Refrigeration

[uvula]

This is being discussed again in multiple unrelated threads. It deserves it's own thread.

Do anyone have any idea why mnkd doesn't do this test? Not needing refrigeration would be great in the developed world and absolutely mindboggling huge for the developing world.

What are we all missing? Is it just a matter of not having the money to do the test? What would the testing cost?

[mannmade]

Posted an answer to this earlier but here it is again... $$$$$ and priorities...
Not to say I wouldn’t like to see...

[uvula]

Is there a standard test for this? Can't you just put a case of product in an oven for 3 months and then use it on volunteer diabetics to see if it works? The cost is some electricity and some paperwork.

[mannmade]

FDA

[mnholdem]

I asked CEO Castagna about a refrigeration study via email back in July-2017:

Good Morning!

Have you considered sponsoring a post-market trial that would provide data confirming that Afrezza cartridges may be stored at room temperature? The impact of that label change would be pretty significant. As a PharmaD you can appreciate the likelihood that pharmacies may welcome not having to refrigerate Afrezza packs, not to mention the reduced costs of shipping. I emailed this recommendation to Matt and Ray last year shortly after Afrezza commercialization was returned by Sanofi-Aventis.

I know we’re shooting for that “ultra-fast acting” label, but not having to refrigerate Afrezza cartridges would be yet another benefit to consumers.

I’m looking forward the team speaking at 2Q17 earnings call. Good luck!

This was Mike's response:

If we felt that would drive growth we would have done it by now. It's the least of our issues and therefore we are spending our capital in other places bc that process below is 24+ months either way before you would be able to pull it off.

---

So there you have it. The MannKind team is focusing on areas that will drive growth.  Combined with the cost and duration ("24+ months) of conducting a study and obtaining approval to upgrade the label, the CEO believes there are higher priorities for capital spending.

[derek2]

Additionally, thermal stability tests were done prior to approval, and the FDA and MNKD agreed on storage requirements that appeared on the label.

Some folks are still hung up on Al's incorrect assertion that Afrezza does not require refrigeration. MNKD's and the FDA's chemists believed otherwise. Being rich, old, smart, and the owner did not make him right.

The FDA and MNKD agreed that, based upon observed breakdown rates of insulin, the 10 days without refrigeration for sealed blister packs was appropriate.

www.accessdata.fda.gov/drugsatfda_docs/nda/2014/022472Orig1s000ChemR.pdf

The applicant proposed in the resubmission dated 6/28/2010 the following shelf life for

the drug product : 24 months at refrigerated conditions (2 - 8ºC or 36 - 46ºF); 10 day for

unopened foil pouches and unopened blisters strips at 25ºC (77ºF); and short term

excursions between 15-30ºC (59-86ºF). Once a blister strip is opened, all cartridges in

that strip must be used within 72 hours.


During the second review cycle Dr. Theodore Carver concluded that “based upon the

stability data submitted for the Gen2 product, a month shelf life for storage at 2-8o

C is
granted with an additional 10 days of storage at room temperature permitted before use

or disposal of the Afrezza drug product.”

Note - "The applicant proposed"

And yes, you probably can store your Afrezza counter to these rules, but you'll probably be inhaling some degraded products. Will it hurt you? Probably not. We've seen a few Youtubers pull some stunts without adverse results (yay). There's always a margin of safety designed in.

Even with the smaller packs of basal and mealtime insulins and with my Trulicity I find it a challenge to find room in our fridge for a 90-day supply. It ends up getting pushed to the back of the shelves and I end up having to rummage around. First word problems for Derek, indeed!

In other wacky news - my daughter's boyfriend is working on his PhD and has qualified for a National Research Council grant in developing algorithms for force feedback in distance robotic surgery and surgery simulation (smart young man). The NRC is trying to get him hooked up with CAE Health Care to work on a joint project. That's the company I work for! Small world...

[bill]

Jun 15, 2018 11:10:00 GMT -5 derek2 said:

Additionally, thermal stability tests were done prior to approval, and the FDA and MNKD agreed on storage requirements that appeared on the label.

Some folks are still hung up on Al's incorrect assertion that Afrezza does not require refrigeration. MNKD's and the FDA's chemists believed otherwise. Being rich, old, smart, and the owner did not make him right.

The FDA and MNKD agreed that, based upon observed breakdown rates of insulin, the 10 days without refrigeration for sealed blister packs was appropriate.

www.accessdata.fda.gov/drugsatfda_docs/nda/2014/022472Orig1s000ChemR.pdf

The applicant proposed in the resubmission dated 6/28/2010 the following shelf life for

the drug product : 24 months at refrigerated conditions (2 - 8ºC or 36 - 46ºF); 10 day for

unopened foil pouches and unopened blisters strips at 25ºC (77ºF); and short term

excursions between 15-30ºC (59-86ºF). Once a blister strip is opened, all cartridges in

that strip must be used within 72 hours.


During the second review cycle Dr. Theodore Carver concluded that “based upon the

stability data submitted for the Gen2 product, a month shelf life for storage at 2-8o

C is
granted with an additional 10 days of storage at room temperature permitted before use

or disposal of the Afrezza drug product.”

Note - "The applicant proposed"

And yes, you probably can store your Afrezza counter to these rules, but you'll probably be inhaling some degraded products. Will it hurt you? Probably not. We've seen a few Youtubers pull some stunts without adverse results (yay). There's always a margin of safety designed in.

Even with the smaller packs of basal and mealtime insulins and with my Trulicity I find it a challenge to find room in our fridge for a 90-day supply. It ends up getting pushed to the back of the shelves and I end up having to rummage around. First word problems for Derek, indeed!

In other wacky news - my daughter's boyfriend is working on his PhD and has qualified for a National Research Council grant in developing algorithms for force feedback in distance robotic surgery and surgery simulation (smart young man). The NRC is trying to get him hooked up with CAE Health Care to work on a joint project. That's the company I work for! Small world...

derek2 What would be handy is information about how rapidly Afrezza's effective dose decays when stored at room temperature. If it took a few months to decay 10% that's quite a bit different than if it decayed 10% in a few days.

[casualinvestor]

I think everyone is overlooking just how cheap it is to refrigerate a box of Afrezza vs it's price. I'm betting it costs just a few pennies to refrigerate (in bulk, with other drugs), and the retail costs is $600-800. Produce that sells for $5/lb gets refrigerated all the way across the country.

Would the refrigeration cost vs "box cost" be a lot higher in other new markets? Definitely. Would customer convenience be higher with a more forgiving temp range? Sure. But I think with limited resources, money and influence, Mannkind is smart to just let the temperature stability issue slide until after Afrezza is profitable.

[derek2]

Jun 15, 2018 12:15:41 GMT -5 bill said:

Jun 15, 2018 11:10:00 GMT -5 derek2 said:

derek2 What would be handy is information about how rapidly Afrezza's effective dose decays when stored at room temperature. If it took a few months to decay 10% that's quite a bit different than if it decayed 10% in a few days.

I agree. Unfortunately, Tables 8 and 9 are redacted in the chemistry review.

It seems that users can "get away" with having Afrezza at room temp for longer than 10 days. That's a choice that people can make. Also, let me put this in perspective from a personal point of view. I break plenty of rules. I use lancets and needle tips multiple times, for example. Some people will say "plenty of diabetics do", other will say "What? You risk infection". So, I'm not trying to be the fridge police. Just pointing out that the trials have already been run and an agreement reached with the FDA. It could be that MNKD doesn't see any value in chasing the issue.

[matt]

Jun 15, 2018 8:56:49 GMT -5 uvula said:

Is there a standard test for this? 

There are standards for how stability tests are done that specify what "room temperature" really means and for that matter what "refrigeration" or "frozen" means.  The international standard is that "controlled room temperature" can fluctuate between 15 and 30 degrees C (roughly 60 to 86 F), and the FDA likes to see samples kept at each end of the range as well as those in the middle of the range.  Usually samples are taken at three month intervals for the first year, six month intervals for the second year, and annually thereafter.  Product must be tested in each container size offered for sale so the 4U cartridge is a different test than the 12U.

There are also specs on direct light and humidity and FDA generally requires that the test product be stored in direct light in humid conditions.  Alternatively, the package can be designed to prevent light or humidity reaching the product, but this has to be tested as well.

Overall, stability testing is not that expensive and there is no excuse to have a short expiration date unless the drug is unstable.  Literally the manufacturer just puts samples in rooms with the specified conditions and then the packages are opened at the specified intervals and tested for degradation using simple chemistry tests any pharma company should be able to do in their sleep.  If Afrezza has restrictive expiration dates then it is likely because the drug is not sufficiently stable in the required conditions. 

Granted, most patient homes may be significantly cooler than 86 degrees, but the drug may sit in a warehouse either in Danbury or at a wholesaler for much longer periods.  Pharmaceutical warehouses and trucks are only cooled to 86 degrees, per the spec, so degradation is a legitimate worry as in the humidity.  Warehouses hold all manner of products and they tend to be located near waterways when possible to allow for containerized freight to be sent via ship so the conditions are often humid.  Summer is never a fun time to visit a pharmaceutical warehouse!

[prosper]

Jun 15, 2018 12:56:12 GMT -5 casualinvestor said:

I think everyone is overlooking just how cheap it is to refrigerate a box of Afrezza vs it's price. I'm betting it costs just a few pennies to refrigerate (in bulk, with other drugs), and the retail costs is $600-800. Produce that sells for $5/lb gets refrigerated all the way across the country.

Would the refrigeration cost vs "box cost" be a lot higher in other new markets? Definitely. Would customer convenience be higher with a more forgiving temp range? Sure. But I think with limited resources, money and influence, Mannkind is smart to just let the temperature stability issue slide until after Afrezza is profitable.

Travelers are often away for 2 weeks or more. Not all hotels, both domestic and foreign have reliable, if any, mini-bars.
At home, it is not the cost for refridgeration, but the space and ease of access that is the concern for many.

[mytakeonit]

I handled shipping of containers across the US and know that it is possible to ship things for free ... if you know someone who ships a lot. Most refrigerated containers are shipped with a lot of extra space and product can be added in if less than 10% of the container. We shipped product mostly from the west coast to Hawaii ... but, also shipped to Florida. These were flat priced containers and thats why I say extra product could be shipped free.

I've been retired almost 25 years but know that it can be done. Even if MNKD gets to the point that they have enough volume to ship their own containers ... the cost won't be that large considering what the products costs.

[sayhey24]

Does anyone remember Puerto Rico and the afrezza donated by MNKD? There was not much refrigeration there.

Testing was done years ago. These would not be part of the lost studies but Dr. Kendall should be able to put his hands on the results if he has not already. I was told on a factory tour getting 3 months is a slam dunk but 2 years would probably be doable. The thing about FDKP in the sealed foil pack is its pretty damn stable.

Everyone has heard the stories of afrezza being left in hot cars for weeks and no issues. Its easy to test on your own, give it a try and see if you get the same glucose lowering results.

[mytakeonit]

I'm not saying that Afrezza needs to be refrigerated. All I'm saying is that if we are going to try to promote it across the US, then we should follow FDA and our label and ship it in the best light as possible.

[mnkdfann]

Jun 15, 2018 19:01:15 GMT -5 sayhey24 said:

Does anyone remember Puerto Rico and the afrezza donated by MNKD? There was not much refrigeration there.

I remember it. AFAIK, there was also never any follow-up reported. IIRC, when someone did ask how Mannkind how it went, there was no response.

I'm not saying that Afrezza needs to be refrigerated. All I'm saying is that the Puerto Rico example may not be a useful one to trumpet without more information.