toxicological risk assessment is happening worldwide, regulatory expectations are not universal. Manufacturers need to work with partners that can execute a safety evaluation and has the necessary regulatory and geographic knowledge to develop a test strategy that supports a successful submission.
