Jun 15, 2014

Medtronic buying Covidien

Big news in the medical device world:

U.S. medical device maker Medtronic said on Sunday it had agreed to buy Covidien for $42.9 billion in cash and stock and move its executive base to Ireland in the latest transaction aiming for lower corporate tax rates abroad.
As big as they are, these two companies don't have that much overlap in the products they sell.  Medtronic focuses on cardiovascular, while Covidien does not have many products in that space.  So from that perspective the deal makes sense.  Although one of the main benefits seems to be a tax advantage for Medtronic, when you're paying $42 billion for a company for a tax advantage, I think it is a clear sign that the US corporate income tax is too high.

On the other hand, the stock market is at an all time high, so you're buying a company at its most expensive. If you're buying it with your shares which are also at all time high, then maybe it all works out, but you have to pay the buyout premium of 40% or whatever it turns out to be.

Entertainingly enough a few years ago Covidien bought ev3 (among others) and was still working on re-branding their products world wide, assuming they re-brand to Medtronic, at this rate, they'll never catch up.

Regardless, we'll see how this deal works out in the long run.

Free pumps

As part of the ACA insurance companies are now required to cover the cost of a breast pump, either a rental or a new one for you to keep.  The FDA considers a breast pump a medical device. A breast pump and basic accessories will run you $150 to $300 with Medela seemingly the current most popular brand.

As a consequence to the new law, if you check eBay or Craigslist you will find many breast pumps sealed in their boxes, available for sale below list price.  Why?  Because people are claiming the benefit with no intention of breast feeding then turning around and selling the devices to those without the benefit (such as those without insurance, on Medicaid, or in other countries).  Now obviously some people intend to breast feed, but it doesn't work out and they don't need a pump, establishing breast feeding can be a struggle and you generally know in the first week if you're going to stick with it or not.  There is nothing wrong with this.  However, the whole situation is generating a lot of waste, in this case it seems like a copay may be appropriate.  If something is "free", you're likely to take it, regardless of if you're going to use it or not.

Just out of curiosity I looked at breast pump MDRs to see what they were reporting, it was what you would expect, potential electrical issues and some potential allergic reactions to materials.  Evenflo also got a warning letter back in 2009.

The Washington Post covered the booming breast pump industry in: The breast pump industry is booming, thanks to Obamacare.

Apr 13, 2014

FDA Dysfunction

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

Oct 28, 2013

Onshoring manufacturing

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

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

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

Oct 27, 2013

Device companies deal with ACA

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

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

Oct 14, 2013

Blogs worth reading - creo Quality

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

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

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

Oct 13, 2013

Excellence in Equipment Documentation

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

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

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

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

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

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

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

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

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

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

Jun 26, 2013

Latex Free Labeling Revisited

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

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


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


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

Mar 9, 2013

New Links

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

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

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

Mar 4, 2013

Tech Talk - Medical Device Particle Testing Part 3


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

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

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

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

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

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

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

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

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

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

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

f.        Perform particulate count matching the validation conditions

Perform the test using the method previously validated.

g.       Flush the model with water

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

h.      Identify particulate (as necessary)

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

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