Determining the size and number of particles found on and within medical devices is important for, hopefully, obvious reasons. Particles released from an intravenous or implanted device can cause increased health risks in a patient. These particles can induce an undesired response by the body or block circulatory pathways among other issues.
The particles may be present on the component itself, generated by wear or from contaminants during the manufacturing and/or packaging process. The particles can be referred to as intrinsic or extrinsic to the device.
● Intrinsic particles are those which derive from the manufacturing, assembly, and packing process of the device often in the form of silicon oil droplets, polymer, stainless steel, and/or forms of elastic particles.
● Extrinsic particles are foreign particles contributed by external sources such as the environment (e.g. cotton fibers, skin cells, or dust from the atmosphere).
Lastly, a device may be used in conjunction with a pharmaceutical formulation. These formulations may also contain particles and are referred to as inherent particles. PTL’s analytical techniques primarily target the subvisible range of particles, generally considered < 50 µm by the United States Pharmacopeia (USP). PTL has several different approaches to remove and then characterize these subvisible particles to provide the size, shape, and quantity as well as the possible source of the particulate.
PTL offers particle characterization services to the medical device industry through the extraction of particles from these critical devices then determination of the size and number of the particles; and, in some cases, their composition. With this knowledge, the engineer and device development team can better control the quality of their final product and troubleshoot the source of contaminants, and the doctor, surgeon and patient can be confident in the longevity and safety of the treatment. In this article, we will cover briefly how PTL approaches determining the cleanliness of a medical device.
AAMI TIR42:2021 and ISO 14708
PTL typically receives client-specific test methods for medical devices which include details on the simulated use and setup instructions. International standards for specific device categories such as AAMI TIR42:2021 Evaluation of particulate associated with vascular medical devices and ISO 14708 Implants for surgery — Active implantable medical devices exist. These medical device methods tend to include similar general steps: A) removal, B) collection, and C) sizing and counting of particles in addition to identification on occasion.
The general medical device methodology differs from automotive and other mechanical component cleanliness testing as it does not typically include a step during which the collected particles are weighed. In PTL’s experience, the reason for not determining the mass of particles collected from medical devices is the much lower expected levels of contaminants than with automotive parts such as crankshafts, bearings, and fasteners. In addition, the particle density of the various types of particles in many cases (e.g. polymers, skin cells, cotton fibers, silicon oil, etc.) is much lower than the metal and inorganic particles often found on mechanical parts. As a result, obtaining repeatable, accurate masses of such low loading can be difficult. Determining the size, shape, number, and composition of foreign particles is of much greater importance when the “machine of interest and use” is the human body!
PTL is frequently asked to test medical devices by the United States Pharmacopeia USP <788> methodologies. USP <788> Particulate Matter for Injections is written to test injectable products rather than medical devices, but many clients use <788> to evaluate the device particle loading levels due to the USP monograph’s popularity, wide acceptance, approval precedence, and readily available instrumentation. The AAMI TIR42:2021 and ISO 14708 also refer to the USP <788> chapter and specifications.
USP <788> describes two approaches –
● Method 1 outlines testing by the Light Obscuration (LO)/Single Particle Optical Sizing (SPOS) technique
● Method 2 employs microscope evaluation and counting of particles collected on a filter.
USP <788> is concerned with particles greater than 10 and 25 µm in injectable products as particles in these size ranges have been shown to have an increased risk to block circulatory pathways and cause issues in the lungs. Medical devices which are intravascular in use (e.g. catheters, guide wires, delivery sheaths, etc.) are also evaluated for particles in these size ranges for the same reason.
Medical device results are typically reported at specific size intervals based on the client’s size range of interest and/or prior knowledge of increased risk factors to the patient. As previously mentioned, common size intervals for medical devices are >10 µm and >25µm as defined in USP <788>, but particles smaller and larger may be relevant depending on the type of device and intended use. The size intervals of interest ultimately must be determined by the device manufacturer to show the device is safe and to set an allowable count level.
Removal of Particles from the Device
The most common mechanism used to remove particles from a medical device is simple rinsing. This can be done with a simple laboratory wash bottle or pressurized sprayer containing filtered water or isotonic saline. These same fluids can also be passed through the device at a specified flow-rate using a pump. The specifics of this rinsing step are determined by the simulated use instructions provided by the client and their knowledge of how the device will be deployed by the surgeon or clinician. PTL also has ultrasonic baths available which can be used to remove particles from the device’s surface or interior. However, the use of ultrasonication should be compared with the typical use and forces the device will experience during treatment to prevent non-representative wear or artificially elevated particle loading levels. Stainless steel dental implements which are routinely cleaned using ultrasonics are an example of the use of ultrasonic removal. Lastly, orbital shakers are also used to agitate a beaker of fluid containing the device over a defined period to liberate particles. The advantage of the orbital shaking approach is, if elevated temperature and/or prolonged agitation is of interest, it is easily applied to the particle removal step. The ISO 14708 standard for surgical implants discusses the use of orbital shakers during the device preparation steps.
Particle Size and Count Testing
Once the particles are removed from the device, they are either collected in a verified clean vessel for direct measurement by a particle sizing instrument such as LO/SPOS or collected onto a filter of specified pore size for microscope/image analysis sizing and counting using vacuum filtration. As previously mentioned, specific sizes of interest are often predefined and the results can be reported within these size intervals. The particles collected on the filter can also be evaluated using techniques such as Raman Spectroscopy or Energy Dispersive Spectroscopy (EDS) in an attempt to identify the chemical or elemental composition respectively. The choice of Raman Spectroscopy or EDS depends on the particle proprieties. Inspection of the size and composition of the particles collected dictate if PTL’s in-house identification capabilities may be applicable or if the filter can be returned to the client for further, more comprehensive identification techniques. If particle identification is desired, it is important to consider the filter media used for collection, thus having a clear goal at the onset of the testing is crucial.
Considerations and Limitations
PTL does not accept recovered or biohazard-contaminated devices. Our typical medical device projects are R&D, device release testing, and/or companies seeking or responding to agency approval rather than analyses of previously used components or failure analyses. The size and geometry of the device are also relevant and should be discussed before submitting samples; for example, long catheters which require torturous path simulated use set-ups. PTL must be able to set up the simulated use apparatus and conditions within our laminar flow benches to ensure low particle contamination levels. Lastly, please note, PTL is not able to offer sterilization nor is our working environment designed for sterile handling.
How Can PTL Help?
Medical device cleanliness projects are frequently different and unique depending on the device, component design, end-use, etc. As a service laboratory, PTL works with our clients to discuss the goal of the testing and how the device is used, and our staff takes the time to review any established testing instructions as well as previous results (if available) to assist in creating customized studies to produce meaningful results. The medical device company and the patient can have increased confidence of successful treatment with reduced risk of complications due to foreign particles. PTL looks to be a partner in our clients’ testing needs and works to achieve cost-effective solutions to manufacturing challenges.
Consider PTL and speak with one of our knowledgeable staff the next time you are interested in determining the size and number of intrinsic and/or extrinsic particles your medical device may contain or are asked by a regulatory agency to demonstrate if your medical device will meet cleanliness requirements!
By William Kopesky, Director of Analytical Services.