I worked on expiration dates studies in pharma. It's well known that you could probably always extend the shelf life to 3-4 years for most drugs that are supposed to expire within 2 only, because tablets for example tend to be very stable.

But nobody wants to run long stability studies, because that costs a lot of money (i.e. several batches that have to be analyzed in regular basis, documented, reported, QA'ed, inspected, etc... - and you need to place them in numerous conditions, too, ambient temperature as well as stressed conditions depending on where you intend to market the drug), and bring very little returns at the end of the day. You'd rather want your engineers to work on developing new formulations and regulatory teams to spend time on the application of new drugs rather than adding one or two years of shelf life to an existing drug on the market.

Also know that you can't "extrapolate" and need actual data based on regulations of the big 3 geographies (US, Europe, Japan). So "models" are not accepted. Also, these agencies are extremely conservative when it comes to what impurities should be considered acceptable and at what levels they should be. Not saying they are necessarily wrong, but this is another constraints. I have seen cases where it was difficult to extend one drug's shelf life because of a single impurity being a little over the tolerated limit.

How did they come to an expected shelf-life of 2 years in the first place?

Some medication that expires quickly can be extended simply by refrigerating it. I wonder what other environmental controls could extend the shelf life of common, expensive medication?

> How did they come to an expected shelf-life of 2 years in the first place?

By storing it for 2 years and testing it after.

> I wonder what other environmental controls could extend the shelf life of common, expensive medication?

Common, expensive is an oxymoron. The vast majority of all medication in use is practically free to produce. The packaging of drugs typically costs more than the drugs themselves. Drug discovery has long concentrated on small-molecular-weight drugs that can be mass-produced for a pittance. The reason drugs cost so much is that proving that they are safe and that they work costs so much. Because of this, there is little economic sense in trying to preserve drugs for longer (which would require more extremely expensive trials), when you can just trash the drugs and order up a new batch that has a combined msrp of $100M for $5k.

In their economics, small molecular weight drugs share more with software than with, say, bread. That is, practically all of the economic cost is upfront investment and the replication cost is non-existent.

> expensive medication

Apart from biologic drugs, most small molecule compounds are dirt cheap to produce. So cheap that nobody is even striving to produce them in a cheaper, more efficient way. If you compare this kind of industry with chemical specialty industries, where the mindset is to increase yield as much as possible, in pharma the production cost is not much of a consideration. So, what you pay for your drugs has almost no relationship to how much it costs to produce. You are paying for patents, market exclusivity and the whole system that goes with it (the pharma companies are not the only ones benefiting from it).

> How did they come to an expected shelf-life of 2 years in the first place?

Stability studies supporting 2 years data (submission to approval takes one year, and compiling all data before submission for filing is a 6 months process, so you can start submission with 1 year stability data in your hands, and tell the regulatory agencies you will provide the 2 years data during the second half of the regulatory review to get 2 years).

Because that's good enough for most drugs. 3 years is usually ideal, but not always necessary. If your drug is used in high volume most patients won't get batches that are produced long ago anyway.

The point is we don't necessarily know, or know to the degree of certainty the FDA requires, how many of these things degrade. Perhaps in certain conditions, they degrade at one rate, but in other conditions (such as a temperature difference), they degrade at a different rate. Testing how drugs perform years after production in multiple different scenarios is necessarily time consuming, because it takes at least that much time to be sure.

I'm a test engineer. Highly accelerated life testing (HALT) can probably be used to closely approximate the shelf life of medicine. You need to look at the parameters that cause degradation (humidity, temperature, light exposure, etc). HALT the samples at different temperature/humidity/lighting extremes and use mass spectrometry to check purity. Use the data to create an algorithm that approximates the product lifetime and then correlate the results with actual shelf life for verification.

Unfortunately, ALT is not a solution, because it's not accepted by FDA, except as a temporary measure.

Any drug submission that supports shelf life via ALT data will be expected to also say "and we're doing real time testing to support this", and FDA will expect the follow up real-time data.

Then perhaps the solution is for the FDA to allow HALT testing. Having said that, I imagine there is little incentive for pharma companies to willingly extend the shelf life of their products - perhaps the real solution is for the FDA to actually require HALT testing.

I think the real thing here is, "Better safe than sorry". It's fine to use things like HALT testing initially to say, "this drug should be effective for 8 years" so that folks can get it to market before 8 years have passed.

But if, in reality, that drug only lasts for a strong 5 years, after which time it loses effectiveness, especially in high humidity or with high UV exposure. We could catch this with real-time tests and adjust accordingly - before it actually affects the general public's health.

A good model really isn't good enough in medicine. Real data from clinical trials is needed, and nobody has an incentive to fund that.

The largest barrier to accelerated life testing right now is that we really don't know all the mechanisms that cause degradation (or understand their impact on stability). There are many lab instruments that already provide HALT metrics on how stable a drug sample is expected to be under different conditions. And the Arrhenius and Eyring equations are useful for empirical modeling. These tools are great for quickly identifying when formulations are unstable. But it's very difficult to say with certainty (at least in the pharma world) that something will be stable for X years unless you actually test it for X years.

For the vast majority of manufactured products, HALT makes sense because any uncertainty that remains after testing is not likely to harm users. But with some of these drugs, any uncertainty, even after HALT, could cause major problems for users. And it seems that the FDA is unwilling to accept that risk. But as far as I know, the FDA is actively seeking methods for performing HALT that produce accurate and repeatable results.

I see medicines in foreign countries wrapped in some kind of aluminum foil. Will that prolong the life of the medicine given there is no oxygen to react?

Given the amount of money spent on medicines, I really think there is a good moral business case to identify the correct expiration dates and save money for people.

We just went through the Health care ordeal. Money saved anywhere is money saved for people who desperately need healthcare to work for them.

Except the medicines themselves aren't expensive. The prices are that high because the pharma companies demand it, because of all the tests, which are their main source of income. That is why prices in the US are so much higher than elsewhere (because of the political power of lobbying and cultural acceptance of price screwing the public on medical things).

Given that it's the very same party that would be doing the testing for expiration dates, I kind of doubt they would research this out of the goodness of their corporate hearts. Effectively the same outcome could be realised without the effort of extra testing anything: by just lowering the price of medicine a bit; big pharma would make less money, the public would have more medicine for cheaper.

There may be other ways to approach this from a moral point of view. High prices for medicines are defended on the basis of high research costs, not high manufacture costs.

A case could be made for legislation that obliges free replacement of out of date medication for the original purchaser, perhaps with a small surcharge.

A case could be made for smaller packages so people are less likely to take out of date medications as well.

Seems simple enough, just extend the expiration dates on the meds that don't turn toxic and that still work.

The issue here though is that it's not in the drug manufacturers interest to have super long dates. Putting labels that expire sooner means they can push higher volume.

There's also the not-irrelevant issue that testing is slow and potentially other than free. How do you find out when a drug expires? You have a bunch of it sit around and test it periodically, right?

I assume that would be done after bringing a drug to market, otherwise drugs could easily be delayed 10+ years if they're shelf-stable.

Nobody said they need to find the absolute last day the drug expires before they can get it to market.

If it's a new drug and they can only say for sure that it lasts 6 months then put that on the label and ship it out. But assuming the drug will be out for 10+ years they should be continually testing the expiration date and updating as they've had more time to make that determination.

But like I said initially (and as you nicely pointed out) that costs money so why bother?

> If it's a new drug and they can only say for sure that it lasts 6 months then put that on the label and ship it out. But assuming the drug will be out for 10+ years they should be continually testing the expiration date and updating as they've had more time to make that determination.

This needs regulatory work. And this bring very little returns, so your regulatory resources are better spent somewhere else. There are other incentives in place.

If scientists are able to calculate the longevity of chemicals, food, and other products without having to wait the actual time period, I don't see how or why pharmaceutical drugs would be any different.

It's very likely it is not favorable to companies to look into this, just as it was revealed that the EpiPen expiration date was not really true.

You're absolutely right! Those calculations can be done without actual testing. The only wrinkle is that doing so comes with the risk of failing to foresee something or otherwise being wrong. So there are some error bars involved.

What kind of error rate are you willing to accept in models of pharmaceutical shelf stability? Bearing in mind that errors potentially translate into deaths, probably disproportionately of the less privileged among us?

I'm not sure how it would be any different than existing expiration dates for OTC medicines, food, dairy, etc. In the case of medication, it is most likely to become less effective over time rather than toxic.

Are they?

"able to calculate the longevity of chemicals, food, and other products without having to wait the actual time period"

I doubt that food companies let their canned beans sit for 3 years to figure out if that August 2020 expiration date holds true.

I would expect the chemistry to be characterised well enough to the point where you shouldn't need clinical tests to know it's degredation profile...

I don't know about that. There are variables beyond theoretical chemistry, like the packaging, the manufacturing process, etc.

I'm not anywhere near knowledgeable on pharma, but I worked on an FDA regulated medical device. If we made a claim, we had to test it. Knowing that e.g. every component in the machine was rated safe between temperatures X and Y did not mean that we didn't have to perform real environmental testing.

Regulations don't want you to rely on models.

From what I read, current expiration dates are produced by the sort of actual testing I described.

I would assume there's also liability to think about. If something goes wrong with a medicine after the expiration date it has to be better for the manufacturer. Also you probably want to leave some room for suboptimal storage

I'm sure there is some degree of companies wanting expiry to be like the dates on grocery items that are really "taste best by" dates but in speaking to manufacturing and development people their are some layers of complexity. Compounds do degrade over time in many cases and things like light, temperature and humidity play a role. In pharmacy warehouses they aren't just required to control climate they have to log temperature 24 hours a day in an auditable format. Because of these factors the target is a moving one and while many things would likely be fine, for prescription medicine the tolerance for risk is so low that it pushes things in a very conservative direction.

There is a great comment farther down about how complex label changes can be. Getting a revised label, or packaging through FDA is an enormous undertaking. This why sometimes dosing seems very weird. If research says we need a 2mg and a 4mg but later in the process patients need a .5mg it's a big mess.

Suffice to say it's a deep rabbit hole.

Any such labeling change would likely result in decades of litigation over the precise meaning of each term when someone inevitably comes to harm while taking the drug. From the manufacturer's point of view it's cheaper and possibly safer to use a single clear good/bad date.