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.

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.

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.

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.

Tech Talk – Medical Device Particles

Another area where the FDA has spent some of their focus is on particulates generated by medical devices.  A particulate is defined by USP 788 as “Particulate matter consists of mobile, randomly-sourced, extraneous substances, other than gas bubbles, that cannot be quantitated by chemical analysis due to the small amount of material that it represents and to its heterogeneous composition.”

The FDA guidance (PTCAballoons and stents) points out that particulate matter can be generated by the manufacturing process or from the breakdown of any coating (e.g., hydrophilic coating) on the device or from the device packaging. If particles are introduced in the bloodstream during use, they may present an embolic risk to the patient. Measurement of the total quantity and size of particulates a device may generate is an indication of embolic risk.

It used to be that medical devices didn’t have hydrophilic coatings and particulate really wasn’t an issue.  Then hydrophilic coatings came along and for a while USP 788 specification was adopted for use with medical devices.  If a small volume injection could have 6,000 or less particles 10 um (micrometers) or larger and 600 particles 25 um or larger, it seemed reasonable that if a medical device generated less than that it was okay.  A general note, particle counts are binned as 10+ um, 25+ um, etc.  The count for the 25+ um bin is included in the 10+ um bin, so the particle count will always decrease as the bin size increases, binning other ways may confuse people.

This worked for a while until people thought about it more and some of the coatings turned out to generate large numbers of particles.  The USP 788 specification has a significant issue, there is no discussion of upper limit of particle sizes, i.e. you could have a bunch of particles half an inch in diameter and still meet the adopted USP 788 specification.  The specification may work for injectables because you will not get half inch particles in a liquid and certainly can’t inject them anyway, but with a medical device you just might be able to.   Since that question has come up, AAMI TIR42:2010 was released with a section on the clinical significance of particulate matter which basically concludes that particulates less than 100 um are not a major concern.  There is less evidence showing any particles larger than 100 um are safe (although they may be).  This just further highlights the inadequacy of using USP 788 as a particulate specification for medical devices.

So while you may still use an adoption of USP 788 as your specification, you do so at your own risk and you’ll probably need some further explanation for the FDA.  What specification you do choose is tricky though, as you probably do not want to set a specification of zero particles 100 um or larger.  First, is this clinically significant?  Second, in my experience every now and then you will get a particle that large, it may not even be from your device, but it will show up in your environment results.  If you have a history of using USP 788 for other devices on the market, you can probably use that if you’re comfortable with it, along with a clinical evaluation of your results on the larger particles.  However, the FDA has left the door open here for you to accept larger numbers of particles than USP 788, which for some coatings may be required, the AAMI TIR42 standard references plenty of literature saying large numbers of small particles are unlikely to do harm.  Alternatively, you could compare your results to results from a similar device on the market, but this method is riskier, expensive, and is going to be less repeatable.

Part 2 of this series discusses the test method and how to validate it.  Also see Part 3, Medical Device Particle Testing.

3D Printing Medical Devices

3D printing is often touted as a big advance that will quickly change our lives.  Medical Design looked at the technology and I thought I’d look at how 3D printing can now affect medical device development and manufacture.

According to Wikipedia, 3D printing is a process of making three dimensional solid objects from a digital model. 3D printing is achieved using additive processes, where an object is created by laying down successive layers of material. 3D printing is different from typical machining which remove material by methods such as cutting and drilling.

I’ll look at three categories, prototyping, manufacture, and other uses.

Prototyping

3D printing looks promising for prototyping with additional materials and maybe a price advantage over SLA.  A cheap injection mold is $10k for one part, 3D printing can make that for part $5.  A 3D printer is certainly a good tool to get physicians and executive types interested.  However, the use of prototypes are limited in the medical device field due to material limitations.

Medical Device Manufacture

At this point, medical device manufacture or even component manufacture with 3D printers seems unlikely until a great deal more development is done for the following reasons:

Multiple materials

 3D printers have difficulties with multiple materials.  You can construct scaffolding and use the 3D printing around it to create a device.  Single material medical devices are usually high volume, molded, packaged, sterilized and sold, (i.e. fittings, tubing, etc.) this doesn’t play to the strengths of 3D printers.

Biocompatibility / Sterilization

Additionally, I’m going to assume that the materials need to be biocompatible and sterilizable.  A look at Shapeways’ material portfolio at this time doesn’t show a lot of promise for medical device applications.

The materials are Alumide, an acrylic plastic, stainless steel, sterling silver, full color sandstone, and ceramics.  Only the ceramics material is listed as food safe.  Starting with a material that is not food safe is a stretch, but let look at some of the materials in more detail.

The stainless steel is alloyed with brass and uses small drops of glue to hold the material together and the material itself is specifically listed as not food safe (the glue is not described).  Alumide is described as nylon plastic filled with aluminum dust, the material is described as not watertight and not food safe.  The silver is a two step mold, so it may be pure silver, silver isn’t really used a lot in medical devices, but there may be some applications.  The ceramics material is food safe and watertight; ceramics are used in some implant devices, but the page says sharp edges are likely to crack, so that limits the applications.  You don’t want any material in your body that is named “sandstone”, so I’ll move on.  3DSystems does offer VisiJet Crystal, another UV curable acrylic plastic, which is USP Class VI certified, so that is probably the most promising material.

Resolution

Looking at the aforementioned Shapeways material portfolio using their strong and flexible plastics, the minimum unsupported wall is 0.7mm, with +/- 0.15mm accuracy this type of resolution removes just about every vascular application you can think of.  That leaves large implants and custom surgical tools as the most promising areas at this point. 

Shapeways seems to be more consumer oriented, so lets look at another company.  3DSystems does claim a resolution of 0.075mm with 0.050mm layers.  However, this needs to be combined with the material to give us its real capabilities.  To be fair, I’ve only looked at the capabilities from a couple companies.

Current Activity

Wikipedia describes how 3D printing can produce a personalized hip replacement in one pass at available printing resolutions the unit does not require polishing, but gives no source.

EOS and IMDS have teamed up to explore custom implants.  Stryker is building knee implants.  Others are apparently making WREX arms.

There is a lot of talk about how 3D printing could improve current devices, and hip implants are frequently cited as a promising area, but few specifics or even record of people working on the technology.

Other

Replacement parts are sometimes mentioned as a use for 3D printed parts, but again, this seems unlikely for the same reasons you can’t currently make components.  You could make the same argument for 3^rd world countries or as a way around regulations (i.e. a physician making herself a device), but you run into the same problem.  So what other applications related to medical devices are there?

UCSD is using 3D printers to print blood vessels.  This seems interesting, in-vitro test models are often expensive and sometimes you want to destroy them during testing, but you can’t.  You could presumably expand this idea to all kinds of models and validate your device on many more anatomy types than previously.

Conclusion

Right now 3D printing is too new to find many applications in medical devices.  Aside from prototyping, the uses of 3D printing in the medical device field are limited, most medical device companies already prototype using SLA, so this will not be a big improvement.  The medical device industry is often 10 years behind the consumer industry, unless the idea is an excellent fit or custom developed for medical devices, since there are very few consumer applications for 3D printing at this time it is probably better to wait until the 3D printing industry is more mature.

How to get startup ideas

Great essay by Paul Graham at Y Combinator, the right way:

The way to get startup ideas is not to try to think of startup ideas. It's to look for problems, preferably problems you have yourself.

The wrong way:

Imagine one of the characters on a TV show was starting a startup. The writers would have to invent something for it to do. But coming up with good startup ideas is hard. It's not something you can do for the asking. So (unless they got amazingly lucky) the writers would come up with an idea that sounded plausible, but was actually bad. 

For example, a social network for pet owners. It doesn't sound obviously mistaken. Millions of people have pets. Often they care a lot about their pets and spend a lot of money on them. Surely many of these people would like a site where they could talk to other pet owners. Not all of them perhaps, but if just 2 or 3 percent were regular visitors, you could have millions of users. You could serve them targeted offers, and maybe charge for premium features. 

The danger of an idea like this is that when you run it by your friends with pets, they don't say "I would never use this." They say "Yeah, maybe I could see using something like that."

I think just about every product I've worked on at a non-startup has been the "wrong" way, where marketing / engineers come up with an idea and sell it to physicians, launch it, and hope it does well.  In some cases, we may have worked the other way, but this was generally due to bad device design from the start and they wanted something fixed.  The team rarely challenges where the project came from, because they generally come from executive management and it is a difficult position.  Large companies aren't usually looking for breakthrough products (every one of them will say otherwise), they are looking for a solid return on investment.

Start Up Blog

Blake Masters has an outstanding series of posts covering Peter Thiel's CS183, a class on start ups.  Class one is here, the index is here,  Class 7 or 8 are where it really gets into it with how to approach venture capitalists.  If you are interested in starting a start up, joining a start up, shutting a competitive start up down, or just like to read about business, you'll enjoy them.

Tech Talk – Medical Device Colorants

In the last few years the US FDA has been asking more questions about color additives (colorants) in medical devices.  A colorant is what makes your medical devices a pretty color, and may be composed of several pigments.  This is not so much a secret to endovascular companies at this point, but if you have any colorant in your device you will get questions from the FDA unless you address them beforehand.  It is important to note, device biocompatibility testing will not save you, you will not be able to hide behind it, and you will have to do more.  Unless you want a delay in your submission processing, I suggest you include them with your initial submission.  Not so much EU or Japan, but you may still get a question now and then. The FDA has issued guidance, but it is not really specific.

What are the questions from the FDA?

1. What are the colorants?  Identify by chemical name and CAS #.
2. What are the colorant weight percent (wt%) in each component and total colorant weight per device?
3. Submit colorant MSDS.  (Hopefully it matches the answers to item 1…)
4. Are the colorants are on 21CFR 73, 74, or 81?
5. Have the colorants been used in any US approved predicate devices?
6. If no to 4 or 5 they probably want to see a toxicological risk assessment.

Recently the FDA has stopped asking for color additive petition for the colorant used if not on the FDA lists, so you probably don’t have to worry about that.  (If you do get that comment you should probably push back because it can take years to get on that list.)

I would stick all this information in the biocompatibility protocol / report you submit them with the materials list and hopefully that would head off any comments and delays in your submission.  Alternatively you might create a separate report since other regulatory bodies don’t always ask and it may raise questions- don’t forget to submit the separate report to the FDA.

For items 1 through 4, you should be able to address those with a little help from your suppliers and a web search for your colorants on 21CFR73, 21CFR74, and 21CFR81.

You should create a table similar to this example:

Complete for all components and then list the total amount of each colorant in the device.  You may split up components by contact type (i.e. blood contacting or not).

If your colorants are listed on the approved colorant lists you don’t really need to worry so much about item 5, but I would complete it for thoroughness.  If not… hopefully your company has used the colorant before, or you’re in for a bunch of meetings trying to figure it out.  Maybe if you had someone else design the device they have used the colorant in other devices and well tell you, but otherwise it is probably impossible to figure this out.  At this point, you want to find anything that has used the colorant, even if it is not the same use as your device.

If you have to go the toxicological risk assessment route (follow ISO 10993-17, Biological evaluation of medical devices – Part 17:Establishment of allowable limits for leachable substances), MDDI has an article on the details.  Also ISO 10993-7 has an example of a toxicological risk assessment for ethylene glycol (EG) (take that Japan!).

I would just pay someone to do it, depending on your approach; you will be out about $20,000+ (with about half testing and the other half the risk assessment) and a couple months.  The analysis usually involves using exaggerated extraction of your device in multiple solvents (saline, ethanol, hexane, etc.), using various chemistry techniques (GC-MS, HPLC, etc.)  to analyze the extract, and then performing a risk analysis on the chemicals found.  If that doesn't work out well, then repeat with leachables and write justifications.  For example, justify why hexane extracts aren't relevant to the clinical use of your device.

NAMSA has a seminar this type of toxicological risk assessment, but your company probably lacks the tools to perform the risk assessment as you may need access to various toxicology databases.  If your company does not have the expertise, most likely they will assign one person to do it, that one person will do it, then have to convince 3 or 4 other departments (regulatory, quality, clinical, etc.) that they did it right and teach them the method.  Whereas if you hire the so called expert, most people accept the results, slap a cover page on it, and ship (unless they disagree with the results…).  NAMSA, Toxikon, WuXi AppTec, and some chemistry labs will all do this for you.

For future medical device designs, I would stick to natural color or colors on 21CFR 73, 74, or 81, which really covers all of your standard colors.  Certainly don’t take whatever your extruder has on hand.  Although another blue catheter is not exciting, you’ll get to market quicker.  These are medical devices, not electronic gadgets for 14 year old girls- your customers won't care.

How to efficiently follow your competition

Working in medical device R&D its important to keep an eye on your competitors.  Marketing is too busy working on presentation font size to be reliable on this.  The easiest way to do so is using Google Reader, you'll need a Google account to make it work.  From there just add Medgadget, your competitor's press release site (if any), and MassDevice to Google Reader.  If  your competitor launches a new device or has an idea it may be covered in Medgadget, more general news in MassDevice.  However, if your competitor has a poor marketing department or is small, some news may slip through the cracks.

To take your stalking to the next level, follow the company on LinkedIn, although this hasn't been that useful for me yet.  Then set up a search using your competitor's name in Google Blog Search.  Google blog search will pick up every little tidbit, but blogs are generally spammy, so you'll ignore a lot of things on there.  You can do the same thing with Google News and Google Patents.  From the FDA website, you can also follow recalls, reported complaints, 510k and PMA approvals, however, you'll probably have to do this manually or just read their monthly digests, the website isn't set up well for this.  For example, PMAs are set up one month per page, and every year has its own page, good luck getting that to work, they do have a feed for recalls though.  Short of actually talking to anyone, that is about as thorough as you can get.  You will obviously have a hard time following a start-up this way as there is usually no news.

While you're setting all of this up, you probably want to set it up for your company as well.  You can use other keywords like the type of device you're interested in instead of the competitor's name.  This blog can also be followed on Google Reader.  You don't have to use Google Reader for this, you can actually set up RSS feeds in outlook and it will email you items into a certain folder, but Google Reader you can log on anywhere with a web connection so I like it better.