As the world of medical technology progresses, so does the landscape of regulatory expectations. Gone are the days when unknown chemicals would be allowed or accepted in preclinical testing. For today’s regulatory bodies, ambiguity in chemical characterization is no longer tolerated. Put simply, unknowns are unacceptable. This approach requires a risk-based approach, demanding a holistic view of all chemical constituents or, in some cases, a detailed focus on a singular compound of concern.
Whether expected or unspecified, all compounds from extractables and leachables (E&L) testing must be analytically screened. ISO 10993-18:2020 explains that analytical screening aims to “discover, identify and semi-quantitatively estimate the concentration of all relevant analytes in a test sample above an established reporting threshold.” Analytical testing labs must first adequately discover or detect the extracted compounds to begin the identification or semi-quantitation processes.
Common compound identification methods
Liquid chromatography-mass spectrometry (LC-MS) is commonly used in E&L testing to identify and semi-quantitate semi-/non-volatile compounds. However, there are several detection techniques for these types of compounds. One approach is to utilize an ultraviolet (UV) detection system, which is limited in detecting compounds without a light-absorbing moiety.
Alternatively, mass spectrometry (MS) detection has emerged as the leading option for detecting semi-/non-volatile compounds in E&L testing. In addition to not relying on a compound with light-absorbing functionality amid other advantages, detection by MS offers more thorough results and complete toxicological risk assessments.
LC-MS vs. UV detection
There are numerous advantages to detecting organic compounds by mass spectrometry during chemical characterization of medical device extracts. Generally, more chemical compounds may be observed by MS detection due to a broader range of chemical functionality that is amenable to ionization in the mass spectrometer (e.g., various carbonyl-containing structures, amines, polyethers, and siloxanes).
In addition, typical LC-MS experiments are performed by analyzing both positive and negative ion modes to increase the range of compounds observed by exploiting different means of ionization. This can further be extended to use both electrospray ionization (ESI) as well as atmospheric-pressure chemical ionization (APCI), yielding up to four unique datasets by which to detect and identify non-volatile and semi-volatile compounds (e.g., ESI+, ESI-, APCI+, APCI-).
The detection limit for most chemical compounds is also lower in MS analysis versus UV (Figure 1). This can allow the analyst to identify more compounds of potential toxicological relevance to help ensure the most robust risk assessment of the medical device. Furthermore, in the event of LC-UV-MS analysis, the MS data is being collected regardless. So, excluding compounds in the characterization report based on UV signal alone will arbitrarily remove compounds from identification and the toxicological risk assessment.
The primary limitations to UV-based detection of semi-volatiles and non-volatiles of extractables and leachables of medical devices are coverage of chemical functional groups and detection limits. Many compounds extracted from medical devices are UV-silent or provide weak signals, such as aliphatic compounds containing esters, amines, ethers, and siloxanes.
In general, much higher concentrations are required to detect samples by UV versus signal from a mass spectrometer. To achieve these higher concentrations, additional sample concentration is often necessary to arrive at the study’s target analytical evaluation threshold (AET), which can exacerbate issues involving compound degradation, volatility, and sample matrix effects.
Detection by UV can also fail to account for significant portions of the non-volatile residue (NVR) mass performed for exhaustive extractions. Similarly, potential compounds of toxicological concern may be present in a relevant amount but below the limit of detection by UV.
Figure 1: UV and MS detection of Irganox 1098 with concentrations ranging from 0.05 μg/mL to 10 μg/mL. The lowest concentration with a signal-to-noise ratio greater than 3 by UV was 0.5 μg/mL.
A case study of a silicone-containing nitinol stent
After performing NVR analysis, it was determined that there was approximately 350,000 μg of non-volatile extractables from an isopropanol extraction per device. Examining the LC-UV-MS data by UV-detection showed no discernable peaks at 200 nm wavelength, and expanding this to detect in a range from 190-400 nm also revealed no peaks.
Conversely, detection by ESI-MS in both positive and negative ion modes revealed numerous peaks (Figure 2) that were further identified as various cyclic siloxanes, fluorinated siloxanes, amines, polyethers and plasticizers. During toxicological risk assessment, these fluorinated siloxanes were determined to have margin of safety (MOS) values significantly below 1.
Figure 2: Overlay of exhaustive extractables of a silicone-containing nitinol stent. Top: MS detection in positive-ion mode, Middle: MS detection in negative-ion mode, Bottom: UV detection at 200 nm wavelength
A final word
As medical device testing undergoes rapid evolution, the quest for thorough chemical characterization becomes paramount. While historically significant, UV detection faces undeniable limitations, especially concerning functional group coverage and sensitivity.
The prowess of LC-MS is undeniable. It casts a broader net, capturing a wide range of compounds at lower concentrations and providing intricate layers of analysis through its diverse ionization modes. The case of the silicone-containing nitinol stent illuminates the sheer contrast between UV and LC-MS detections, emphasizing the risks of potential undetected hazards. However, harnessing the full potential of LC-MS requires expertise and nuanced understanding. Medical device manufacturers who might not possess this specialized know-how in-house stand at a pivotal crossroads. Here, the role of an experienced lab testing partner becomes invaluable. Teaming up with a seasoned laboratory ensures that the complex methodologies of LC-MS are navigated with precision while also assuring comprehensive chemical characterization and thorough toxicological risk assessments.
Medical device packaging validation helps ensure that a medical device cleared for commercialization will arrive to the end-user in an uncompromised, sterile state, and non-sterile product remains uncompromised during its journey to the user. Here are five important best practices to packaging validation testing, according to the ISO 11607 standard.
Your medical device has finally been approved, and packed for shipping to the shelves. But what happens when the package drops in distribution or temperatures spike in transit? Will it still be safe for use by the time it makes it to patients or healthcare providers?
That’s what medical device packaging validation testing aims to find out. Quality and compliant packaging ensures a medical device arrives as intended to the end-user. To validate that the packaging is just that – quality and compliant – manufacturers are required to conduct a series of tests:
Simulated distribution/transportation (“shake, rattle, and roll”) testing: evaluates the ability of the package and shipper to protect the product through handling, shipping, and distribution environments, which may result in damage such as puncture, abrasion, and seal failure.
Shelf-life determination testing: serves as key interim data to support product shelf-life dating until real-time data are available.
Package integrity testing: evaluates the integrity of packaging to be maintained during the production, shipping, and life of the product.
Seal integrity testing: assesses how users interact with the packaging system, including seals, to determine its functionality, ease of use, and potential risks.
Each category of testing has several sub-test methods. Medical device manufacturers refer to ISO 11607 to develop an appropriate test plan.
Packaging Validation Testing Best Practices Guided by ISO 11607
ISO 11607 packaging for terminally sterilized medical devices is the principal standard for medical device packaging validation testing. It is broken up into two parts:
ISO 11607-1: Requirements for materials, sterile barrier systems and packaging systems
ISO 11607-2: Validation requirements for forming, sealing and assembly processes
All in all, ISO 11607 stands as a globally acknowledged standard, cited by regulatory bodies worldwide. Both the US FDA and the EU MDR incorporate this standard into their evaluations. It ensures adherence to integrity, usability, and sterile barrier requirements, while also addressing risk mitigation for device packaging.
Missteps and retesting can be costly and cause market delays, so it’s important to get these final steps right. To help, we summarized five important best practices that every medical device manufacturer should know.
5 Medical Device Packaging Validation Testing Best Practices
#1. Build Packaging Around the Device
Successful packaging validation starts with how well you design your medical device’s packaging in the first place. In other words, you shouldn’t be putting your device in a package that already exists and hope it works. While it may be more efficient to reuse configurations, you risk over- or under-estimating packaging needs (like bubble wrap or cardboard layers) and ultimately put the device in jeopardy.
Instead, plan your medical device packaging design and materials by evaluating the:
Nature of your medical device
Planned sterilization methods
Intended use
Expiration date
Transport circumstances
Storage environment
Successful packaging – and a successful validation – will be informed by these parameters. It’s critical to know, for example, your various shipping modes and design packaging that can withstand that type of environment and test it accordingly.
While it takes more time on the front end, the time and money saved from retesting or failure will be well worth it. This is all about starting with the end in mind.
#2. Prioritize Protecting Sterile Barriers
For sterile products, sterilization commonly constitutes the final stage in the medical device manufacturing process. But it’s not the medical device’s last stop.
From there, it must remain sterile until the moment it’s needed for use. This sterility directly impacts the medical device’s safety, effectiveness, and usability. If the sterile barrier is compromised, there’s no way to prove if the contents are sterile or not, putting end-users at risk (or forcing them to discard a perfectly usable device). This means your packaging needs to protect sterile barriers above all else.
By conducting rigorous usability evaluations, you can address any usability issues that may compromise the seal integrity. For example, burst strength testing according to ASTM F1140 determines a package’s ability to resist internal pressure and measures the strength of the package seals.
Ultimately, usability evaluation contributes to the development of reliable and user-friendly packaging solutions that uphold the integrity and sterility of medical devices.
#3. Don’t Neglect Usability & Aesthetics
ISO 11607 places an emphasis on usability evaluations as a part of packaging validation testing. These evaluations demonstrate that the sterile contents can be aseptically removed from the sterile barrier system. According to section 7 of ISO 11607, usability evaluations should assess how well the instructions:
Identify a clear location on the package to begin opening it.
Describe the opening technique that doesn’t contaminate or damage the contents.
Describe how to aseptically present the product into the sterile field.
These usability instructions are critical to patient safety – and so is making sure that these instructions and other labels stay legible during routine storage and use. In addition to usability, this has a lot to do with aesthetics. What will the packaging look like after distribution or long time on the shelf? Wrinkled, damaged, or illegible labels are an aesthetic problem with usability implications. Don’t neglect this!
#4. Document Everything
Your medical device packaging validation testing is only as good as it is documented. Keep a paper trail of everything, including:
How the packaging has been designed.
The test plan.
Results of the tests.
As regulatory expectations evolve, having the right documentation will be helpful in case repackaging or revalidation is needed.
#5. Work with a Trustworthy Testing Partner
While it’s possible to conduct medical device packaging validation testing in-house, most medical device manufacturers work with testing labs to help them get the job done. However, it’s important to be critical about who you partner with. Make sure your partner checks, at least, these three boxes:
Real-time and accelerated aging capabilities
Waiting for real-time aging data can delay your product’s go-to-market. Accelerated aging studies (ASTM F1980) serve as key interim data to support product shelf-life dating until that real-time data are available. This means it’s critical to have reliable results from these studies.
When vetting a partner, make sure they can perform these tests in a variety of settings to ensure all package types and materials are compatible with the temperature and humidity exposure limits.
Environmental conditioning capabilities
Environmental conditioning testing (ISTA Series and ASTM D4332) exposes medical device packaging to freezing and tropical temperatures for impact assessment, supporting the package system’s ability to withstand worst-case scenarios. This helps ensure the product’s stability during and after distribution.
When vetting a testing lab, make sure they can do these studies. (Not all can!)
True complete in-house testing
Some labs don’t have the resources or equipment needed to handle simulated distribution/transportation testing – a pinnacle of medical device packaging validation. In that case, they outsource the “shake, rattle, and roll” test to yet another lab, subjecting your packaging and product to additional handling and environmental conditions it wouldn’t normally encounter (and leaving room for error).
Unnecessary shipping and handling during validation creates room for error. Avoid this entirely by working with a testing partner that can handle this testing in-house.
Conclusion
Medical device packaging validation testing is an important final step. You have worked hard to design, develop, and clear your medical device product for commercialization – now make sure it stays that way with the best packaging, validated with these best practices in mind.
WuXi AppTec is an experienced preclinical testing partner for device manufacturers. We offer everything from validation of the packaging/seal integrity, simulated distribution/transportation testing to shelf-life determination.
Talk to an expert about your upcoming project to see how we can help.
As a global company with operations across Asia, Europe, and North America, WuXi AppTec provides a broad portfolio of R&D and manufacturing services that enable the pharmaceutical and healthcare industry around the world to advance discoveries and deliver groundbreaking treatments to patients. Through its unique business models, WuXi AppTec’s integrated, end-to-end services include chemistry drug CRDMO (Contract Research, Development and Manufacturing Organization), biology discovery, preclinical testing and clinical research services, and cell and gene therapies CTDMO (Contract Testing, Development and Manufacturing Organization), helping customers improve the productivity of advancing healthcare products through cost-effective and efficient solutions. WuXi AppTec received AA ESG rating from MSCI in 2022 and its open-access platform is enabling more than 6,000 customers from over 30 countries to improve the health of those in need – and to realize the vision that “every drug can be made and every disease can be treated.”
Medical device developers are constantly looking for regulatory changes that may impact how they work. Sometimes minor changes in regulation can make their lives a lot easier, while alterations add extra steps to a process elsewhere. Changes to ISO 10993-17 have been anticipated for years, and one aspect of the new version will significantly impact device manufacturers—the toxicological screening limit (TSL).
What is the Toxicological Screening Limit (and why is it important)?
Chemical characterization (i.e., extractables and/or leachables) are often conducted as a first step in a biocompatibility testing program. However, these studies may yield hundreds or even thousands of compounds that subsequently require evaluation in a toxicological risk assessment (TRA). Evaluation of these large datasets in a TRA are both time-consuming and costly, and often the outcome is a recommendation to conduct additional testing. Ultimately, more tools are needed to streamline large risk assessments and help toxicologists better characterize potential risk.
This is where the toxicological screening limit (TSL) comes in. TSL is the cumulative exposure dose to an identified constituent over a specified time that will be without appreciable harm to health. The TSL can be used to establish whether the total quantity of an identified chemical constituent that is present, or that can be extracted, is at a quantity too low to elicit genotoxicity, cancer, systemic toxicity or reproductive/developmental toxicity.
There are two TSLs included in ISO 10993-17:2023—120 µg (micrograms) for short-term risk (≤ 30 days) and 600 µg (micrograms) for long-term risk (> 30 days). In short, if the total quantity of an extracted chemical (accounting for number of devices used at one time), falls below the threshold of 120 µg, no further evaluation of that chemical is required, and if greater than 120 µg, but less than 600 µg, the risk assessment could focus on short-term risk only. Therefore, the TSL screen has the potential to streamline very large datasets of extractable compounds by reducing the number of chemicals that need to be evaluated in the TRA.
The implications of the TSL for manufacturers are considerable. For example, if 1,000 chemicals are extracted in a chemical characterization study, but 70% of those chemicals fall below the short-term TSL (120 µg), this would result in a much smaller TRA, with only 30% of the chemicals requiring evaluation. By reducing the number of chemicals, and the time necessary to complete the TRA, manufacturers can get the results of their assessments earlier and make more informed decisions regarding how to move forward.
Finally, it is worth noting that application of the TSL is optional; however, the potential time- and cost- savings are significant and certainly provide the manufacturer with an option for streamlining TRAs.
How the TSL Relates to ISO 10993-17:2023
The TSL was introduced in ISO 10993-17:2023 to prioritize chemicals for toxicological risk assessment. Borrowing from the threshold of toxicological concern concept from ISO/TS 21726:2019, the updated standard establishes both a short-term and long-term limit based on exposure duration.
Exposure duration is crucial in determining potential toxicological risk. As mentioned above, ISO 10993-17:2023 includes two TSLs, short-term (≤ 30 days, TSL = 120 µg) and long-term (> 30 days, TSL = 600 µg). In both instances, the maximum total quantity of a chemical must be less than the TSL to meet the criteria for exclusion from further evaluation in the risk assessment. When maximum total quantities are below 120 µg, they can be excluded from evaluation of both short- and long-term risk; however, there may be circumstances where a chemical can be excluded from evaluation of long-term risk, but short-term risk will still need to be considered (e.g., maximum total quantity is > 120 but < 600 µg).
Applying the TSL to data generated in a chemical characterization study allows the toxicologist to conduct a comprehensive TRA more efficiently. By screening out compounds below the proposed thresholds, toxicologists can focus their evaluation on those compounds extracted at higher concentrations and have an increased likelihood of presenting a toxicological concern.
Provided that the specified criteria are met—such as the chemical constituents are identified and not Cohort of Concern substances. If the maximum total quantity of a chemical falls below the TSL, no further risk evaluation is deemed necessary. However, the comparison between each chemical’s maximum total quantity and the TSL values must still be documented in the TRA.
For medical device manufacturers, this adds a degree of precision to the risk assessment process and aids in efficiently allocating resources, focusing on the chemicals that require the most attention. As such, understanding and applying the TSL is not just an academic exercise but an essential part of ISO 10993-17:2023.
What Device Manufacturers Should Consider
The introduction of TSL holds immense significance for device manufacturers, potentially saving them significant time and resources. However, several considerations are crucial to effectively leveraging this new tool.
Foremost is understanding the maximum total quantity of each chemical. The maximum total quantity is either the amount that is present, or that can be extracted from a device, and also considers the number of devices to which a patient can be exposed at one time.
For example, if 50 µg/device is extracted from a device in an exhaustive extraction, and a patient is exposed to one device, the maximum total quantity is 50 µg, which would be below the short- and long-term TSL, and as such, would not require further evaluation in the TRA. However, if the patient could be exposed to 10 devices simultaneously, then the maximum total quantity would be 500 µg. In this case, it would fall below the long-term TSL, but not the short-term TSL, and would still need to be evaluated for short-term risk in the TRA.
However, knowing when TSL can be applied and when it cannot is vital. Below are some examples of specific scenarios where the TSL cannot be used:
Cohort of Concern chemicals: Cohort of Concern chemicals are highly potent toxicants and are excluded from use of the TSL.
Unidentified compounds: Constituents with unknown or incomplete chemical identity cannot be screened using the TSL approach as it cannot be ruled out that they are not Cohort of Concern chemicals.
VOCs from gas-pathway devices: Volatile organic compounds (VOCs) from gas pathway devices are evaluated using approaches and thresholds described in the ISO 18562 series.
Infants and neonates: Devices intended for this vulnerable population cannot rely on the TSL for safety assessments due to their unique susceptibilities.
Even if certain compounds are screened using TSL, documentation comparing the chemical’s maximum total quantity to the TSL remains essential.
In 2022, WuXi AppTec evaluated the protectiveness of the proposed TSLs (short- and long-term) using our internal database of more than 18,000 real-world medical device extractables. This evaluation determined that 1% and < 0.5% of the chemicals evaluated for short- and long-term potential risk, respectively, may result in a derived tolerable intake (TI) less than the TSL.
These observations are consistent with, and lower than, the historical frequency distribution of no observed adverse effect level (NOAEL) values used to establish the well-accepted non-cancer threshold of toxicological concern (TTC) values (i.e., lowest 5thpercentile, protective for > 95% of chemicals). Overall, based on an evaluation of medical device extractables from 2015 to 2021, the results support the protectiveness of the TSL approach for medical device chemicals. These data were also presented at the 2022 Society of Toxicology conference.
However, with ongoing advancements in research and technology, our understanding of chemical toxicities continues to evolve. Hence, staying informed about the latest research and regulatory developments is crucial. For complex devices or uncertain situations, consulting with regulatory experts can provide much-needed guidance and ensure the most appropriate application of the TSL approach.
Final Thoughts
Incorporating the TSL into risk assessment could herald significant efficiency gains for medical device manufacturers without compromising safety. However, it’s important to remember that ISO 10993-17:2023 does not make the application of TSL obligatory—instead, it provides an optimized route to manufacturers who wish to streamline their testing processes. Therefore, manufacturers can perform comprehensive evaluation of all chemicals in their devices if they choose. One key to correctly applying the TSL is partnering with a well-equipped, experienced lab that understands its intricacies and can aptly incorporate it into the TRA. Moreover, evolving standards like ISO 10993-17 underscore the importance of collaborating with a laboratory that keeps pace with regulatory changes, ensuring manufacturers navigate the dynamic landscape of medical device regulation with confidence and compliance.
High-resolution quadrupole time-of-flight (QTOF) gas chromatography–mass spectrometry (GC-QTOF-MS) provides a powerful combination of high mass accuracy with trace level detection capabilities. Applying the technique to extractables and leachables testing (E&L) semi-volatiles analysis results in increased identification abilities utilizing accurate masses while reducing the reliance on spectral compound databases.
E&L testing is used to generate chemical information that can support a toxicological risk assessment (TRA). Chemical characterization can yield hundreds, sometimes thousands, of chemicals for toxicologists to assess—many of which are present in very low levels and only present a toxicological risk if they are highly potent. Accurate and complete identification of compounds in the chemical characterization study is critical for completing a TRA that is useful for evaluating the biological safety of the device materials as well as any unexpected constituents related to manufacturing processes.
As explained in ISO 10993-18, E&L profiling of medical devices generally includes analysis for volatile organic compounds (VOCs), semi-volatile organic compounds (SVOCs), non-volatile organic compounds (NVOCs) and elemental impurities. Although some SVOCs can be determined based on liquid chromatography–mass spectrometry (LC-MS), GC-MS is the primary tool used for their detection, identification and semi-quantitation. The current norm for E&L testing uses low-resolution GC-MS (i.e., single quadrupole) instruments. This article explores the advantages of utilizing high-resolution GC-QTOF-MS instrumentation for the analysis of SVOCs.
Low-Resolution GC-MS SVOC Profiling
In current practice, after compounds have been detected and extracted for spectra, those that are above a pre-defined threshold (i.e., the analytical evaluation threshold or AET) are then searched against in-house and commercially available nominal mass spectral databases. Combined, the compounds in these databases number in the hundreds of thousands. A significant percentage of compounds detected above the AET in a typical E&L study will be identified based on database searching. The remaining compounds will be identified manually and rely heavily on analyst expertise in structural elucidation and may result in either a complete or partial identification (e.g., compound class or sub-structure).
Perhaps the greatest limitation that an analyst faces when attempting to determine the structure of an unknown based on low-resolution GC-MS data is that the mass measurements in mass-to-charge (m/z) lack the precision and accuracy required to discriminate between potential element combinations of the same nominal mass. As a result, the elemental composition of ions measured with a low-resolution instrument cannot be determined based on their mass measurements (e.g., the elemental composition of an ion at 44 m/z could be one of several different combinations, including C2H6N, C3H8, C2H4O, CH2NO, and CO2).
Shown below is a spectrum for N,N-dimethylpropanamide acquired using a low-resolution instrument. The elemental composition of the ions, including 44 m/z, cannot be determined based on the mass measurements. Although incredibly useful for database searching, low-resolution spectra present significant limitations when manual structural elucidation is required.
N,N-Dimethylpropanamide spectrum obtained using a low-resolution GC-MS system.
High-Resolution GC-QTOF-MS SVOC Profiling
Unlike low-resolution instruments, high-resolution QTOF systems provide mass measurements to the fourth decimal place with low parts per million (ppm) mass error, enabling the elemental composition of ions to be determined with high confidence. Furthermore, acquiring data using low energy ionization (around 10-15 electron volts (eV) vs. 70 eV for high energy) increases the likelihood that the intact molecular ion will be detected. The spectrum below shows the results obtained when analyzing N,N-dimethylpropanamide with a high-resolution system.
N,N-Dimethylpropanamide spectrum obtained using a high-resolution GC-QTOF-MS system.
Using the accurate mass measurement of the 44 m/z ion the elemental composition is unequivocally determined to be C2H6N. With such information, an analyst is better equipped to determine the structure of what could otherwise be an unknown, partially identified compound, or incorrectly identified compound.
Low & High-Resolution Combination Profiling
At first blush, it may seem that low-resolution GC-MS systems will be replaced in the E&L laboratory with high-resolution ones, but that may not be the case. The main reason is how extensive high-energy, nominal mass, GC-MS compound databases are. Although GC-QTOF-MS data can be searched against such databases, spectral differences are often observed because of the different instrument types. This means even if a compound is in a database, it can be more challenging to match it to the high-resolution spectral data. Therefore, working with the nominal mass data is often preferable for most compounds in a typical extractables study. Other factors that reduce the likelihood of widespread adoption of accurate mass GC-MS include increased study costs to cover up-front, operational and maintenance costs associated with this advanced technology.
The future of SVOC profiling for E&L could include a combination of both low- and high-resolution analyses. Compounds above the AET in the low-resolution data would be identified, semi-quantitated, and reported using initial database searches, leveraging the high-resolution data on an as-needed basis to support more challenging identifications. With this approach, it would be possible to manage the need for more expensive instruments by collecting high resolution data and analyzing representative samples from a study when additional information is warranted.
Case Study
Consider the example of a tentatively identified compound of special concern, such as a carcinogenic nitrosamine. For the unknown spectrum below, N-Nitroso-diisopropylamine was the top NIST database hit and showed good retention index agreement with the reported value. With the nominal mass spectrum for this low-level compound, it is not possible to rule out the identity being the nitrosamine.
Comparison of the unknown spectrum (red) versus the NIST database spectrum for N-Nitroso-diisopropylamine (blue).
High-resolution analysis using GC-QTOF-MS resulted in the spectrum below for the unknown. N-Nitroso-diisopropylamine as a potential identification was ruled out based on the 130.0862 m/z ion corresponding to C6H12NO2+ rather than the molecular formula of N-Nitroso-diisopropylamine (C6H14N2O). An alternate identification was proposed based on the analysis of the entire spectrum and utilizing information about the sample.
High-resolution spectrum of the unknown acquired using GC-QTOF-MS.
High-resolution spectrum of the unknown acquired using GC-QTOF-MS.
Conclusion
The example above demonstrates the power of high-resolution GC-MS data to aid in the identification of SVOCs. Rather than requiring costly investigations to evaluate compounds of concern, the approach of running samples by high-resolution GC-QTOF-MS alongside low-resolution GC-MS can greatly reduce the likelihood of time-consuming investigations. Additional benefits include more complete and accurate identifications and a decreased reliance on databases.
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.
