Particulate contamination

[MedDev12]

Hi everyone,


I’m looking for insights or experiences related to setting acceptance criteria for particulates generated during the manufacturing process for medical devices.

From my review, AAMI TIR42 does not provide specific guidance on maximum allowable particle counts. Instead, it advises that manufacturers establish their own limits based on the nature of the particles and the clinical application of the device.
Similarly, ASTM F2394 and relevant FDA guidance documents give detailed instructions on constructing the tortuous path test stand and defining the particle size ranges to analyze, but they do not specify acceptable particle count levels. I went through the FDA database, hoping I could find some information from other similar devices. No help.
It appears that manufacturers are responsible for defining scientifically and clinically defendable particulate limits.
If anyone has experience or best practices for setting these limits, such as approaches, justifications, or reference points you’ve found effective, I would really appreciate your input.

Thank you in advance for your help.

 

[Tidge]

From my review, AAMI TIR42 does not provide specific guidance on maximum allowable particle counts. Instead, it advises that manufacturers establish their own limits based on the nature of the particles and the clinical application of the device.

1) What is the typical environment where your device will be used? [for target-forming: your device should probably not introduce as much/more particulate in the environment of use]

2) Is there a clinical (or regulatory) expectation about specific particulate sizes? [for target-forming: you should probably meet or exceed these expectations]

3) Is there (in literature) limits beyond which there is no analysis? [for target-forming: you aren't obligated to do "new science" in an area, unless your device relies upon the "new science"]

I recommend including an analysis/statement about "nanomaterials" if your device does not rely on such materials, to demonstrate that you have an awareness of the European regulation(s) and that you are not introducing nanomaterials (incidental or otherwise) into patients.

 

[yodon]

Adding on to what @Tidge said, what are the risks?

 

[MedDev12]

1) What is the typical environment where your device will be used? [for target-forming: your device should probably not introduce as much/more particulate in the environment of use]

2) Is there a clinical (or regulatory) expectation about specific particulate sizes? [for target-forming: you should probably meet or exceed these expectations]

3) Is there (in literature) limits beyond which there is no analysis? [for target-forming: you aren't obligated to do "new science" in an area, unless your device relies upon the "new science"]

I recommend including an analysis/statement about "nanomaterials" if your device does not rely on such materials, to demonstrate that you have an awareness of the European regulation(s) and that you are not introducing nanomaterials (incidental or otherwise) into patients.

Hi,

Thank you for your questions.

The device is a Class III long-term medical device. It is typically used in a controlled surgical operating room environment. Manufacturing and sterilisation controls ensure that particulate levels and other environmental factors are kept below levels acceptable. There is no available literature, and 510(k) summaries do not specify explicit limits for manufacturing residual particulates, nor do they provide harmonised regulatory limits for particulate size or quantity for our device. It is the manufacturer’s responsibility to establish acceptable limits based on risk assessments. The device does not utilise engineered nanomaterials and does not depend on nanoparticle-based mechanisms. (We already have a statement) Manufacturing and sterilisation processes do not intentionally introduce nanomaterials.

Regarding risks, one clinical concern is blockage in the capillaries in patients. Capillaries are only about 7 microns in diameter. The average human hair is 100 microns. So a particulate matter ≥ 100 microns may block the blood flow if they are introduced into the blood capillaries.
However, our PMS has not recorded any such cases so far.
We plan to quantify manufacturing residues to assess their potential toxicity. However, determining acceptable limits is still under consideration. We are unsure how to set the appropriate thresholds for manufacturing residues (not environmental small particles), including alarm and action limits, and how to implement them without existing guidelines or standards.

 

[Tidge]

... and 510(k) summaries do not specify explicit limits for manufacturing residual particulates, nor do they provide harmonised regulatory limits for particulate size or quantity for our device. It is the manufacturer’s responsibility to establish acceptable limits based on risk assessments.

Specific to the FDA, here is my takeaway from reviewing a wide variety 510(k) and working on several different types of medical devices (including Class III):

If there isn't a detailed guidance or consensus standard for a specific device/class of device, the FDA expects to see some critical thinking and analysis. If nothing else, there is the old standby of grabbing competitor/predicate products and demonstrating "similar _____". Particulates have an extra twist, because you also need to demonstrate that you are keeping the particulate levels where they need to be in production... that is, you just can't one-off study a couple of lots and claim equivalence, as can be done with some performance characteristics.

510(k) summaries typically don't include details of HOW these sorts(*1) of analyses are done... companies don't want to make it easy for competitors to know how they satisfied the FDA, so typically all you will see in a public 510(k) is a summary statement.

(*1) For example: For electro-surgical devices, the FDA requires that new devices don't cause "too much" tissue damage (I'm simplifying) but there is no standardized or consensus approach, and no limits of acceptability or unacceptability... and because these tools are used in surgical practice by a wide variety of medical professionals and on a variety of patients for a variety of conditions... it's not as if there will ever be consensus... yet the FDA wants to see some analysis and testing on those devices.There are a variety of papers on how groups have tried to do this testing, but it is a far cry from being standardized... it is pretty embarrassing IMO that even some of the nuttier tests in "consensus standards" from UL, NSF etc have had more rigor applied to the test methods than those papers!

TL; DR: Your company is trying to make and market the device, so you are supposed to be the experts. Demonstrate your expertise and understanding of the risks related to your device. Here you need to demonstrate that you understand the risks related to particulates and how you are controlling them.

I've seen this precise question come up during FDA audits (for multiple sites, at different times), and the (same) company couldn't answer it either time. At the first site, they threw in the towel and gave up that part of the business. At the second site they got a 483 and AFAIK are still dealing with it.... all because they weren't able to answer a simple question in a field they are supposed to be experts in.