The particulate Predicament

INTRODUCTION

If you haven’t suffered through an investigation into particulate excursions in a cleaning validation effort or environmental monitoring program, bravo and good job; this either means your job responsibilities have nothing to do with these areas, or you’ve been unreasonably lucky and likely should be ridiculed for this.  For the rest of us unfortunate creatures, particulate investigations can very quickly spiral into a never-ending rabbit hole of testing, questioning, non-sequiturs, and cash incineration.  Why is this, though? What is it that makes particulate such a tricky adversary when trying to track down root causes and solve them?  In my experience, the answer is two (2) fold.  

First, everything generates particulate to some degree.  Every movement, every breath, and every interaction between materials creates particulate on some scale.  Studies have found that through movement, humans emit (yes, I said “emit”) particles sized from 2.5 to 10 µm at a quantity of nearly 1,000,000 per hour (Bhangar et al, 2016).  That is on top of the smaller 0.8 µm particles that are emitted during speech and breathing (Morawska et al, 2009).  After the Covid-19 pandemic, I think the world at large is acutely aware of just how many droplets and particles we move around as humans, but this awareness seems to stop as soon as we start to test medical devices for particulate.  Samples are very often received with no real attention to detail with respect to how they are handled, how they are packaged, and under what conditions they are shipped. Then it’s a five-alarm fire when results are inconsistent and unexpected.  So, if you want to stop reading now and not dig into all the particulars, do yourself a favor – if you’re testing for particulate, pay attention to everything and don’t go grab samples off the line with your bare hands, throw them in a zip lock back, and hope for the best.  I know this sounds ridiculous, but you’d be surprised how many samples show up in this condition…or not even in a bag, just rolling around a cardboard box, with the assumption that particulate isn’t a tough test to past.

Second, no specific requirement for allowable limits of particulates exists within the context of most medical devices. ISO 19227:2018, Implants for surgery—Cleanliness of orthopedic implants—General Requirements, provides a framework for evaluating device cleanliness, including evaluation of particulates, though specific limits to which implantable devices must adhere are barely hinted within the standard.  The language of the standard really gives a reader the impression that the authors didn’t want to touch that particular monster with a ten-foot pole. Instead, in clause 5.7 the only advice is that specifications related to particulate should be generated from a risk-based approach and that the type and sensitivity of particulate analyses should be sufficient to mitigate the identified risks (“risk based approach” is the new standard language for “figure it out yourself so we can tell you that you’re wrong later”). TIR42:2021, Evaluation of particulate associated with vascular medical devices, is referenced within the ISO 19227 standard as a pointer for guidance in establishing a risk-based approach to particulate limit establishment and likewise provides a meta-analysis of particulate limits that exist in vascular applications with a strong foundation in injectable requirements as documented in USP<788>.  So, what we have vague guidance which relies on a de facto standard that is based on particulate limits of injectable drugs; as you can imagine, this causes issues.  Comparing medical instrumenst, bone screws, or any of the wide variety of devices that make contact with human patients to an intravenously injected drug is not exactly a fair fight or clinically representative in any way.

So, what do we do? In my experience, the best first step is to pause.  Don’t do the knee-jerk reaction of testing yourself into oblivion – tell the quality department to breathe for a moment and take a reflective pause.  Then, after you’ve poured yourself a nice drink, do what the standard says.  Ensure you understand your particulates (not just quantity and size) but also makeup and morphology, evaluate the risk within the clinical context of your device and ensure you’re testing to limits which are appropriate.  Then, and only then, should you continue testing and do so with a very firm understanding of the pedigree of your samples, the state they are in at the time they are shipped to and received by the lab, and with full assurance that the testing methodology and acceptance criteria are appropriate.

RISK EVALUATION

The scope of the standards, and their associated risk-based focus, highlights a primary risk associated with particulates is related to their potential to negatively impact the vascular system, namely causes of blockages and/or embolisms.  To that end, the standards present the evaluation for devices that make direct contact with circulating blood and contain recommendations concerning quantities specific to this context.  If these are the types of devices you’re concerned with – we would recommend adherence to relevant standards, which do provide more specific guidance.  If you’re not making devices that directly contact circulating blood – continue.  Risks associated with particulate still exist for devices that do not make direct circulatory contact. However, the nature of the risk is different, and, as we will see, the particulate quantities necessary to activate the risk are much higher.  The general principles of the risk evaluation still apply, though the ultimate risk associated with the outcome of the evaluation is expected to be less.  In the context of implants and instruments that do not directly contact a patients circulating blood, the primary risks associated with particulate are as follows:

Inflammatory Response & Macrophage Generation

Particles within the 1-10 micron range are phagocytosable, meaning they can be engulfed by immune cells like macrophages. This would trigger the release of proinflammatory cytokines such as TNF-α, IL-1β, and IL-6, which are known to promote localized inflammation around the implant (Cunningham et al, 2013).     

Particles larger than 10 microns, such as 25-micron particles, are generally too large to be phagocytosed by macrophages. This means they are less likely to trigger the same intense immune response (inflammation, cytokine release) as smaller particles. Since phagocytosis is a key driver of cytokine production (e.g., TNF-α, IL-1β, IL-6), the immune response to larger particles would be less pronounced, resulting in lower levels of inflammatory cytokines (Callejas et al, 2022).  The irritation caused by 25-micron particles results more from their physical presence rather than triggering an immune response through phagocytosis. 

Osteolysis & Implant Loosening
Phagocytosed particles, primarily in the 1-10 micron size, induce a pro-osteoclastic response, which activates osteoclasts (cells responsible for bone resorption). This process leads to bone loss around the implant, weakening its stability and potentially leading to implant loosening or failure over time (Hellab et al, 2003).

Larger particles like those around 25 microns can cause mechanical irritation at the implant site. This can lead to chronic inflammation over time, not due to phagocytosis, but due to the physical presence of the particles rubbing against tissues. Instead of being engulfed, 25-micron particles may become trapped in fibrous tissue, leading to fibrosis (formation of scar tissue), which can still contribute to localized discomfort and implant instability but with a slower progression compared to smaller particles (Goodman et al, 1990).

Toxicity
Smaller particles, such as submicron and nano-scale debris, have been shown to alter cell behavior significantly. These particles can trigger inflammatory responses in various cell types, including macrophages, fibroblasts, osteoblasts, mesenchymal cells, and odontoblasts. The inflammatory response is characterized by the release of several mediators such as IL-6, IL-1β, TNF-α, and PGE2, which can lead to mutagenic and carcinogenic effects. The cytotoxic effect of debris is size-dependent, with smaller particles (nano-scale) intensifying inflammatory responses and having a higher mutagenic potential (Messous et al, 2021).

Particles released from devices can also release potentially harmful organic and elemental constituents into the body, potentially leading to local tissue damage, inflammation, bone resorption, implant detachment, and systemic toxicity. The release of such particles, especially in implantable devices, can be influenced by factors such as implant surface structure, wear, and corrosion, making it challenging to prevent their release completely (Zhou et al, 2021).

  WRAPPING IT UP

At the end of the day, it is up to each manufacturer to come up with their own means of establishing limits and justifying their appropriateness.  What is listed above is a representation of an approach which you may consider, though based on an understanding of your device, its particles, and specific risks which may exist. It should also be plainly noted that the most effective course of action is first to produce a device which is safe and effective – loosening limits should never be a crutch to lean on as a means of accepting poor quality or putting patients at risk.  With that said, trying to achieve limits which are absolutely decoupled from the reality of a devices’ intended use helps no one.  There are some instances, such as in the case of highly porous or 3D printed devices that no matter how truly clean or safe your device is, particles are still going to be present and inconsistently so; living within that reality & and appropriately assessing risk to promote reasonable limits isn’t giving up or accepting less for your patients.  So, if you’re in the middle of a particulate debacle – good luck and godspeed…we believe in you.

REFERENCES

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Callejas, J., Gil, J., Brizuela, A., Pérez, R., & Bosch, B. (2022). Effect of the Size of Titanium Particles Released from Dental Implants on Immunological Response. International Journal of Molecular Sciences, 23. https://doi.org/10.3390/ijms23137333.

Cunningham, B., Hallab, N., Hu, N., & McAfee, P. (2013). Epidural application of spinal instrumentation particulate wear debris: a comprehensive evaluation of neurotoxicity using an in vivo animal model.. Journal of neurosurgery. Spine, 19 3, 336-50 . https://doi.org/10.3171/2013.5.SPINE13166.

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Messous, R., Henriques, B., Bousbaa, H., Silva, F., Teughels, W., & Souza, J. (2021). Cytotoxic effects of submicron- and nano-scale titanium debris released from dental implants: an integrative review. Clinical Oral Investigations, 25, 1627 - 1640. https://doi.org/10.1007/s00784-021-03785-z.

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