Particulate testing of cardiovascular medical devices is an important and valuable step on the road to regulatory clearance, market success, and patient safety. Device manufacturers that incorporate particulate testing into their product development plans early are better equipped to navigate the regulatory clearance process and potentially reduce time to market. After premarket regulatory clearance is achieved, and the cardiovascular device is on the market in clinical use, postmarket lot release particulate testing and monitoring can help ensure product quality and safety going forward.
Particulate Testing of Cardiovascular Devices: What Is It, and Why Is It so Valuable?
Particulate testing determines the quantity and size of residual materials present on a cardiovascular device. Residual material includes substances resulting from the manufacturing process, such as metal shavings or millings from drilling; substances resulting from the packaging of the product, such as cardboard, packaging lint, or glue resins; and any particulates resulting from handling of the device during the manufacturing, packaging, or shipping processes. Residual material also includes coatings and adhesives present on the device that unintentionally slough off during clinical use, as well as any other foreign contaminants, such as dust or skin cells.
It is important that manufacturers ensure that these contaminants and byproducts of manufacturing are removed as they pose potential health risks to patients. When a device is used on a patient, particles could be released into their bloodstream and become lodged in the patient’s vascular capillary system. Whether this is harmful to the patient depends on the number and size of the particles as well as where and to what degree they cause an occlusion. In some cases, these occlusions could lead to blood clots and even stroke. In addition, the patient’s immune system may react adversely to the particulates.
Though these health risks are rare, a review of the FDA’s warning letters shows that adverse events related to particulates are all too common. As devices become more complex with specialized coatings and components, the device’s potential to release particulates and injure a patient increases. Therefore, the FDA has increased its scrutiny of particulates in cardiovascular devices.
For this reason, most cardiovascular device types are candidates for particulate testing. Chief among these are stents, stent-delivery systems, vascular catheters (guide catheters, angioplasty “balloon” catheters, and microcatheters), coated guide wires, introducers, and guide sheaths.
Active implantable devices—in particular, pacemakers and their associated accessories—are required to be particulate tested in compliance with international standards EN 45502/ISO 14708.
Premarket Product Validation
Particulate testing provides significant value to the manufacturer and, eventually, to the patient using the device. In our experience, manufacturers that follow published guidance and have written justification for their selected test methods, validation of the method, and demonstrated consistency in their particulate test results are more likely to experience a smoother U.S. FDA clearance process and speedier market launch.
Premarket particulate testing incorporated as part of the product validation process includes compliance with the following standards:
- ANSI/AAMI TIR 42 Evaluation of Particulates Associated with Vascular Medical Devices (approved 2010): This report offers guidance to medical device manufacturers in applying analytical methods for particulate testing, identifying potential sources of particulate contaminants, and guidance for developing acceptable limits for particulates.
- FDA’s Class II Special Controls Guidance Document for Certain Percutaneous Transluminal Coronary Angioplasty (PTCA) Catheters (issued 2010): Section 13, “Particulate Evaluation,” is particularly important to manufacturers submitting 510(k) clearance applications, as it lists specific methods FDA wants to see employed in particulate testing, such as worst-case scenario and exercise of the device.
- EN 45502 Active Implantable Medical Devices (published 2010), and ISO 14708 Implants for Surgery – Active Implantable Medical Devices (published 2014): These two harmonized standards set an acceptable level of residual particulate matter for such active implantable medical devices as pacemakers.
Particulate Testing of Cardiovascular Devices
As particulate testing of cardiovascular devices varies by device type and manufacturer, no standardized acceptance criteria have been established. Therefore, it is advisable for a manufacturer to identify an unbiased, third-party laboratory with whom to partner to create acceptance criteria specific to their device. (See Figure 1) In creating this criteria there are three major steps of the process that generally remain constant:
Step 1: Create a protocol. Incorporate a vascular model (where applicable). Working closely with the third-party lab facility, the manufacturer and lab collaboratively write a test protocol incorporating a vascular (or “tortuous”) model mimicking arterial conditions to which the device will be subjected during testing (simulated use conditions).
Step 2: Perform method validation. The laboratory will validate the test protocol per the FDA’s Class II Special Controls Guidance Document mentioned previously. The purpose of the validation is to show that any particulate matter exposed to the vascular model is recoverable in the analysis.
Step 3: Test the device. Testing varies by device type but there are commonalities across devices. For instance, testing should typically include:
- Associated accessories per your regulatory agencies’ preferences—to see if the interaction of devices and accessories causes particulates to slough off during use.
- Simulated use conditions for each device type that will accurately mimic how the device is used clinically.
- Human factors associated with practitioner and patient that may result in unintended use or mishandling of the device during procedures that may contribute to additional particulates.
Step 4: Ongoing Monitoring. Particulate testing is strongly advised during both premarket product development and also for postmarket monitoring and quality purposes.
Establishing Acceptance Criteria
For medical devices there are few standards published providing clear guidance for particulate matter on devices, with the exception of EN 45502. Therefore, the manufacturer has the primary responsibility to establish standardized acceptance criteria for their specific cardiovascular device and its intended use. Often the manufacturer’s acceptance criterion is based on standards that don’t necessarily apply to cardiovascular devices, but contain specifications for particulate matter of other products in the vascular pathway (i.e., USP ). However, some regulatory bodies frown upon leveraging these standards to determine acceptance of a product that does not fit within that standard’s scope, such as applying the USP specifications for particulate matter in injections to a medical device.
A recommended best practice as outlined in ANSI/AAMI TIR 42 suggests obtaining comparative data on particulate matter from a predicate device. If the data from the legally marketed device or predicate is comparable to the test device, the manufacturer has reasonable assurance of patient safety and may use this data to justify its establishment of acceptance criteria values. Action and alert limits can then be established based on the acceptance criteria and the percentage of the maximum limit that the manufacturer is willing to accept during routine production monitoring.
The value of particulate testing for the device manufacturer in the postmarket environment includes monitoring of the manufacturing processes and techniques and the amount of residual material being generated. Lot-release testing helps determine whether the packaging and handling processes for devices are adequately clean. It also helps the manufacturer assess changes or variance in the manufacturing process to set alert and action limits to avoid costly product recalls or adverse clinical outcomes.
Recommended Identification Measures If Particulates Are Detected
If particulates are detected, further investigation of recovered particulate matter may be required to determine where they originated or at what step in the manufacturing process the particulates occurred. (See Figure 2) Manufacturers seeking additional information about the particulates recovered during testing can choose a variety of options to further identify possible sources of contamination including:
- Microscopic particle investigation for visual inspection of particulate matter.
- Fourier transform infrared spectroscopy (micro-FTIR) scan using an analytical test to determine the composition of recovered solid material—not just quantity and size of particulates, but qualitative identification against known materials in the database.
Data obtained from particulate testing is typically in the form of “particles-pertest- sample” depending on the equipment and lab that performs the testing. Particles-per-test-sample or particles-perdevice is a measure of the total particulate load of that sample and theoretically, how much particulate matter will be exposed or introduced to the patient. (See Figure 3)
For example, a guide wire may be tested via a worse-case, tortuous path using a microcatheter and hemostatic valve as accessories. If the wire was exercised within the microcatheter (contained within the model), then the microcatheter is flushed, the extract produced would, theoretically, contain the amount of particulate that could be exposed to a patient during use. As mentioned earlier, the health risks to patients associated with this potential particulate exposure is what concerns regulatory agencies.
Choosing Wisely: Finding a Third-Party Laboratory with Expertise and Experience in Particulate Testing of Cardiovascular Devices
Establishing acceptance criteria and testing for particulate matter can be a daunting task; therefore, identifying a qualified third-party laboratory with whom to partner is strongly recommended. The following criteria should provide helpful guidance for selecting a laboratory partner for your cardiovascular device particulate testing:
- Years of experience working with manufacturers of cardiovascular devices, such as stents, catheters, guide wires, and active implantables.
- Expertise in writing appropriate test protocols and preparing clinically relevant study designs including validation of the test method using appropriate test controls.
- Comprehensive knowledge of, and even participation in the development of, relevant international standards and experience with regulatory guidance documents.
- Capability to perform further investigation of recovered particulate matter to identify source and consult on solutions.
It is important to stress that decision makers at cardiovascular device manufacturers are advised to incorporate third-party particulate testing of their devices into their product development schedules and postmarket monitoring processes. Failure to do so can result in problems ranging from complications in obtaining regulatory clearance and delayed product launch to postmarket quality and serious patient safety issues. With some understanding of the importance of particulate testing and a partnership with a carefully chosen third-party laboratory, however, device manufacturers will be well positioned to reduce the risk of these problems occurring and to maintain good control and oversight of their cardiovascular products and manufacturing processes.
This article was written by Ryan Lunceford, Particulates Department Manager, CQIA (ASQ), Nelson Laboratories, Salt Lake City, UT. For more information, Click Here .