97 - Stability Indicating Methods & Shelf-life (S7E7)

ever get that feeling like you want to really
understand something, you know, like something
kind of complex, but without having to like wade
through a ton of textbooks. Oh, absolutely. Yeah.
I think we all do. Yeah. Well, today we're doing
just that. And we're zeroing in on a really,
really important part of medicine that often
doesn't get talked about much. Right. And it's
how we figure out if a drug is going to stay
effective and safe, like you know, from the time
it's made until it could actually end up in your
medicine cabinet. Yeah, that's key. Yeah, absolutely.
So we're talking about its stability and shelf
life. Yep. It's super important because it makes
sure that those treatments that we all rely on
are actually going to work when we need them.
Right, exactly. It's the foundation of everything.
You've got to know that what you're taking is
going to actually do what it's supposed to do.
And for this deep dive, we've got a whole bunch
of really interesting info from what happens
when drugs break down to all the regulations
and stuff that make sure this whole process is
done right. I think our goal here is to break
it down, kind of like give you the core principles
so you understand the essentials of how we guarantee
a drug's quality throughout its entire life,
you know, from beginning to end. Right. Without
getting bogged down in, you know, all the super
technical stuff. Right, because it's not something
you normally talk about at dinner, right? No,
not really. Drug stability. But, you know, when
you think about it, it's like the thing that's
kind of silently protecting us, right? Yeah.
every single prescription we get filled, every
over -the -counter thing we buy, you know? That's
a great point. Yeah. I mean, if a drug's not
stable, it's not going to work the way it should,
right? It might not have that therapeutic effect.
And the worst case scenario, it could even, like,
create bad byproducts. Yeah, absolutely. So understanding,
like, how a drug's lifespan is established, it's
actually super relevant to all of us. It is,
definitely. Yeah. And with all that said, I think
it's important to lay out what we're going to
we're going to talk about. We're going to we're
going to go through the main parts of this whole
area and we'll look at the specific tests that
are done. We'll look at how scientists take that
data that they get and figure out what it means.
OK. And we'll even touch upon some some real
world stuff that that shows why these concepts
are important, you know, in the real world. Yeah.
So, yeah, let's get into it. Let's get into it.
OK. So the first thing I noticed is is this term.
stability indicating methods. Sounds kind of
technical. It does, yeah. But what's the basic
idea here? Well, basically a stability indicating
method. It's a very precise analytical technique.
And what it's designed to do is it's designed
to measure very specifically how much of the
active ingredient is in a drug product. OK. But
it also measures any substances that it might
degrade into over time. Oh, wow. So you're looking
at the good stuff and the stuff that's changed.
And what's really crucial about these methods
is they're able to tell the difference between
the active drug and those breakdown products
without interference from all the other stuff
that's in the formulation. OK. So that's things
like fillers and coatings. OK. OK. So it's like
it's almost like we have this really, really
powerful lens that allows us to see exactly what
happens over time. It is. And to just focus on
the active component, right? Yeah. Yeah. Exactly.
And in pharmaceutical analysis, the textbook
we have, there's this great example with butorfenol.
Yes. Can you unpack that a little? Yeah. So in
the book, figure 9 .38, it shows how they use
something called HPLC, which is high -performance
liquid chromatography coupled to ESMS. That's
electrospray ionization mass spectrometry. And
they use this to find and analyze impurities
and degredients, which are just those breakdown
products. In butorfenol, when it's in a water
-based solution, And what's really cool is this
tool, this method, it doesn't just find these
breakdown products. It actually lets scientists
figure out what they look like. chemically, you
know, your structure. Okay. So in the case of
butorfenol, they found a few degradants, including
hydroxybutorfenol, ring -contracted butorfenol.
There's keto -butorfenol and 1110 -butorfenol.
And each one of these has a unique mass -to -charge
ratio. Wow, that's incredible. So we're not just
talking about like a general breakdown, but you're
actually seeing what's happening at a molecular
level. Exactly. That's amazing. Yeah. And this
brings us to another point that was mentioned,
the need for validated analytical methods. Right.
Why is it so important that these methods are
validated? It's super important. Validation is
the key because it makes sure that the tests
that we're using are accurate, that they're reliable,
and they give us the same results every time
we use them. Right, yeah. We have to be certain
that what we're seeing, that data we're getting,
it's a true reflection of the drug stability.
Right. And it's not because... there's some problem
with the testing procedure itself. So the ICH
Q6A guideline, which is in our materials, it
talks specifically about what needs to be done,
the requirements for specifications for the test
procedures, and what criteria we need to accept
new drug substances and products. So it really
underlines, emphasizes how important these validated
methods are. Got it, so they're like setting
a standard for how these tests should be done.
Exactly. And I'm assuming it's not just boot
dwarf and all that gets this kind of like close
attention. No, no, no, no, not at all. The textbook
also mentions Femida Deen. Yeah, so figure 9
.37 in that textbook, it shows how they use mass
spectrometry to identify the degredients, those
breakdown products of thymatidine. Okay. And
similar to the batorphenol example, they get
these really detailed mass spectra under different
MSMS conditions. That's tandem mass spectrometry.
Okay. And this gives them a really good understanding
of what structural changes happen when thymatidine
breaks down. Got it. So we can we can really
see through these examples. Yeah. You know how
powerful these stability indicating methods are
and how they help us to really understand what
happens to a drug over time. Yeah. Right. And
this kind of leads us into how these stability
studies are actually done. Right. So it's more
than just one text. Right. Oh, absolutely. Stability
studies are they're designed very carefully to
simulate kind of like all the different conditions
that a drug product might face throughout its
journey from when it's made to when it gets to
the patient. So this involves taking both the
raw drug substance and the final formulated product
and exposing it to a bunch of different environmental
factors. So we're talking temperature, humidity,
even the light. And this is done for extended
periods. And the goal is to sort of speed up
the natural breakdown process so that scientists
can really see what's happening, what breakthrough
products are being made, and understand how the
drug breaks down. So this accelerated testing,
it helps us predict how the drug's likely to
behave under normal storage conditions over its
shelf life. Okay, that makes sense. So we have
these really sophisticated methods, right, to
really see what's happening, and we're kind of
putting them through these stress tests. Exactly.
So let's talk a little bit more about the actual
protocols themselves, right, like the testing
protocols. What would a typical one look like?
So they're very comprehensive. They're designed
to look at every critical aspect of a drug product's
stability. It's not just about is the chemical
structure changing. You look at the physical
stuff too. So you look at how it looks. You look
at how quickly it dissolves. If it's a solid
epharia, you look at the particle size. And you
also got to check to see if it's microbiologically
stable. So you want to make sure it doesn't get
contaminated with anything nasty over its shelf
life. Oh, OK. looking at everything, right? It's
not just one. It's everything. And in the good
drug regulatory practices, the document we have,
it really focuses on the importance of testing
both the drug substance and then the final drug
product. Right. Why is it important to make that
distinction? Well, because the active drug substance,
when it's on its own, it might behave a bit differently
than when it's all mixed together with the other
ingredients in the final product. So those inactive
ingredients, the way it's manufactured, even
the packaging, all that can affect how stable
the active ingredient is. So that's why... you
know, the regulators want stability data on both
the raw material and the finished product to
get a really good picture. Makes sense. And in
section C .7 .1 .3 of the good drug regulatory
practices, they really emphasize the needed four
test methods and specifications for both. OK,
yeah, that makes sense, because the final product
is ultimately what we're going to use, right?
The patient's going to use. So we need to be
really, really sure that it's stable. Absolutely.
In that form. Right. And speaking of the final
form, our CFR Title 21 regulations, they point
out how important it is to test the container's
enclosures. Oh yeah. Why is that a concern? Well,
think of it like this. The container enclosure
system, they're the bodyguards. Right. They're
protecting the drug product from everything outside.
Right. So these components, they need to be tested
to make sure they're not going to react with
the drug. Right. That they can keep moisture
and other things out. And really importantly,
that they're not going to leak any harmful stuff
into the product. Oh, wow. OK. And this is all
in 21 CFR 211 .84A3. They actually mandate this.
testing, or they say, you know, you can accept
a certificate of testing from a good supplier,
you know, as long as the drug manufacturer actually
verifies those results. Got it. So even the packaging
is under scrutiny, right? Oh, yeah. Make sure
it doesn't mess up the drug. Yeah. And it sounds
like for some really specialized drug products,
like PT drugs, which are... Positron emission
tomography drugs, they use them in imaging. Right,
right. The requirements for testing the incoming
components might be a little different. Yeah,
so 21 CFR 212 .6 B1, it says that if the testing
that you do on the final PE tree drug product,
if it includes checks to make sure the right
components were used, then the requirements for
testing each incoming component aren't as strict.
So basically, looking at a certificate of analysis
from the supplier might be enough. But if they
don't do that, if that final testing doesn't
doesn't cover that, then you gotta do more rigorous
testing on every single ingredient, active and
inactive. You gotta make sure you got the right
stuff. It's interesting how the regulations are
so specific to different types of products. So
we're getting all this data from these very rigorous
stability studies. How do scientists take that
data and actually figure out how long a drug's
gonna stay effective? So it's a process. They
take that data and they analyze it very carefully
to see how fast the drug breaks down under all
those different conditions. And this uses something
called degradation kinetics, which is basically
the study of how the concentration of the drug
changes over time. And things like temperature,
they can really affect how fast a drug breaks
down. So they look at this relationship very
closely using mathematical models and all that.
So generally speaking, a higher temperature will
lead to a faster breakdown? Most of the time,
yes. OK. Which is why doing those accelerated
stability studies at higher temperatures gives
us so much good information. Right. You can see
how it's going to behave under stress. Got it.
And there are these regulatory guidelines, like
the ICH Q1A. And they provide frameworks for
how to design these studies and how to use that
data to figure out what the shelf life of the
drug is under normal conditions. And ultimately
that is what determines the storage instructions
that we see on the label. whether it needs to
be kept in the fridge, whether it needs to be
protected from light, whether it can be at room
temperature, all of that comes from those stability
studies. The goal is to make sure that the drug's
good until that expiration date, as long as you
store it properly. So what happens if you have
a batch of a drug substance and it hits its expiration
date? But when they do further testing, it seems
like it's still stable. Can they extend the usability
of that? 21 CFR 211 .16666 allows for retesting
to extend the usability, but only if the data
supports it. Right. So this retesting, it has
to be done properly. It's got to be documented.
And it's got to show that the drug substance
still meets all those quality standards. It's
not just about how it looks. You've got to prove
it with analysis. Right. It's not just an arbitrary
thing. No. It has to be based on evidence. So
what about if there are changes made to the manufacturing
process or the formulation of a drug, does that
affect the shelf life that they already figured
out? Oh, yeah, absolutely. Any big changes to
how a drug is made or the ingredients, it can
totally change its stability. So the regulators,
they usually ask for more stability studies after
those changes are made just to make sure that
those modifications haven't messed up the drug's
quality or the shelf life. Right, so it's constant,
like, vigilance, right, to make sure that these
medications are... are good. Yeah, you gotta
keep checking, you know, gotta be sure. So our
sources, they don't really give us, like, specific
case studies in the way that we might think of
them, like, you know, stories. Right, right.
But we can definitely see how these principles
are used in the real world. Oh, yeah. In some
of the details. Like, for example, that Boder
-Fannell degradance analysis. Yeah. It really
shows all the work that goes into understanding
stability. Right. So understanding these specific
breakdown products, it's not just like, you know,
theoretical. No, it's practical. It helps manufacturers
to... change their formulations or the packaging.
Right, exactly. To prevent these substances that
might not be as effective. Or could even be harmful.
Yeah, from forming in the first place. So it
directly affects the medicine. Exactly, you got
it. And if we look at saxagliptin, which was
mentioned in accounts in drug discovery, it comes
off its target molecule in the body really slowly.
It has a half -life of like 50 minutes at body
temperature. So this means it's pretty stable.
in a biological system. Now, this isn't like
a traditional shelf life study. Right. You know,
for something in a bottle. Right. But it shows
how important it is to understand how a drug
interacts and sees effective over time. Right.
Which is kind of the same idea. Right. Yeah.
OK. Yeah. And when we think about, you know,
developing formulations specifically for children,
like we saw in drug development, a case study
-based insight. Right. Stability's got to be
a huge consideration there, too, right? Oh, yeah.
I mean, a liquid medication for a child. Totally
different. It's going to have totally different
requirements. Yeah. And challenges than like
a tablet, right? Absolutely. Huge difference.
And the development of sustained release formulations.
They talk about that in developing solid oral
dosage forms. Right. That requires a ton of stability
testing. Right. But yeah. Because that mechanism
that controls how the drug is released over time,
it's gotta stay intact. It's gotta work right
the whole time. The whole shelf life. Right.
So even without specific dramatic case studies,
the need for all this testing and this accurate
shelf life prediction, it's in everything. It
is, it's built in, it's everywhere. So just to
wrap up. We've seen how important those stability
indicating methods are to understanding how drugs
change over time. We looked at all these really
comprehensive tests that they go through to see
how resilient they are. under different conditions.
Right. And we talked about how they take all
that data and then they figure out the shelf
life. Yeah. And what storage is needed. Exactly.
It's all about making sure that the medicines
that we rely on are good. Are good quality and
they're safe. Yeah. And it gets us to a final
thought I want to leave you with. OK. You know,
think about all this stuff that happens behind
the scenes. All these tests, the regulations,
the scientists. It all affects the medicines
you take every day. So what questions does this
bring up for you about how good pharmaceutical
products are over time and the science that makes
them reliable? It really makes you think about
that expiration date on the box a little differently.
It does. Definitely. Well, thanks for joining
us on this deep dive. Yeah, thanks for having
me. We hope this was a good shortcut to being
well informed. Absolutely. Keep questioning and
keep learning. We'll see you next time.