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.

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.

St. Jude's impressive product development time

St. Jude has recently announced approval for its optical coherence tomography / fractional flow reserve (OCT / FFR) system called ILUMIEN (fyi: they have a cheese video of water with words flashing across on their site, the Light Years Ahead tagline is good though).  The press release for FDA approval was on October 26, 2011.  The press release for EU approval was on July 14, 2011.  I'm sure the two extra months the FDA took was value added questions about colorant or something (assuming they did both submissions at the same time).

Anyway, I thought it would be fun to look at St. Jude's performance on this new medical device product development timeline from start to approval.  In this case we have a unique opportunity because we know when St. Jude bought Radi (the FFR part), and when they bought LightLab (the OCT part).  These dates are all approximate, since St. Jude could have waited a few days or weeks to make announcements, but ballpark is good enough for this blog.  St. Jude bought Radi Medical AB for $250 million on December 21, 2008.  St. Jude bought LightLab for $90 million on July 7, 2010.  The EU review was probably 45 business days or about two months, giving a 10 month product development time line.

I will assume they couldn't really get started until July 2010, if so, I think it is impressive to combine these two systems, even if they added no features beside switching, and get approvals in basically a year.  Sure they could have done some work on the cart, and presumably they have some hardware picked out before 2010, but most of the hardware and software will have to wait until you know the specifics- which a company won't give out until it is bought.

Maybe you can make your software modular and they can add in applications quickly as it grows, but it initially came from Radi, and smallish companies don't usually think that far ahead.  Maybe they started on this in 2008.  But more realistically, the software group was given two programs that had no intention of interacting and they managed to make it work in 6 months and 2 months of test.  Oh yeah, the two teams are probably at different sites, so you have that difficulty to constantly work through as well.

There is another wrench to throw into the works, IEC 60601-1:2005 (3rd edition), which is scheduled for EU implementation on June 1, 2012, you'd be crazy not to build a new system to 60601 3rd edition and have to redo it in a year or so for the EU.  So I'm guessing that there was also an update of at least LightLab's system and probably Radi's system to 60601-1 3rd edition included in this device as well.  Now maybe these companies had already made the transition, but small companies I know are behind on this requirement.  Yes, some of the changes are minor, but they still involve significant amounts of work.  Additionally, the 60601 testing itself takes a reasonable amount of time that would have to be worked in.

Now this is assuming the quality of the product is adequate, they could have rushed out junk (although I have no reason to think this based on the water video), I am impressed that they were able to complete this new product and get it approved in such a short period of time, congratulations to them.  Could your company pull this off?

Tech Talk – Stroke Treatment with Medical Devices

I thought I’d move into a newer area for medical devices, stroke treatment.  Stroke affects more than 700,000 people a year in the US alone, of these, over 150,000 die.  Most of the strokes are ischemic in nature.  Unfortunately the treatment options are very limited and time to treatment is absolutely critical to a good outcome.  Successful recanalization of the occluded cerebral vessel during the acute ischemic event is associated with lower three month mortality and improved functional outcome.  [Source]

Intravenous Tissue Plasminogen Activator (tPA) is the FDA approved drug for acute ischemic stroke for up to three hours after the stroke.  This drug can dissolve the clot and is sometimes applied right at the clot through a catheter.  This is generally the first form of treatment; however, tPA is not effective in all cases and can cause bleeding in the brain, particularly in older patients. 

Mechanical removal of the clot using a medical device is being performed more and more alone or in conjunction with tPA.  These devices have some advanatges over tPA, including more rapid achievement, ability to treat large vessels, and lower risk of hemorrhagic events.  Only two neurothrombectomy devices are currently cleared for use in the US.  You don’t have to be a rocket science to figure this one out- 700,000 people affected and two cleared devices, stroke treatment is a screaming opportunity for medical devices.

The FDA defines these devices as neurothrombectomy devices, these are devices intended to retrieve or destroy blood clots in the cerebral neurovasculature by mechanical, laser, ultrasound technologies, or combination of technologies.  The FDA has provided guidance on these devices, one note of interest is that a clinical trial must be performed due to the high risk of the device.

There are some general procedural steps common to both devices that I will cover quickly now.  Both devices must have access to the clot itself.  This means advancing a guide wire and catheter using angiography to the clot first. Don’t tell cardiologists, but this is more difficult in the head than in the heart- there are many more possible pathways and the vessels are generally smaller and more easily damaged.  If the patient has been given tPA any damage can be catastrophic.  Angiography is also used to measure the vessel diameter so the appropriate sized device can be chosen.

Another procedure common to both devices in certain situations is the use of a balloon guide catheter with aspiration.  The balloon guide catheter is inflated, which blocks blood flow in the blood vessel with the clot.  Aspiration is then applied, this means taking a large syringe (typically 60 ml) and pulling it back, sucking whatever you can out of the blood vessel, alternatively you can buy a pump to do this.  Minimizing balloon inflation time is important because the lack of blood flow is what causes a stroke, you don’t want to compound the problem.

The two approved devices are shown below:

                                            Merci Retreiver (left) and Penumbra System (right) Image source.

The first FDA approved neurothrombectomy device was the Merci Retriever by Concentric Medical.  The device was approved through the FDA 510(k) process in 2004, the current indication for use is:

Merci Retrievers are intended to restore blood flow in the neurovasculature by removing thrombus in patients experiencing ischemic stroke. Patients who are ineligible for intravenous tissue plasminogen activator (IV t-PA) or who fail IV t-PA therapy are candidates for treatment. Merci Retrievers are also indicated for use in the retrieval of foreign bodies misplaced during interventional radiological procedures in the neuro, peripheral and coronary vasculature.

The Merci Retriever system includes a flexible nitinol wire coil formed into what looks like a corkscrew.  The latest version of the device has filaments (made of suture material – I would guess nylon) that provide an additional mechanism for securing the clot during removal.

Basically, the device is advanced distal to the clot, deployed, turned, and when pulled back through the clot it captures the clot in the corkscrew and the device is then removed from the artery while under balloon aspiration.  The balloon aspiration (pulling a vacuum on the vessel while a balloon blocks it) minimizes pieces breaking off from the clot and causing additional issues.  [source]  You can watch a demonstration of the device here. 

Concentric Medical was recently bought by Stryker for $135million, which goes along with Stryker's previous purchase of Boston Scientific’s neurovascular division.  I don’t know what Concentric’s revenue was, but I think this sounds like a good acquisition, with the caveat that the Concentric team must remain focused on Stroke treatment and not get caught up in all the other things Stryker does.

The second device in use is the Penumbra System of Continuous Aspiration Thrombectomy by Penumbra. The Penumbra System is used for the “revascularization of patients with acute ischemic stroke secondary to intracranial large vessel occlusive disease…within 8 hours of symptom onset”.  The device is first advanced to the blood clot, the Penumbra Catheter’s tip is then placed at the proximal end of the clot.  The Penumbra “separator” is advanced to the clot, aspiration is started, then the separator is used to help to break up the clot (or “debulking”) and make it easier to suck into the guide catheter.  The separator has a straight tip and a cone (purple cone shown in the picture).  In theory, there should be less damage to the vessel with this system, this is important if the patient has received tPA and that has not worked. 

As reported in a State of the Evidence article, the clinical effectiveness of the devices, defined as the having a good outcome (modified Rankin Scale score 0 to 2), rates ranged from 21 to 36% with the MERCI and 20 to 48% with the Penumbra System.  These numbers are not necessarily comparable to each other as the devices can be used for different types of clot.  Presumably the Merci retriever is typically used for “hard” clots and the Penumbra system is used for softer clots (This is just my guess).

Other types of devices sometimes used off-label in the US, such as snares, exist, but I would expect their use will decline as more devices get approval for stroke treatment.  Additionally, stent retrievers are available in the EU, but not yet approved for the US, I assume these devices will be approved in the next year or so and if you were so inclined you could roadmap out which ones are doing well in the EU and make an investment on that.  The EU is currently two or so years ahead in types of devices available for stroke treatment.  Other devices are certainly under development, with ideas from coronary or peripheral vascular being expanded for use.  Startups include Insera Therapeutics who is developing a snare type device.   I wasn’t able to identify any more in a few minutes of Google searching- if you know of any, leave a comment and I’ll add them later.

Update:  In 2012 two more stroke treatment devices were approved by the FDA, thee Solitaire FR by Covidien and the Trevo by Stryker.  Clinical trials for both of these devices showed that they were superior to the Merci Retriever.  

Tech Talk – Anatomy Models and Medical Device Testing

One important consideration to take into account while designing and testing medical devices is how they’re going to be used. In the case of vascular devices, they will be used in arteries and veins and I’ll describe some of the test considerations. While performing your verification testing, you want to ensure that you have a reasonable clinical model to perform testing under.

For example you might have a device that is intended to be used in the Right Coronary Artery (RCA) as shown below (image from Wikipedia):

How do you ensure your device works correctly without using it on a person? You find an appropriate model.

Models of various anatomies are available from Elastrat and Shelley Medical Imaging Technologies. ASTM F2394 also contains a schematic of a two dimensional (2D) model recommended by the FDA for some applications. Although it is best to ensure you pick a model based on the vessel characteristics that your device will likely see (such as vessel diameter and tortuosity). Using the ASTM or another off the shelf model can get you into trouble if for example you’re testing a guide catheter and pushing it into the smallest vessels when it is only intended to sit in the aortic arch.

A 2D model is easy to construct and use, but not necessarily the most accurate, it generally consists of just two pieces of machined plastic (bottom with a clear top) with a piece of tubing inserted. The easiest model consists of just a radius as shown below (by the way, I did the diagram myself in MS PowerPoint!).

Ask your clinical source what the tightest radius your device is likely to see in-vivo and simply machine a curve of that diameter. Insert a piece of silicone tubing into that radius to simulate a vessel wall more accurately than hard plastic and you’re ready to get started (you can use pig vessels to line your tortuous pathway, but this is no fun to set up). It is easy to create 2D models of various tortuous pathways. Creganna (Medical Device Technology, May 2006) shows an example tortuous pathway in some of their coronary block model simulated use testing:

You can see the simulated aortic arch as the large looping arch (start from the top most pathway) and then into tighter arteries as the model continues.

A 2D model obviously lacks some realism as it is possible that your device will need to turn multiple planes during use. Although it may be argued that the worst case scenario is actually the 2D model as it stresses only those two dimensions, adding the third dimensions allows additional flexibility in most devices as they are generally concentric. In the case of a non-concentric model, you can perform your testing to the worst case in the 2D model, setting your weakest side up to take the most abuse. The 2D model is also arguably tougher on your device than clinical use as the give is limited to the wall thickness of the tubing you insert.

For 3D models, you’re probably better off buying one from the companies listed above, although they can get expensive, and can be damaged so you need to be careful. An example heart model from Elastrat is shown below.

Once you have your anatomy model, you generally want to further simulate clinical conditions, either by flowing 37C saline through the model, or a mixture of glycerin and water to simulate blood flow.

Now you want to run whatever tests you can using the model. For example, a guide wire or catheter turns to failure test is simple enough, just hold the distal end and turn the proximal end until the device breaks. However, to really simulate use, you should put the device through the model, and while the device is still in the model, hold the distal end then turn the device until it breaks. The addition of the model adds a bit of complexity to the test, but is a better test system.

I have seen the FDA question models, so document your clinical justification why the model you use is appropriate in the protocol. If you’re using a model that you bought, you should ask them to provide you with the justification.

Tech Talk – Catheter Bonding

Tech Talk – Medical Device Catheter Bonding

For my second tech talk I thought I’d briefly cover catheter bonding. The typical vascular catheter is made of several types of polymer; it is of obvious importance to connect them in a precise way. A typical bond will consist of two types of tubing; a popular choice is Arkema’s Pebax. Pebax is a USP class VI material that stands up well to sterilization and takes colorants well; it is widely used in current catheters. Bonding will consist of something like 72 durometer on the proximal end of a catheter to 63 durometer on the next step, then moving down the catheter until you reach 35 durometer at the tip. Ideally, the two pieces of tubing are the same size, but they can be of slightly different inner and outer diameters. Starting with your two pieces of Pebax tubing:

Since Pebax isn’t as smooth as most physicians desire, a PTFE or HDPE liner is usually used on the inside of the catheter. The liner allows for smooth delivery of other devices such as guide wires or other catheters down the catheter. A liner will not be required for something like an inflation lumen. Liners may also be multiple layers to better bond with the Pebax. A mandrel is placed inside the liner or lumen. The mandrel is usually coated with PTFE (by companies like Applied Plastics) or parylene for easy removal later on in the process.

Fluorinated ethylene propylene (FEP) tubing is then placed over the Tubing joint. FEP is available off the shelf in multiple diameters and wall thicknesses, it can also be custom made if required by companies such as Zues and Fluortek. Using FEP forms a more consistent and even joint.

Apply heat to the FEP tubing to shrink it and melt the Pebax. Pebax melts at around 174°C so usually 190°C is enough heat. To heat, Beahm Designs makes off the shelf heaters that apply a constant stream of air at a set temperature. Alternatively heat guns can be used, although long term you should look for a more controllable solution.

After heat is applied and the part is allowed to cool, cut off the FEP tubing with a razor blade (slice more parallel to the tubing, not straight into the middle of the FEP) and remove the mandrel and you have a very nice piece of tubing that is very difficult to tell where the transition is.

For a catheter you may actually have five or six transitions such as this depending on the stiffness you want and the number of lumens you want at each point. It is also possible, but not as desirable to join two types of tubing using adhesive, this may be required if the polymers are too different to heat bond. In this case, one piece of tubing fits into the other.

The adhesive used for medical devices is generally made by Dymax or Loctite and can be UV or heat/time cured. UV cure is superior for manufacturability as you can quickly pass it to the next operation, but it may not be possible to use UV adhesives in all cases.  The geometry of this catheter is more difficult and the liner may have to be tapered.

Advanced Polymers also sells a polyester heat shrink tubing that can be left on the device and used in catheter bonding if these two methods don’t quite work for you.

After bonding you will want to validate your design and process using methods such as tensile test to ISO 10555 and burst pressure to ensure it is high quality. Catheter bonding is something that has been fairly extensively developed and you can get lots of support from suppliers, but it always turns out you need to know one extra trick that you have to develop yourself.

References for this post are The Medical Device R&D Handbook by Theodore R. Kucklick, Beahm Designs, Arkema, and personal experience.

Tech Talk – Guide Wires

I sometimes enjoy The Oil Drum’s tech talks, so I thought I’d give one a try.

Guide wires, or guidewires, are used in the vasculature to act as a guide for other devices, an example video shows guide wire and stent.  Guide wires are generally more flexible and steerable than devices used to treat or diagnose patients.  Typically, once access to an artery is gained, the guide wire is inserted and steered under fluoroscopy to the location of interest.  Then one or more devices (usually catheters) are delivered over the guide wire to diagnose and treat the condition.

Guide wires usually come in diameters of 0.010” to 0.035” with 0.014” being the most common (0.013” is equivalent to one french or 1/3 of a mm – so the typical guide wire is slightly over 1 french in size).  Guide wire lengths vary up to 400 cm, depending on the anatomy you want to reach and the work flow.  The flexible distal tip portion is usually 3 cm long, the slightly less flexible portion is usually 30 to 50 cm long, the less flexible proximal portion makes up the balance.

The user requirements of a guide wire are can it quickly get to where it needs to go and then can I reliably deliver devices over it without patient safety issues.

A typical guide wire construction is shown below:

In this diagram, the blue proximal section is the hypotube, similar to a syringe needle (minus the sharp end).  The hypotube is generally coated in PTFE- but other coatings are also used.  The PTFE coating allows devices to more easily slide over the guide wire and is probably the major component in device “deliverability” on the guide wire side.  It is easier to slide a catheter over a guide wire with PTFE than it is to slide a catheter over a guide wire without PTFE.  The PTFE coating of the hypotube can be a tricky part of manufacturer and is usually outsourced.  Just as your pans vary in quality of the non stick surface, so do guide wires and different variations in processing and materials can affect how well your guide wire delivers devices.

The core wire material is usually nitinol or stainless steel and tapers from the proximal end to the tip.  At the tip it is generally flattened.  The core wire affects the torquability of the device; you want the tip of your guide wire to turn in a 1:1 ratio with the proximal end.  The torquability affects the steerability of the device, can it get to where you want to go.  Nitinol core wires are harder to kink, but can lose some torquability.  The core wire is attached to the proximal end of the hypotube using solder or adhesive.

Alternative guide wire construction can look like this:

In this design there is no hypotube, the core wire is the proximal portion of the device.  Coating is applied directly to the core wire and you have better torquability because you are turning the core wire directly, instead of turning the hypotube, which turns the core wire.

In both designs, the next section is a more flexible distal section, usually consisting of a wire coil.  The connection is made to the hypotube or core wire by solder or adhesive at this point.  The coils are more flexible than the hypotube and the distal portion of the device is suited to navigate to the desired portion of the anatomy.  There may be several types of coils attached together or one long coil where the coil spacing changes.  The more proximal section of the coil is generally made of stainless steel for cost savings.  The distal tip coil of the guide wire is made of radioopaque metal, generally a platinum alloy, but a palladium alloy may also be used.  Some hospitals recycle these religiously for the $4 in platinum they can get in the tips.

At the very distal tip, the wire coil is soldered to the core wire using tin - silver solder, although in some older wires the core wire may be attached using adhesive.

The tip itself is rounded into a ball shape, which the solder or adhesive naturally forms when applied to the tip.  This allows the guide wire to follow the curve of the vessel and is generally called an atraumatic tip.  From a manufacturing point of view, manufacturers are very careful to not allow any burrs in the tip assembly for fear of vessel damage, but I have not seen any direct reports of vessel damage caused by badly made tips.

The tip itself is always shaped by the user to aid in steerability, usually to around 45 degrees.  Usually the tip is shaped by using an introducer or needle.  Here is a video of a shaped tip, although this method isn’t encouraged.  Some manufacturers offer tips pre-shaped.  One notable alternative tip construction is shown below:

In this case an extra wire has been attached to the core wire and the tip to allow better tip shapeability and can give a softer tip.  Depending on where you want to go in the vasculature different tip softness is desired, for example in the cerebral vasculature usually the softer the better.  Tip softness can be measured as tip load, the amount of force (or load) it requires to bend the tip a certain amount.  Obviously you want the tip to flex instead of damage the vessel wall.

The distal portion of the wire is coated with a lubricious coating, generally a hydrophilic coating, older wires used hydrophobic coatings, but they are becoming rarer.  The hydrophilic coating is a proprietary coating that manufacturers generally outsource and pay a considerable amount of money for.  There is some skill in developing a coating that does not come off of the guide wire, and retains its lubricity over time.

When building a guide wire you want to start at one end and work your way down, starting at the tip and working to the proximal end.  Making guide wires is not that labor intensive with the most skill you need is to be decent at solder and soldering cleaning.  You need to work at keeping them undamaged in manufacturing due to their small size and the less flexing of the wire you do the better.

There are other variations on guide wires, such as plastic coatings and different combinations of coils and hypotubes, but I’ve covered the major ones.  Guide wires are basically a commodity at this point and only the regulatory barriers to entry and the fact that physicians aren’t typically price sensitive are keeping it as a reasonably attractive market to pursue.

When performing performance verification testing on a guide wire, some common tests are turns to failure (you clamp the distal tip and turn the device until it breaks), particulate / adhesion tests (of the coating), tip tensile strength, torquability (which you turn the proximal end of the guide wire a set amount and measure how much the distal end turns), tip load, radioopacity, and deliverability (where you measure the force it takes to move a catheter along the guide wire).  DDL has uploaded this video on testing a guide wire to ISO 11070, but I’ve never used that particular test.

For validation testing you generally request feedback on navigating a guide wire to the desired location in a bench or animal model and delivering a device over the guide wire.

I was unable to find the size of the guide wire market, but every endovasculature procedure uses at least one guide wire, many times more.  Many companies outsource the manufacture of guide wire to a contract manufacturer; it is difficult to enter the market fresh at this point.  However, as a company, you want to sell a guide wire so you can get your 40% margin on an outsourced guide wire instead of the competitor getting 60%.  Also, it is generally beneficial to sell a whole suite of devices when selling to a hospital, if you sell only catheters you will have a harder time getting shelf space unless you can bundle it with other products.

More information is available at:  PCI equipment: Guidewire selection.  And the FDA chimes in with helpful guide wire tips on device safety-  always read those IFUs.

New product turn over

MedCity News has an article on J&J exiting the coronary drug eluding stent business:  End of J&J stent business carries lessons for medical device innovators.  It is very surprising to me that they are just leaving the market, surely with $400 million revenue this year they could make something happen.  I know they were getting their clock cleaned, but what kind of signal does this send to their R&D organization as a whole?  We're not afraid to throw in the towel?  Obviously J&J has a lot of smart people and I've never run a Fortune 500 company.

The take away message from the article is you need to keep innovating...  I have no idea why you wouldn't, you need to turn over your devices regularly to stay competitive, plus each time you do it you can raise prices and increase margin.  Plus you're paying those engineers anyway (hopefully)- don't let them get distracted on non value added side projects.  How often you turn over your devices with new models depends on the devices, guide wires and catheters, every 1-2 years you should have a new model or at least a respectable line extension.  Other devices can take longer depending on their complexity and regulatory approval time, obviously for drug eluding stents you need a more significant investment. 

That being said, don't do it just for the sake of having something new, if the device isn't actually improved a reasonable amount they customer will notice.  I was part of one launch with really good immediate sales, then a huge fall off because the customer realized this new product didn't meet any need the old one didn't, in fact it was worse (from their point of view, from the company point of view it was cheaper.)  After the initial buys, the customers didn't reorder, they saw right through it despite the best efforts of marketing.  If you're investing in a medical device company this is one thing you want to look for, are they launching new products at a reasonable rate, or are they just sitting back and letting things happen?

Anyway, congratulations to Abbot, Boston Scientific, and Medtronic enjoy your extra sales. 

How to help

From a recent FDA press release:

The FDA is helping advance the development of an artificial pancreas system...

I think they should be more clear.  What they are really doing is releasing a new guidance document which "will help provide clarity for manufacturers, investigators and reviewers in the development of the artificial pancreas system. It proposes safety and effectiveness goals that the FDA may require researchers and industry to meet when developing a type of artificial pancreas system".  Some other things are listed (like a workshop...), but they aren't actually advancing the science.

It is quite a stretch to say this actually helps to advance the development of anything, it just sets expectations, which is great, but lets call it like it is.  To advance the development, you need to be working on the device itself, not what you may require as the regulatory pathway. This is probably oversimplifying, but if we were to say all cars must get 50 mpg meeting a defined criteria, I don't anyone would claim that we were helping to advance the development of high mileage cars.  (I have some FDA praise slated for a future post, so don't feel bad for them)

Not that this is limited to government.  This is a fairly common response when a project team runs into an issue.  The project manager calls a meeting to help resolve the issue and the theory is we all pitch in and solve it.  In reality there is one guy doing 90% of the work on this problem and it takes too long to really bring another person up to speed on all the required details and anyway they have their own stuff to do.  The meeting (or workshop...) just serves to piss the person doing all the work off by either suggesting common sense things he's already done or doing, giving him unnecessary work, or suggesting unnecessary work that he has to fend off.  If he is your subject matter expert, trust him, who else is going to solve the problem, the Sr. Director?

If you're the project manager- one on one the guy doing the work, figure out what he wants.  Also know his weaknesses and compensate.  If he's great at solving the problem, but can't write a report or presentation that passes management muster, then get your ace report writer primed and ready to take over. If he doesn't have the attention span to stand around in the lab for 14 hours straight and supervise testing, make sure the lab guys know what is expected and fill in to keep them running.

I've seen projects delayed for months because everyone was too busy solving the problem with meetings (Why don't we look at this... How about a build that does this.... Did you write that PO yet...) to get hands on time to actually solve the problem.  If you're not working on the device, on the manufacturing floor, in the test lab, you're not advancing the development of the device.

Update 1: If you'd like to read more on the FDA and company responses on the artificial pancreas, try here or here.

510(k) Approval Timeline Part 2

My original 510(k) approval timeline is my post popular post ever!  I didn't even follow up with my latest project information.  We extended the disposable product line and it was 30 day FDA review, no questions asked / response required, approval in April to May 2010.  We justified not doing sterilization, biocompatibilty, shelf life, and packaging.  All in all it was about as good as it can get time wise.  Timeline went something like this:

• August to December 2009: Concept and prototype to design
• Jan to March 2010: Product build and verification / validation testing
• April to May 2010: 510(k) Approval

Our validation was an animal study using a physician, who filled out a questionnaire like one to ten, how much is this better than the predicate device after he or she used it, oh boy did I learn something there, I'll go over that some other time.

Now we just have to sell them...

The Attribute Gage R&R

There is not that much information about the attribute gage (gauge) R&R readily available online (that I was able to find), so I thought I'd cover what I've done.  First the basics, an attribute is something you can't quantify, generally a visual inspection- is this part "red" or something like that.  While it generally seems simple, especially to the technical leads, operators can often get tripped up trying to pass or fail parts based on a description or a couple pictures.  In the red example, can operators compare against the Pantone effectively and is this repeatable?  You want to have your acceptance criteria and how you are proposing to test it with trained operators set up beforehand.

Your gage R&R should mimic what you do on the line and should be set up that way.  If the operator does an inspection on the attribute before passing the part, then a final QC does that same inspection, you have two inspections and this should be part of your testing.  You should present this as the entire package when possible.  QA types tend to freak out when they hear you would accept a 10% possibility of passing a bad part, when in reality its 0.1%.  Having the two (or more) inspections will be really helpful when you get to the acceptance criteria portion.

Test Method: You need to determine the number of operators, parts and trials.  Trials is easy, just use three, everyone does, obviously more is better, but three is generally good enough and you don't want to be looking at parts all day.  For operators, you need two, but if you have three or more lines or shifts, you can include those easily enough.  The number of parts is where it gets tricky and you're going to have to make a judgment call.  Generally medical device companies rely on some sort of confidence and reliability based on the severity or RPN of the potential failure, however, in the case of gage R&R everyone seems to follow auto industry guidelines which are usually a smaller quantity, 30 is generally defensible either way.

The Acceptance Criteria:  The key one medical device companies are concerned with is the probability of a miss, which is defined as:

• Probability of a Miss = (# times a bad part was passed) / (# of opportunities) [i.e. number of inspections]

You need to base this on what is acceptable and preferably tie this back into your risk analysis (you may have to increase sample size).  The good news is, if you're doing two of the same inspection, you can set it up so that your acceptance criteria can be something like:

• Probability of a Miss (2 inspections) = (# of times a miss by one operator that were missed by another operator) / (# of opportunities)

In that way you can argue that different types of misses will be caught by different operators, but you are only concerned with the fact that it is caught at some point in the process.  Setting it up this way significantly lowers the likelihood of a miss and allows you some flexibility.

Other Information:  I recommend keeping it simple and only requiring a certain probability of a miss in your protocol (maybe effectiveness as well).  You'll want the rest of the information you can collect documented, but that is a business decision, not a safety decision.  You can cover:

1. Effectiveness - (# of parts correctly identified) / (# of opportunities) [a low effectiveness indicates your process is probably not robust and will give you trouble over time, greater than 70% is generally acceptable]
2. Probability of a false alarm = (# times a good part was rejected) / (# of opportunities) [waste]
3. Repeatability = (# agreements) / (# parts inspected) [calculate per operator and total, if an operator has low repeatability, less than 80% or so, he or she needs retrained]
4. Reproducibility = (# agreements among all operators) / (# parts inspected)
5. Bias = (Probability of a false alarm) / (Probability of a miss) [calculate per operator and total]

The Test Setup:  For this you'll need two experts in the attribute being inspected, the experts will sort out the good parts from the bad, label them in some fashion, and randomize them.  In my experience you should have at least 25% bad parts, even though your process isn't likely to have 25% reject rate (hopefully).  It is nice to include some very marginal parts, but those can be hard to find and agree on.  Don't have the operators performing the test make the parts if you can avoid it.

The Test:  You want to set it up so an operator makes a determination and someone else records it, don't let the operators know the sample being given to them, previous results, or talk amongst themselves.  Do the testing on the line and try to keep the production pace.  During a gage R&R I find the operators tend to err on the cautious side.

The Results:  There you go, you can now say your test method is qualified and have the data to back it up.  You can also make operator decisions based on the results, maybe move one around to catch things earlier in the process, which one is the go to person, etc.  I find the attribute gage R&R easier to perform than the variable one, yet it is generally more important than a dimensional one from a safety perspective because there are more things I can't measure easily.

510(k) Infographic

I tried my hand at making an infographic full of 510(k) information.  Well I really only collected the facts and let a graphic designer do the rest, he fixed up some stuff from yesterday so I'm happy.  Click to enlarge!

Non conforming materials

Dealing with non conforming materials has become a more time consuming part of my job recently and a topic of debate within the company. The FDA has 21 CFR 820.90 on non conforming product which says:

"(a)Control of nonconforming product. Each manufacturer shall establish and maintain procedures to control product that does not conform to specified requirements. The procedures shall address the identification, documentation, evaluation, segregation, and disposition of nonconforming product. The evaluation of nonconformance shall include a determination of the need for an investigation and notification of the persons or organizations responsible for the nonconformance. The evaluation and any investigation shall be documented."

The FDA's definition of product in this case includes components and material. This has been interpreted by many as every nonconformance requires a full on investigation into the root cause and a corrective action, pictures, documentation changes and the whole deal. In fact, some have argued that each non conformance needs a CAPA that must be closed before the material can move on to the next stage. That is all fine and good unless you want to make money, lets be realistic here.

Besides, as a startup most of the corrective actions don't necessarily get too far. Lets say I get one custom cable out of 20 with a bad crimp that gives an intermittant signal. The signal is checked as it leaves the vendor, but since it was intermittant it wasn't caught. The conversation goes something like this:

Me: One of your cables had a bad crimp and the signal was intermittant.
Vendor: We're sorry, we check them 100% before they are sent out, return the cable and we will credit your account the $28 the cable cost or just recrimp it yourself.
Me: Okay.

I admit that getting after vendors isn't one of my strong points (isn't that for purchasing?), but we need these guys more than they need us- I don't want to source another vendor and then wait for their lead time to get more parts. Now if the cable is miswired or the part tolerance is too tight, then I'll fix the drawing, but our device has many parts and from time to time you're going to run into one off problems that shouldn't require huge amounts of wasted effort.

On the other end of the spectrum, I do know that the FDA will write you up if you just scrap every non conformance below a certain dollar value without explanation or investigation, so that is out of the question. So far I've been unable to convince people to include routine rework in the manufacturing process, this will be fine until nothing gets done because everything is waiting on evaluation and disposition then we will change. The best solution seems to be to link non-conformances with a risk analysis, then spend the majority of your time on the ones that could lead to patient risk or entire lots of incoming material being bad. At least that way I don't spend two hours on four dirty $2 boxes.

Misconceptions on medical device costs

The Happy Hospitalist has a post on a vacuum assisted wound closure device, Wound VAC, his post and the Wound Vac site have videos and everything. Anyway, Happy complains about the cost:

"I checked with Happy's Hospital wound care nurse. Guess how much these cost retail, should you wish to purchase them outright?

...

Nope. She tells me to buy them outright is thirty thousand dollars. Thirty grand for a LCD screen and some surgical steel, surrounded by a power supply.

I suspect parts and manufacturing would run you about $300. Legal costs about $29,700."

No one pays retail anyway! I think those numbers are a bit off, since you can't buy a lab vacuum pump for less than $1000, let alone an easily portable one with a color touch screen, battery, alarm system, controller and medical grade power supply, I would guess the cost of goods is more likely around $4000. It is tough to say since I don't know what exactly is included in a system. Medical device assembly is not as cheap as you think it is, traceability requirements tend to drive up costs, plus it is difficult to outsource. This isn't consumer electronics where you can just throw it together and hope it works.

There are some legal costs, but I bet they're not more than $100 per device. Although I'm obviously not an expert. What you're mostly paying for is meeting regulations and the design and validation of the next wound care device. Those alarms don't write and validate themselves.

58 is too young to die

Unless you've been living under a rock the last week, you now know that Tim Russert has unexpectedly died at age 58 of a heart attack.

WebMD describes the condition:

That's when the bottom chamber [of the heart] beats at 400-600 times per minute, has no effective blood flow to the brain, you black out, and then, unless it's reversed, you die in three to five or seven minutes or so. This is the rhythm that's treated with an external defibrillator, and had one been available and used, it's certainly possible that he could have been resuscitated.

While Health Blog goes into some more details:

None of that prevented a cholesterol-laden plaque from rupturing while he was doing voiceovers Friday morning for this Sunday’s edition of Meet the Press. The resulting clot, an autopsy indicated, apparently caused his heart to go into ventricular fibrillation which led to cardiac arrest. The autopsy also showed he had an enlarged heart–a manifestation of coronary disease.

This report from the New York Times indicates efforts to revive him through CPR were almost immediate, followed by unsuccessful attempts at defibrillation when an ambulance arrived.

It sounds like he received about the best treatment that can be reasonably expected (CPR then the defibrillation when the ambulance showed up) and presumably had good care leading up to this (some thoughts by others at Kevin, M.D. blog). Although defibrillators are more common than ever, I think the odds of someone recognizing that one is needed within 5 to 7 minutes is pretty low. If some good comes of this, I imagine it will be more defibrillators, more people who at least can potentially recognize when one is required and the limitation of stress tests. Although now every negative stress test might lead to patients demanding cardiac catheterizations and that is not necessarily a good thing.

Photo from Wikimedia Commons.