Mark Cabonce, MS, DABT and Kim Ehman, Ph.D., DABT, WuXi AppTec05.02.22
Outsourcing pre-clinical safety testing or keeping it in-house is a nuanced and multi-factored decision. Large manufacturers may have the expertise to conduct required testing but lack the capacity for it. Conversely, laboratory testing partners may provide invaluable experience and regulatory insights that can accelerate testing.
Outsourcing testing makes sense for some manufacturers but not for others. One of the primary considerations manufacturers must weigh is whether the data generated from testing will be complete and robust enough to meet regulators’ expectations and achieve a successful submission.
To get to this answer, there are five questions device manufacturers should consider as they consider outsourcing versus in-house chemical characterization testing.
First, highly trained scientists are required to run extractables/leachables (E/L) testing studies, interpret the data, and identify all compounds. Scientists must also understand regulatory expectations, making in-house expertise in this area very challenging. It can be done, just not quickly.
Even manufacturers with state-of-the-art facilities and qualified personnel may need help easing internal capacity issues. Respecting product launch timing is paramount to premarket success, and outsourcing testing is an effective way to alleviate internal pressure and still meet crucial milestones. But it is essential to work with a laboratory testing partner with experience relevant to the manufacturer's research, device type, and methodology. Manufacturers should also ask for client references and review potential partners' workflow and communication processes.
One of the most important techniques for providing physical or chemical information is E/L testing, which can yield thousands of compounds that may or may not have been anticipated. Any compounds found at or above the analytical evaluation threshold (AET) provide the basis for a device's toxicological risk assessment. After chemists identify and quantify compounds at or above the AET, toxicologists evaluate each compound’s potential risk. When the margin of safety (MOS) for one or more compound is less than 1 (i.e., estimated exposure exceeds a tolerable intake), the toxicological risk assessment (TRA) may be considered "equivocal" and require mitigation strategies (i.e., simulated-use chemical characterization or targeted analytical studies) to satisfy regulators' concerns and support the device’s biocompatibility.
The FDA expects manufacturers to understand and document all chemical constituent data points including:
When considering the compounds used to manufacture and package medical devices, inaccuracies, oversights, or unknowns should be regarded as unacceptable. Lab partners guide numerous medical devices toward regulatory success every year. Those with advanced chemical and toxicological capabilities can provide the critical rationale for how a specific device meets or exceeds safety thresholds. Unknown compounds can derail a medical device's submission package and jeopardize its chances for approval. More importantly, unidentified compounds from E/L studies in medical devices could compromise patient safety.
Simulated-use extractions and targeted analysis are often effective risk mitigations strategies. Simulated-use studies test devices under physiologically relevant conditions—human body temperature, saline solutions, etc.—to determine a realistic patient exposure to potentially harmful chemicals. Targeted analyses compare chemicals of concern against known standards to quantify them precisely, but these analyses are not an option when a constituent cannot be clearly identified. These studies are generally more effective when few potentially problematic constituents exist because of the specificity required.
Every medical device requires biocompatibility testing to help manufacturers understand how materials interact, possibly degrade and, when applicable, absorb in vivo. Chemical characterization will not address the local effects of compounds within medical devices, so these biocompatibility tests are typically required:
In some cases, genotoxicity testing—the potential to damage genetic information, cause cell mutations, and/or cancer—will sufficiently address risks identified by the TRA.
Mitigating risk after a toxicological risk assessment generates an equivocal result is a step-by-step approach that must be customized to the device and the specific finding. If additional testing fails to mitigate risk properly, extreme options like relabeling or even retooling a device can be effective, but they can significantly impact its marketability or timeline. Risk mitigation can be costly and time-consuming, so it is important to plan ahead to ensure manufacturing milestones are not negatively impacted when risk mitigation is required. Collaboration between manufacturers, chemists, and toxicologists—whether it happens in-house or is outsourced—is the best way to determine the most appropriate strategy for a specific device.
Consider ISO 10993-18:2020, for example. Although the FDA does not recognize some aspects of the entire standard, it expects complete chemical characterization and a toxicological risk assessment for virtually any medical device submission. The European Medicines Agency (EMA) recognizes the ISO standard as state-of-the-art (the most recent published version of an accepted standard) and requires EU manufacturers to comply. But the EMA also empowers local regulators (notified bodies) to interpret “state-of-the-art” and guide manufacturers toward compliance.
Meanwhile, Japan's Pharmaceutical and Medical Device Agency and its Ministry of Health, Labor, and Welfare expect detailed information on the device's physical and chemical makeup; raw materials used in manufacturing; methods used to manufacture and sterilize it; detailed design and physical features; and the device's expected duration of body contact. Manufacturers can also expect Japanese regulators to conduct a data integrity review to confirm data reliability and request raw data resulting from all biocompatibility testing.
In China, the National Medical Products Administration oversees policies and standards governing medical devices, cosmetics, and drugs. Like notified bodies in the EU, device manufacturers must work with a Chinese legal entity to ensure regulatory compliance. Manufacturers also need to provide samples for all device submissions and product, packaging, and labeling information translated into Chinese.
Staying current with regional interpretations of global standards can be challenging. Manufacturers can navigate those waters independently but working with a partner that has experience with regulatory bodies in multiple markets can alleviate regional complexities and avoid timeline delays.
These meetings also provide manufacturers guidance and feedback on their devices and test plans before final submission. If regulators are unsatisfied with a device's pre-submission documentation, it will usually emerge at the pre-submission meeting. If manufacturers choose to work with a laboratory testing partner, these experts can also attend pre-submission meetings to provide counsel and address specific questions.
In the EU and China, notified bodies and legal entities serve as the touchpoint between manufacturers and regulators. Pre-submission meetings with the FDA are one of the only times manufacturers can receive direct feedback from regulators. An effective pre-submission meeting can reduce the time and money spent preparing final submissions and significantly reduce the chance of regulatory rejection. Experienced laboratory testing partners often have existing relationships with regulators to help manufacturers stay abreast of new developments, which is another factor to consider when deciding to outsource or keep testing in-house.
Mark Cabonce, M.S., DABT, is a principal toxicologist with a focus on medical devices and combination products. Before joining WuXi AppTec, he was a toxicologist managing regulated in vivo and in-vitro acute toxicology studies, assessing formulation dossiers for GHS classification and labeling, and preparing risk assessment in support of domestic and international product registrations. He earned a M.Sc. degree in biology from St. Louis University, and has been a diplomat of the American Board of Toxicology since 2005.
Dr. Kim Ehman, Ph.D., DABT, is a technical director of Regulatory Toxicology, with a focus on medical device and combination products. Dr. Ehman has over 18 years of toxicology and medical device experience, with expertise in toxicological risk assessments for medical devices, food and beverage products, and electronic nicotine delivery systems. Prior to joining WuXi AppTec Medical Device Testing, she worked as a toxicologist for RTI International, Toxicology Regulatory Services, and Altria Client Services. She received her PhD in parasitology from McGill University and conducted postdoctoral research at the U.S. EPA in developmental neurotoxicology. She earned a B.Sc. degree in biology from Seton Hill University.
Outsourcing testing makes sense for some manufacturers but not for others. One of the primary considerations manufacturers must weigh is whether the data generated from testing will be complete and robust enough to meet regulators’ expectations and achieve a successful submission.
To get to this answer, there are five questions device manufacturers should consider as they consider outsourcing versus in-house chemical characterization testing.
1. What Expertise Already Exists and What is Needed?
Medical device manufacturers without in-house access to qualified chemists, chemistry laboratories, and toxicologists have little choice but to outsource testing to meet the expectations set forth in ISO 10993-1, -17, and -18 for chemical characterization and toxicological risk assessment. For them, the answer is simple. But manufacturers with an in-house laboratory or that already employ qualified scientists must consider other factors.First, highly trained scientists are required to run extractables/leachables (E/L) testing studies, interpret the data, and identify all compounds. Scientists must also understand regulatory expectations, making in-house expertise in this area very challenging. It can be done, just not quickly.
Even manufacturers with state-of-the-art facilities and qualified personnel may need help easing internal capacity issues. Respecting product launch timing is paramount to premarket success, and outsourcing testing is an effective way to alleviate internal pressure and still meet crucial milestones. But it is essential to work with a laboratory testing partner with experience relevant to the manufacturer's research, device type, and methodology. Manufacturers should also ask for client references and review potential partners' workflow and communication processes.
2. How Thorough Is E/L Testing?
ISO 10993-1:2018 identified physical or chemical information as the first step in any biological evaluation and risk assessment process. The revised ISO 10993-18:2020 provides extensive direction on identifying and quantifying constituents present in medical devices. A medical device's fit for use depends on its chemical, toxicological, physical, electrical, morphological, and mechanical properties, but any of these properties can add to overall risk.One of the most important techniques for providing physical or chemical information is E/L testing, which can yield thousands of compounds that may or may not have been anticipated. Any compounds found at or above the analytical evaluation threshold (AET) provide the basis for a device's toxicological risk assessment. After chemists identify and quantify compounds at or above the AET, toxicologists evaluate each compound’s potential risk. When the margin of safety (MOS) for one or more compound is less than 1 (i.e., estimated exposure exceeds a tolerable intake), the toxicological risk assessment (TRA) may be considered "equivocal" and require mitigation strategies (i.e., simulated-use chemical characterization or targeted analytical studies) to satisfy regulators' concerns and support the device’s biocompatibility.
The FDA expects manufacturers to understand and document all chemical constituent data points including:
- Materials of construction (including chemical constituents)
- Chemical substances introduced during manufacturing (mold release agents, process contaminants, sterilization residuals, cleaning agents, packaging, etc.)
- Findings from exaggerated/exhaustive, simulated-use or other targeted extraction studies
When considering the compounds used to manufacture and package medical devices, inaccuracies, oversights, or unknowns should be regarded as unacceptable. Lab partners guide numerous medical devices toward regulatory success every year. Those with advanced chemical and toxicological capabilities can provide the critical rationale for how a specific device meets or exceeds safety thresholds. Unknown compounds can derail a medical device's submission package and jeopardize its chances for approval. More importantly, unidentified compounds from E/L studies in medical devices could compromise patient safety.
3. How Can Risks be Mitigated if a Device Contains Chemicals of Concern?
With the number of chemicals identified in most E/L studies, equivocal results should be anticipated. Initiating a study with timelines that consider mitigation activity for equivocal results is recommended. The harsh solvents used in extractables testing provide a very conservative view of potential patient risk. Regulatory success with medical devices depends on how well manufacturers work with skilled chemists and toxicologists to mitigate that risk.Simulated-use extractions and targeted analysis are often effective risk mitigations strategies. Simulated-use studies test devices under physiologically relevant conditions—human body temperature, saline solutions, etc.—to determine a realistic patient exposure to potentially harmful chemicals. Targeted analyses compare chemicals of concern against known standards to quantify them precisely, but these analyses are not an option when a constituent cannot be clearly identified. These studies are generally more effective when few potentially problematic constituents exist because of the specificity required.
Every medical device requires biocompatibility testing to help manufacturers understand how materials interact, possibly degrade and, when applicable, absorb in vivo. Chemical characterization will not address the local effects of compounds within medical devices, so these biocompatibility tests are typically required:
- Pyrogenicity: The potential to cause a fever.
- Sensitization: The potential to cause a delayed hypersensitivity reaction.
- Irritation: The potential to cause irritation in the skin, mucosal, or ocular tissues.
- Cytotoxicity: The potential to cause cell damage or death.
- Hemocompatibility: A device’s compatibility with blood (if it has blood contact).
In some cases, genotoxicity testing—the potential to damage genetic information, cause cell mutations, and/or cancer—will sufficiently address risks identified by the TRA.
Mitigating risk after a toxicological risk assessment generates an equivocal result is a step-by-step approach that must be customized to the device and the specific finding. If additional testing fails to mitigate risk properly, extreme options like relabeling or even retooling a device can be effective, but they can significantly impact its marketability or timeline. Risk mitigation can be costly and time-consuming, so it is important to plan ahead to ensure manufacturing milestones are not negatively impacted when risk mitigation is required. Collaboration between manufacturers, chemists, and toxicologists—whether it happens in-house or is outsourced—is the best way to determine the most appropriate strategy for a specific device.
4. How Well are Regulators' Expectations Understood?
Depending on the market, regulatory nuances and interpretations can differ. Global standards organizations like ISO and AAMI write and revise standards consistently to ensure medical devices are safe and effective. However, regulatory bodies interpret global standards to match their expectations within their jurisdictions. Interpretations may also evolve as regulators acquire new information through submission reviews. Manufacturers can anticipate complex and regionally nuanced guidance depending on where they submit their devices.Consider ISO 10993-18:2020, for example. Although the FDA does not recognize some aspects of the entire standard, it expects complete chemical characterization and a toxicological risk assessment for virtually any medical device submission. The European Medicines Agency (EMA) recognizes the ISO standard as state-of-the-art (the most recent published version of an accepted standard) and requires EU manufacturers to comply. But the EMA also empowers local regulators (notified bodies) to interpret “state-of-the-art” and guide manufacturers toward compliance.
Meanwhile, Japan's Pharmaceutical and Medical Device Agency and its Ministry of Health, Labor, and Welfare expect detailed information on the device's physical and chemical makeup; raw materials used in manufacturing; methods used to manufacture and sterilize it; detailed design and physical features; and the device's expected duration of body contact. Manufacturers can also expect Japanese regulators to conduct a data integrity review to confirm data reliability and request raw data resulting from all biocompatibility testing.
In China, the National Medical Products Administration oversees policies and standards governing medical devices, cosmetics, and drugs. Like notified bodies in the EU, device manufacturers must work with a Chinese legal entity to ensure regulatory compliance. Manufacturers also need to provide samples for all device submissions and product, packaging, and labeling information translated into Chinese.
Staying current with regional interpretations of global standards can be challenging. Manufacturers can navigate those waters independently but working with a partner that has experience with regulatory bodies in multiple markets can alleviate regional complexities and avoid timeline delays.
5. What is the Level of Preparation for a Pre-submission Meeting?
Pre-submission meetings are valuable touchpoints between regulators and manufacturers that should not be overlooked. Manufacturers should have a detailed understanding of their device, including its intended use, features, functions, testing strategy, and its comparison to predicate devices.These meetings also provide manufacturers guidance and feedback on their devices and test plans before final submission. If regulators are unsatisfied with a device's pre-submission documentation, it will usually emerge at the pre-submission meeting. If manufacturers choose to work with a laboratory testing partner, these experts can also attend pre-submission meetings to provide counsel and address specific questions.
In the EU and China, notified bodies and legal entities serve as the touchpoint between manufacturers and regulators. Pre-submission meetings with the FDA are one of the only times manufacturers can receive direct feedback from regulators. An effective pre-submission meeting can reduce the time and money spent preparing final submissions and significantly reduce the chance of regulatory rejection. Experienced laboratory testing partners often have existing relationships with regulators to help manufacturers stay abreast of new developments, which is another factor to consider when deciding to outsource or keep testing in-house.
The Bottom Line
Cost and timeliness remain key contributors to developing medical devices, and determining whether to outsource testing or keep it in-house impacts both. Manufacturers are the device’s experts, but tight timelines and heavy workloads can make it difficult for them to educate regulators. Incomplete or erroneous documentation delay those opportunities even more and few manufacturers have the resources or appetite to start over after regulatory failure. Regardless of their decision, device safety and effectiveness must be manufacturers’ primary goals.Mark Cabonce, M.S., DABT, is a principal toxicologist with a focus on medical devices and combination products. Before joining WuXi AppTec, he was a toxicologist managing regulated in vivo and in-vitro acute toxicology studies, assessing formulation dossiers for GHS classification and labeling, and preparing risk assessment in support of domestic and international product registrations. He earned a M.Sc. degree in biology from St. Louis University, and has been a diplomat of the American Board of Toxicology since 2005.
Dr. Kim Ehman, Ph.D., DABT, is a technical director of Regulatory Toxicology, with a focus on medical device and combination products. Dr. Ehman has over 18 years of toxicology and medical device experience, with expertise in toxicological risk assessments for medical devices, food and beverage products, and electronic nicotine delivery systems. Prior to joining WuXi AppTec Medical Device Testing, she worked as a toxicologist for RTI International, Toxicology Regulatory Services, and Altria Client Services. She received her PhD in parasitology from McGill University and conducted postdoctoral research at the U.S. EPA in developmental neurotoxicology. She earned a B.Sc. degree in biology from Seton Hill University.
