Apr 13, 2014

FDA Dysfunction

Marginal Revolution has a post on the FDA and sunscreen:
Excellent piece in the Washington Post on the FDA and sunscreen: 
…American beachgoers will have to make do with sunscreens that dermatologists and cancer-research groups say are less effective and have changed little over the past decade.  That’s because applications for the newer sunscreen ingredients have languished for years in the bureaucracy of the Food and Drug Administration, which must approve the products before they reach consumers.
…The agency has not expanded its list of approved sunscreen ingredients since 1999. Eight ingredient applications are pending, some dating to 2003. Many of the ingredients are designed to provide broader protection from certain types of UV rays and were approved years ago in Europe, Asia, South America and elsewhere.
If you want to understand how dysfunctional regulation has become ponder this sentence:
“This is a very intractable problem. I think, if possible, we are more frustrated than the manufacturers and you all are about this situation,”
Who said it? Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research! Or how about this:
Eleven months ago, in a hearing on Capitol Hill, FDA Commissioner Margaret A. Hamburg told lawmakers that sorting out the sunscreen issue was “one of the highest priorities.”
If this is high priority what happens to all the “low priority” drugs and medical devices?
The comments bring up the fact that the EU and how it is generally five years ahead of the FDA in approvals for some devices.  Transcatheter Aortic-Valve Implantation (TAVI) is a good example, where the EU has second and third generations of devices from a wide range of companies available.  The US has two first generation devices approved.  This is a good situation for the original approval to be sure, as they profit from their willingness to spend enough to perform a large clinical trial and get US approval.    However, I'm not so sure it is so good for the US consumer, even if the improvements of some of these products may be minimal or equivalent to the first device approved, it at least introduces competition and lowers the price. OTOH you could argue that it may not be so good for the EU consumer as they may have some ineffective devices on the market that people are buying.  Both systems require companies to demonstrate safety, I am assuming they both do so effectively.

Oct 28, 2013

Onshoring manufacturing

Medical devices are largely designed in the United States and while the US has a decent size medical device manufacturing industry, it has been significantly moved offshore the last twenty or so years. The offshoring I've been part of hasn't worked out nearly as well as the executives planning the move has hoped with the offshore sites running into labor or quality problems that took years to work through. Two articles have recently caught my attention on companies starting to inshore production.

The NY Times published an article which covers the negatives of out sourcing and companies who have shifted manufacturing to the United States:

Time was foremost among them. The Indian mill needed too much time — three to five months — to perfect its designs, send samples, schedule production, ship the fabric to the United States and get it through customs. Mr. Winthrop was hesitant to predict demand that far in advance.
There were also communication issues. Mr. Winthrop would send the Indian factory so-called tech packs that detailed exactly what kind of fabric he wanted and what variations he would allow. But even with photos and drawings, the roll-to-roll variance was big. And he couldn’t afford to fly to India regularly, or hire someone to monitor production there.
He also found that suppliers deferred to his wishes, rather than being frank about some of his choices, which weren’t, he conceded, always good ones.
These negatives match my observations and aren't easily solvable. Additionally, Atomic Delights details how Apple makes the Mac Pro in the United States:
What makes Apple fascinating is not that they are using some wiz-bang alien technologies to make things - even here in Portland, Oregon, all the technologies Apple shows in this video are in-practice across numerous local factories. What makes Apple unique is that they perform their manufacturing with remarkable precision and on a scale that is simply astonishing, using techniques typically reserved for the aerospace or medical device industries.
Usually a company undergoes an expensive clean up the line activity (clarifying documentation, improving equipment, etc.) before offshoring, then still runs into the problems. I think if companies spent more of the money they spend on offshoring on improving production processes then they could be just as profitable in the US.

Oct 27, 2013

Device companies deal with ACA

QMED details how one medical device company is dealing with the 2.3% tax on medical devices imposed as part of Obamacare:

To cover reduced margins, merit Medical no longer provides 401(k) matching for its employees. In addition, the company stopped donating to charities it previously supported, such as Junior Jazz and The Leonardo. That said, the company has not had to lay off any of its employees yet. In total, the company employs 1,700 people. “You take that kind of money out of a company and something has to give and it's basically research and development or marketing, and those are jobs,” notes Fred Lampropoulos, CEO of Merit Medical.

Oct 14, 2013

Blogs worth reading - creo Quality

creo Quality has a couple of excellent blog posts worth checking out, first off is Fast and Furious Medical Device Product Development: 
Ten months ago, I started a medical device product development project with an entrepreneur / CEO. The goal he made very clear was that before the end of 2013, he wanted to have the device on the market. The device is semi-complicated. It’s an electronic gadget driven by custom firmware. Plus, there are plastic parts and pieces, disposable components, and so on. Before kicking off the project, I had a few conversations with the CEO about project timeline. He reiterated time and again one year, one year, one year. I told him that while theoretically this schedule was possible, 18 months was more realistic–mostly because of FDA wildcard. So we talked about FDA and 510(k) process. After hearing about all of this, the CEO said he thought FDA would only take 90 days to provide clearance and that we should plan accordingly.
 Read the blog to see where they are now.

In early July, I submitted a 510(k) for a fairly simple and straight forward disposable, single use device. The predicate was a very good match. Of course I followed FDA guidance documents, checklists, etc. for what to put into a 510(k). I also reviewed the RTA checklist as I compiled the 510(k) documents. Of course I felt the submission was complete. Why would I send it to FDA if otherwise? A couple weeks after submitting, I received a “refuse” response from FDA. The response included the RTA checklist with reviewer comments.
 I have never been part of a refuse to accept from the FDA, but this: 
In early August, the RTA response was submitted. A couple weeks later, I received a phone call from a FDA reviewer–someone different than the person who first reviewed the submission. He had a few questions, I had a few of my own. He said he would get back with me and did so the next day, this time with a few more questions. I was kind of confused at this point. Some of the things he asked about was marked as fine by the first reviewer. Other points of discussion pertained to how we addressed the issues identified by the first reviewer. Keep in mind, we discussed the specific action plan with the first reviewer who agreed with our plan. Any way, the second reviewer said he needed to discuss the issues with the branch chief and would get back with me.
 I have had happen, one reviewer at the FDA says do something this way, the next reviewer goes the opposite way.  In my case I was only involved in the second reviewer part, but we had conducted some biocompatibility testing based on the first reviewer's comments, the second reviewer didn't like the methodology.  We were able to back the testing up with other data, but it was not a sure thing we wouldn't have to repeat the testing entirely.  It was very frustrating for the entire team and the management.  However, there is not much you can do but suck it up. 

A similar situation happens from time to time in a company, say a new regulatory person on a project will have a new viewpoint, however, the good ones will generally only voice the opinion then not push it unless they absolutely think it is a show stopper.  They will stick with the old decision instead of refocusing the entire team to their whim.  Quite a few people are unable to distinguish between "Must Have", "Nice to Have", and personal preference.   Probably 90% of the comments I see are personal preferences that reviewers have.  Those are fine to have early in the process when many edits are being made, but a waste of time later on.  Think about it next time you are considering rejecting an ECO.

Oct 13, 2013

Excellence in Equipment Documentation

Penelope Trunk has an interesting post on Jake Breeden's Tipping Sacred Cows which lists sacred cows in corporate life that we should reconsider:

Balance: Disguising indecision as a bland compromise that attempts to achieve many things but ends up accomplishing nothing
Collaboration: Creating a culture of learned helplessness with little individual empowerment and accountability
Excellence: Spending too much energy producing perfect work instead of developing the quick-and-dirty solution needed now
Fairness: Keeping score and evening the score to make sure no one gets more than their “fair share”
Passion: Racing down a path seeking success only to find burn-out and misbehavior instead

I think Excellence is a controversial sacred cow, so I wanted to use an example from my medical device factory.  We have a comprehensive equipment program, whenever you have a piece of equipment it will take you at a minimum two to three weeks to get it qualified.  The two to three weeks process time applies to off the shelf equipment we probably already have 15 of that we're already using. 

21CFR820.72 and 21CFR820.70(g) cover equipment requirements, 820.72 is mainly calibration, 820.70(g) is as follows:
(g)Equipment. Each manufacturer shall ensure that all equipment used in the manufacturing process meets specified requirements and is appropriately designed, constructed, placed, and installed to facilitate maintenance, adjustment, cleaning, and use.
(1)Maintenance schedule. Each manufacturer shall establish and maintain schedules for the adjustment, cleaning, and other maintenance of equipment to ensure that manufacturing specifications are met. Maintenance activities, including the date and individual(s) performing the maintenance activities, shall be documented.
(2)Inspection. Each manufacturer shall conduct periodic inspections in accordance with established procedures to ensure adherence to applicable equipment maintenance schedules. The inspections, including the date and individual(s) conducting the inspections, shall be documented.
(3)Adjustment. Each manufacturer shall ensure that any inherent limitations or allowable tolerances are visibly posted on or near equipment requiring periodic adjustments or are readily available to personnel performing these adjustments.

These requirements can be summarized as the equipment must be sustainable and qualified.  These requirements can generally be satisfied by information in the equipment manual and the process testing that you have to do anyway. 

However, as mentioned above, at my work we go far beyond the requirements, we must release a custom drawing of the equipment, custom maintenance procedure and form, - this information is in the manual, but we like to copy it into our own forms.  All of these are held to the internal standards, even though they are absolutely worthless, if I want to do any maintenance work on the equipment, I'm going to reference the manual, not the drawing an engineer threw together to meet a requirement.

A software evaluation must be completed even if the equipment obviously has no software, along with forms for installation qualification (IQ) assessments: line voltage, environment, EMF, safety, calibration, etc.  While it is necessary to perform and document an IQ, the company culture has developed tribal knowledge requirements to do so, if you don't justify the need to not validate the non-existent software properly, well you'll just have to do it again, of course the templates contain no guidance on these.  You can't justify out of measuring line voltage even though your soldering iron clearly works fine.  Operation qualifications are sometimes performed when only installation qualification is needed because justifying out of them has become difficult.

At all steps you need appropriate sign offs, which generally consist of four or five people.  While this is someone's version of excellence, it really accomplishes nothing that isn't included in the manual for an off the shelf piece of equipment. 

A review of warning letters from the FDA reveals the most common issue with equipment is not performing required preventive maintenance or calibration.  In fact, as far as I can tell, no one has ever been cited for not finding a calibrated volt meter and checking the voltage before plugging a piece of equipment in.

All the time making excellent equipment documentation is time spent not working on further understanding of the production process.  If you're spending your energy on getting approvals for a drawing you made of box oven #12, then you are not improving something meaningful.  

Jun 26, 2013

Latex Free Labeling Revisited

On April 23, 2013 the FDA issued draft guidance on the Use of ISO 10993, "BiologicalEvaluation of Medical Devices Part 1: Evaluation and Testing"

This guidance document would finally supersede Blue Book Memorandum #G95-1 for medical devices.  I won't go into much now, but it does include a section on Labeling Devices as "-Free" (such as Latex Free, DEHP Free, etc.) which I've cut and pasted below:

 So there you have it.  It seems reasonable and easier to label with "Not made with natural rubber latex" than to go with the old "Latex Free" which had ambiguous requirements.  While this guidance is still in its draft form, this section seems fairly non-controversial and I'm sure you could go ahead and start following it now without issue.

If you do not like the proposed rule, you are still free to comment on it by following the instructions on the guidance document.

Mar 9, 2013

New Links

I've added Ford & Associates to the links on the side.  He has a blog covering mostly medical device quality and regulatory news, but the feed isn't working right for me at this time.

I've also added a link to Knobbe Medical's Blog.  All of Knobbe Medical bloggers are very well dressed so you know they're not wrong (feel free to use that quote on  your website guys).  I can assure you that I don't clean up so nice.  For some reason their feed doesn't seem to work either, maybe its Blogger's issue.

Just FYI, I signed up as an Amazon associate, if you buy anything through one of the Amazonlinks on this site, I get a small percentage at no additional cost to you.

Mar 4, 2013

Tech Talk - Medical Device Particle Testing Part 3

Note: This is the final part of the medical devices particle testing tech talk, see part 1 and part 2.
Once the particulate test method has been validated, it is appropriate to start product testing.  The FDA guidance documents suggest testing finished devices subjected to sterilization, performing testing on the extremes and an appropriate intermediate size for the product matrix, and assessing both inter- and intra-lot variability.  A common way to meet these requirements is to perform testing on samples from design verification, aging, and three lots of process qualification.
The best practice would be to also test lots produced under worst case coating process conditions, which is the thickest allowable coating applied using the minimum cure time, although the FDA did not mention this.  If you do particulate testing as part of lot release testing, it is in your best interest to test the worst case coating process conditions.
It is desirable to finish as much testing as much as possible in one day; this makes the results more consistent and minimizes the amount of time spent cleaning.
A typical test format is:
  1. Perform test on water with glassware
  2. Perform test on water through the model without test device
  3.  Perform test on water through the model after test device is cycled
To test, first ensure the water and glassware to be used are acceptably clean.  For these examples it is assumed the validated particle method used 50 ml of water.  For example, if the test includes using a syringe to inject water into your model then collecting the effluent in a beaker, use the syringe to inject 50 ml of water into the sample collection beaker and test it.  The result should show a small number of particles in the 10+ um bin and very few (i.e. 0, 1 or 2 per ml) in the larger bins.  If necessary, clean your test glassware some more and then retest.
Next, get baseline results.  This can be done by injecting 50 ml of water through the model, collecting it in the test collection container, and then performing the particulate test.  This is the baseline and should be subtracted from your test device results.  Typically, the baseline has more particulates than the glassware test, but it should still not be that many.  If you see more than 5 large particles (i.e. 50+ um), I would rinse the model with water and perform the test again.  The baseline test may be performed before every sample test, per sample group, or per day.  Any of these methods is defensible.  You should also re-determine the baseline if a test condition changes, such as a new bottle of water is used. 
Then you’ll perform your test to typical use conditions. 
As before, a typical test might be:

a.       Fill model with 10 ml water, collect any effluent in sample container

This step ensures the model is hydrated prior to use, very few endovascular procedures are performed with a system that is not hydrated.  If the system is not hydrated the devices will likely generate extra particulates.

b.      Fill guide catheter with 1 ml water, collect any effluent in sample container

This step ensures the guide catheter interior is hydrated prior to use, for the same reasons as listed above.

c.       Perform simulated use with your device which takes 4 ml of water (obviously varies by device volume), leave device in model, collect any effluent in sample container

This step is the meat of the test.  Simulated use should match the IFU and typical use.  For example, if you have a guide wire and the IFU states to hydrate it for 30 seconds, you should hydrate it for 30 seconds prior to insertion into the RHV, through the catheter and into the model (the water used to hydrate is not used in the test).  Continuing the guide wire example, the guide wire should be advanced to a clinically relevant position in the model, and then retracted, the advance and retractions should be performed a clinically significant number of times.  For a PTCA catheter, the FDA guidance suggests inflating to the maximum labeled diameter.

d.      Flush guide catheter with 10 ml of water, remove device from model, collect any effluent in sample container

This is a typical example; the guide catheter is often flushed during endovascular procedures.  Using the guide wire example, you would flush through the guide catheter because it is standard practice and you will capture any particles removed from the outside of the guide wire.  Flushing through the guide catheter ensures you collect the most particles.  Alternatively you can perform a flush through the model with the guide wire in place, but the particles generated by the guide wire in the guide catheter will not be captured.  One could also perform both flushes to be conservative.

e.      Flush model with 25 ml of water, entirely empty model into sample collection container

Flushing after the device is removed from the model ensures that any particles generated during device removal are captured.

f.        Perform particulate count matching the validation conditions

Perform the test using the method previously validated.

g.       Flush the model with water

To ensure the model is clean for the next test, flush with water.  You can determine how much water is required by testing the effluent after a flushing, or you can perform a baseline test prior to every test as mentioned above.

h.      Identify particulate (as necessary)

Identifying the type of particulate can be done to determine the source of the particulates.  It is generally only attempted when an unexpected number of large particles are detected.  TIR42 lists typical methods for particulate matter determination.  To identify the particulate you have to retain the remainder of the sample, or collect it from the particle counter effluent.  Collecting the sample from the particle counter effluent can be challenging due to the particle counter volume.

To analyze your results, subtract the baseline the sample test results.  If the baseline had a higher result than the test (resulting it a negative number) it is generally acceptable to change that bin to zero, how to deal with this situation should be discussed in the protocol.  Finally it is generally desirable to convert the results to a per device basis and determine if the results met the specification.

Feb 11, 2013

Medical Device Tax

The medical device tax is a 2.3% tax on medical devices, everything from bed pans to surgical tools.  It was signed into law as part of the Affordable Care Act, also known as Obamacare.  As I understand, the logic behind it was if more people are getting more care, more medical devices are being sold and therefore medical devices can pay some of the way.  This logic doesn't follow for drugs, whose companies have better lobbyists.

What is a company to do?  Assuming you are a public company and a certain margin is expected you can either pass the costs on to your customers or cut back on generally marketing and/or R&D (you could also cut quality, but I wouldn't recommend that).  I suspect if you're in the low margin bed pan business, you pass the costs on, you don't have a bunch of bed pan R&D to cut.  If you are the stent or some other product with higher margin, I suspect you also pass the costs on to your customers.  You have some brand leverage and a product you can differentiate yourself from the competitors so switching is more difficult.

Alternatively in either case you could just suck it up, maybe decrease your dividend and hope your investors are kind, but I'm telling you right now, CEOs are looking for ways to pass costs on to their customers.  That is their job, to look out for the company.  Passing the costs on to the customers defeats the whole purpose of the tax, lets look at the cutting R&D option as well.

The Incidental Economist has a post title the job killing medical device tax parts 1 and part 2.  He quotes a recent paper by Bryan Schmutz and Rex Santerre on the device tax and R&D, in part:

simulations show that the recently enacted excise tax on medical devices, taken alone, will reduce R&D spending by approximately $4 billion and thereby lead to a minimum loss of $20 billion worth of human life years over the first 10 years of its enactment.
So decreased R&D spending on medical devices reduces health care quality, which again defeats the purpose of the tax.

The incidental economist has seven points about the tax, none of which I entirely disagree with, however a one I think deserves comment.
One can be confident that the medical device industry will benefit tremendously from the large increase in the number of insured individuals to begin in 2014.
On this point, it depends on the device, some devices are presumably being used to treat the entire population that needs treated now.  These devices would typically be used in emergency cases.  For example, if you're having a heart attack, if you show up at the hospital, you'll get the treatment you need.  If there are people out there not getting treated, it is not because of insurance, more likely its due to access to medical care (i.e. they live in a place that can't deliver the needed treatment), or patient education (i.e. they think they'll be fine if they just wait it out).  More insured people won't increase device use here.  The devices most likely to be used more are the low margin ones, which are generally manufactured overseas.

In fact, a company could end up in a situation where the low margin products increase, the higher margin products don't increase, and you have a tax to deal with where you must cut R&D on high margin products, and/or pass the tax on to customers, neither of which was the purpose of the tax.

One of the comments brings up a good point about start ups:
This is a 2.3 percent tax on gross sales, right? If gross sales are $10, and profits are 10% or $1, then a 2.3 percent tax on gross sales wipes out roughly a quarter of the firm’s profits. For early stage companies with sales but with current operating losses, or negligible profits this could easily mean either paying taxes on losses or imposing losses on break-even revenues.
There are a decent number of companies with a few products and don't currently make a profit as they expand, they don't lose much either, but they are constantly on the edge.  It would be somewhat interesting to see how a company like Thoratec would have grown with this tax in place.  This makes it seem to me that a start up economics may change and a start up may try to sell itself or its products to a larger company sooner, as the transition from small to medium sized company is now harder.  This would result in the 10 or so large diversified companies that dominate the market continuing to do so.

All of this remains to be seen, and I'm trying to keep an open mind about it, but it doesn't make much sense to me right now.

Jan 14, 2013

Tech Talk – Medical Device Particle Test Method Validation

See the previous Tech Talk for Medical Device Particles.

As part of their focus on particles, the FDA has required test method validation of your particulate testing.  Their method validation is described as follows: 

“You should describe and validate particle counting and sizing methods. We recommend that you introduce a known amount of various particle sizes into the test setup and quantify the amount of particles recovered. The number of particles recovered should closely approximate the number you artificially introduced into the system. For a system to be considered validated, ≥90% recovery should be demonstrated for the ≥10 μm and ≥25 μm size ranges.”

Why do they say this?  In my experience, larger particles settle to the bottom of your sample container.  So if you don’t do a proper validation and sort it all out you will not get an accurate count of the most important particle sizes.  In older tests from various companies I have reviewed this was actually happening.

So where to start with this?  First off, read ASTM F2743 for a general guideline.  You will want to do this testing in house, the test labs (NAMSA, WuXi AppTec, Nelson, etc.) will all do it but it will be expensive, most likely you will have to travel to their site, and you have to validate the model you are using your device with anyway.   So just buy a HIAC 9703, which is the same machine the test labs use, you can call them and confirm- maybe they have upgraded by now. 

You also want a good supply of low particulate water for your testing.  Low particulate water can be just reagent grade water, buy from any chemical supply company for cheap.  You also may have an internal system that can produce low particulate water, just check in your HIAC, although it is probably less effort to just buy the bottles of water.  All testing / flushing and rinsing should be done using this water.

During the testing you will probably want some clean glassware, it is actually not that hard to keep the glassware clean during the testing, rinse a clean container with low particulate water a few times and you’re probably good to go.  Just don’t dry anything with paper towels; you’re better off air or shaking it dry.  The USP standard requires a laminar flow hood, but you’ll probably be okay as long as the room is reasonable clean and you shut down the wood sander before you start.

Then you’ll want to buy some particulate standards so you can do your validation, the only source I’ve found for these is Fisher Scientific, I prefer the Count-Cal particles and will assume you use these particles.  This is where you may want to think about it some or just buy the following sizes 10 um, 15 um, 30 um, 70 um and 100 um.  You can skip the 10 and 100 sizes and still meet the USP and FDA guidance, but if you’re going to validate the method, you might as well do it only once and not worry about it again.  If you read the literature on the particle standards you will see that for example the 15 um size has all particles above 10 um.  So the 15 um size will validate the 10+ um bin, etc.  The 10 um size is nice to have to show that the under 10 bin is working properly (i.e. you are not counting everything).  I’ve seen people assume the 10 um standard is a normal distribution and that the count above 10 um is one half of the total count, I think this is a questionable assumption and it is better to use the 15 um size to validate the 10 um bin.

You will also note by reading the literature that comes with the standards the count is not calibrated, only the particle size.  So you cannot accurately use a particle count value calculated from the standard literature to compare against, you should measure the standard yourself and use that as your baseline.  This is important to understand and you’ll probably have to explain it to many people in management and quality who cannot be bothered to think about it beforehand.

You’ll want to create a custom test using the HIAC software, measure the particle sizes you’re planning on calibrating to (i.e. at least 10, 25, and 50, probably 70 and 100), discard the first run and display total count and run count. 

The literature that comes with the particles standards says to discard the first run on the small particle sizes, which the machine can do automatically.  The literature that comes with the particle standard also says to discard the last run on the large particle sizes, but this assumes you are collecting all liquid in your sample- you cannot do this if you’re mixing with a stir bar.  You can discard the first and last runs manually, or discard just the first run and make sure you leave some sample in the sample container when the runs are completed.

I would set your test up to do 5 runs total of 5 ml each and discard the first and last run you will have to discard the last run manually.  5 runs require 25 ml of sample plus enough extra to clear the stir bar by a bit.  I’m basing my experience off of small devices, if you’re testing another type of device, adjust the volumes as appropriate, but I would not use a smaller volume.

For the test method validation, your tests should go something like this:

        1.   Wash methods, glassware and HIAC
        2.   Water through model / tortuous path (results will be used as baseline)
   3.   Particle standard (start with largest)
        4.   Remaining particle standards

The first test will be low particulate water in the sample container (ideally a 100 ml beaker- see below).  You want to ensure your water is okay, your cleaning method is good, and your HIAC is clear.  The test you just made should be used for all testing here on out, the standard tests don’t include all particle sizes and are of limited utility.  I would perform these steps to test:

        1.  Put beaker on HIAC stand, align with tape so it is consistent every time
        2.  Put clean stir bar in beaker, cover with parafilm, stir at highest speed setting
        3.  Wait for two minutes while stirring (recommended in USP 788)
        4.  Run test

If you get poor results, then you generally want to rinse more, using soap to wash during particulate testing doesn’t always help unless you’re desperate and willing to rinse a lot.  Using IPA can help but also requires a lot of rinsing, IPA should not be used except when needed, do not use it between every test.  Starting with clean glassware and rinsing a lot with the reagent grade water is your best bet.

Let us talk about mixing the samples briefly.  Gently shaking or inverting the samples is not adequate.  Without stirring with the stir bar while the HIAC is testing, larger particles (50+ um) will settle.  You can easily test this using a large particulate standard.  If you test while stirring you will get a higher particle count overall as well, is this from the stirring or did they settle previously and now you’re counting them?  It doesn’t matter as long as your baseline is consistent with your test.

Once you’ve done this, you’ll need to do some thinking.  How are you going to run your particulate tests long term?   Basically this breaks down to what sample volume you can collect, which depends on your model and device size.  I think ideally you want to end up with at least 50 ml of sample.  One half of the sample will be used to flush the model after use, so you have 25 ml of water to work with for the testing.  A 50 ml sample fits nicely in a 100 ml beaker with a stir bar and the HIAC sample collection probe fits in while still allowing stirring.  You’ll want to make sure the probe is not too close to the stir bar as the stir bar does generate particles (or bubbles which are counted as particles).

A typical set up for a catheter would be your appropriate tortuosity model, with fittings on both ends, on the proximal end a touhy borst with a Y fitting, through the touhy borst is a standard guide catheter.  Your device is delivered through the guide catheter, additional accessories devices may be used if used with your product.

Your typical use might end up like this, fill model with 10 ml water, fill guide catheter with 1 ml water, perform simulated use with your device which takes 4 ml of water (obviously varies by device volume).  Flush guide catheter with 10 ml of water, flush model with 25 ml of water.  There is no magic to the quantities, you just want a complete flush of the system you’re testing and to get around 50 ml or more of sample water.  Going forward, I’m just going to assume your water volume is 50 ml.   You may also flush through your device if appropriate, you should be careful extra steps have a tendency to generate particles and if they’re not done clinically, you’re just asking for trouble. 

An example of a simulated use for a catheter would be to prepare your catheter (i.e. remove from packaging and hydrate), place your catheter in the guide catheter, advance and retract over a guide wire through tortuosity several times and maybe deliver a stent.  In this case you would definitely flush through the model as the distal end of the catheter is exposed to circulating blood.  If the clinical use was to flush through the guide catheter, you would flush through the guide catheter as well.  If the clinical use was to flush through the catheter (i.e. a contrast injection), you would flush through the catheter as well.

Before testing your device, verify that your model is not generating significant amounts of particulates and use it as a baseline.  You’ll want to make sure it has no dead zones before starting and it is best if the model can be easily drained.   If you’re using a guide catheter or other accessory device, you may want to include that in the baseline, I would do this.  When choosing what accessory devices to use in your baseline, use clinically relevant devices, but also chose ones that are unlikely to generate particulates.  You want a solid guide catheter and guide wire, not something that generates a large number of particles that can obscure the results from your device.  If the accessory devices generate too many particles you may consider other alternatives, like plain PTFE tubing if that is reasonable. 

Once your model is set up with associated fittings and any accessory devices you want to include in the baseline, inject 50 ml of water through, collect the effluent in the clean sample container and drain the model into the sample container.  Perform your test on the sample, I would repeat three times, average each bin, and use this as your pre-test baseline.  You’ll probably want a post-test baseline as well, or alternatively you could take a pre-test baseline prior to every test.  Your model should really have very few particles and hardly ever one 50+ um.

Some people want to collect all their samples, and then test them all, but I feel pretty strongly that you should test your samples as you obtain them.  Letting them settle in the sample container isn’t going to do you any favors down the road, you’ll probably get low particle counts now, but when you need to do some comparison testing or need to make a change it will be more difficult to reproduce. 

To validate your test and model, take the 70 um particle standard bottle and make a “standard solution”, to make the standard solution:

         1.   Shake the 25 ml bottle of 70 um standard solution vigorously for 10+ seconds
         2.   Pour entire 25 ml of 70 um standard solution into a 400 ml beaker
         3.   Pour 200 ml of LPW into beaker
         4.   Pour 25 ml of LPW into the empty standard solution bottle, rinse and then pour into the beaker
         5.   Put clean stir bar into 400 ml beaker and stir at a moderate speed, do not stop stirring
         6.   Cover with parafilm when not in use

Now you’ll want to test 50 ml of your 70 um standard solution using the procedure above and see what you get at the readout from the 50 um size (the 70 um particulate standard is 100% above 50 um), you should be ballpark of the bottle count at the 50 um size (after you take into consideration the dilution we did) and all of your runs 2-4 should be consistent, use the average of the runs.  You should be about half of the bottle count at the 70 size, but that is less accurate and I wouldn’t sweat it too much.  If you see your last run spike then you’re probably too close to the stir bar and you may want to consider increasing your sample size or raising the HIAC sample intake if possible, if you do this, repeat the test. 

Once you’re happy with those results you can inject 50 ml of the standard solution into your model, collect the effluent and see how you do.  Average the runs from your test (discarding which runs you said you would).  Subtract your baseline result average before you calculate the amount recovered.  You want to recover more than 75% of what you put in per the FDA guideline.  The 70 um particle size is the most challenging, which is why we started here, so don’t worry too much if you don’t get it the first time.  If you’re not recovering at least 75% of your starting particles- your particles most likely have settled in your standard solution.  Turn up your mixing on the standard solution and start over.  You’ll want to proceduralize the mixing.  If you recover more than 110% you probably want to look at your environment and wear a hair net or breathe more through your nose or something.

Repeat with the rest of the particle standards, you want more than 90% recovery with at least the 15 and 30 um sizes and you have finished the particle testing test method validation.

See Part 3: Particulate Testing of Medical Devices.