126 - Stability Testing & Forced Degradation (S9E6)

Welcome back to the Deep Dive, everyone. Today,
we're going to be taking a look behind the curtain
at something I think is really fascinating in
drug development and something a lot of people
probably don't think too much about, stability
testing. And I mean this is where it gets kind
of cool is that there's this whole thing called
forced degradation right where they're actually
Intentionally like trying to break the drugs
down exactly before they even give it to anybody
which I think is wild It does sound counterintuitive
doesn't yeah Yeah, you know, but it is an absolutely
vital part of the drug development process Yeah,
and actually this deep dive We're gonna really
unpack why subjecting these drug substances to
all these stresses right from the very beginning
isn't about destroying them. It's about creating
a much stronger, safer medicine. for all of us.
So we're going to be using a lot of different
sources today, drawing on real world drug development
scenarios, actual case studies. We're also going
to be tapping into the regulatory guidelines,
those important guidelines set forth by the ICH,
and of course, the bedrock of it all, the fundamental
principles of pharmaceutical analysis. So we've
got a lot of ground to cover and what we really
want to do today is kind of like connect the
dots between this initial almost like destructive
sounding phase and the high quality treatments
that we ultimately rely on. Yeah. So can we just
jump right into like why like what is the fundamental
reason behind conducting these what are called
forced degradation studies. So yeah let's break
this down. So when scientists perform forced
degradation studies they're not simply trying
to see how fast a drug will you know. decompose
or degrade. It's a very systematic investigation
into how that drug can break down when it's subjected
to a variety of different arched conditions.
Oh, interesting. And this proactive approach
is really essential. And it allows the researchers
to get a jump on, kind of anticipate potential
issues that might pop up later, whether that's
during the manufacturing process, storage, or
even, heaven forbid, after it's administered
to a patient. So it's like getting a glimpse
of what the weaknesses might be from the very
beginning, even before you even start really
developing it further. Exactly. You want to stress
it and see where the vulnerabilities lie. And
we mentioned this in the outline of this episode,
but understanding the degradation pathways I
think is really important. How does knowing the
ways in which a drug might break down, how does
that help us? Yeah. Yeah. Well. by really thoroughly
understanding those pathways, we gain valuable
insights into what the drug breaks down into.
Those degradation products are also sometimes
called impurities. And knowing this stuff is
just crucial for ensuring the drug is reliable
and safe for patients long term. So if we can
understand and map out how a drug breaks down,
then we can develop really smart strategies to
prevent that, or at least minimize it from happening
at all. So I'm curious, what kind of stresses
are they putting these drugs under? Is this like
a pharmaceutical? torture chamber or something?
Well, I mean, it's a little more, you know, scientifically
rigorous than a torture chamber, but you are
on the right track with the idea of extreme conditions.
OK, so based on the the sources that we have
for this deep dive, these stresses typically
involve, you know, major shifts in temperature.
There's intense light exposure, particularly.
ultraviolet and visible light, which as we know
even from the basics of pharmaceutical analysis,
that requires precise calibration of UVV spectrophotometers
to even measure that accurately. So there's that,
there's exposure to water. Right. Which can cause
something called hydrolysis, which is, you know,
a very common way that molecules will break down.
Think of it like, you know, if you leave certain
foods out. Right. Exposed to humidity for too
long. Right. They get all soggy. They'll go bad.
Yeah, exactly. OK, so heat, light, water. That
makes sense. What else? So we've got heat, light,
water. They're also looking at oxidation. OK.
Which is basically a reaction with oxygen. And
this is so important to understand that it even
feels like biocatalytic oxidations are really
studying carefully how these reactions happen
and how we can control them. And then there's
pH extremes. So, you know, exposing the drug
to a really acidic environment or a really basic
environment. OK. Because if you think about it,
you know, when you take a drug, it might have
to go through the stomach. It's very acidic.
Which is super acidic. Right. And even if it
has like, you know, that protective enteric coating.
Right. It's still, it's got to hold up through
all those different conditions. So they're really
trying to see how it does across that whole spectrum.
So these aren't just random stresses that they're
putting on it. This is very specific to what
the drug could potentially encounter. You got
it. These conditions are specifically selected
to really mimic the challenges that a drug substance
or the final drug product that you might pick
up at the pharmacy might face from as soon as
it's made to when it's sitting on the shelf to
when you're actually using it at home. OK, so
the drug has been stressed. We've put it through
the wringer. What happens next? How do they actually
figure out how it broke down? This is where some
really intricate science comes into play. So
after the drug's been exposed to all these controlled
stresses, they very carefully analyze what's
left. They're trying to find out exactly what
that original molecule transformed into. And
like we were saying earlier, these resulting
molecules are called the digredents or impurities.
Right. And how do they actually see these transformed
molecules? What are they using, like little tiny
microscopes? It's even cooler than tiny microscopes.
They have these really advanced analytical techniques.
Oh, wow. And one combination that's really highlighted
in some of our pre -clinical development material
is LC -NMR -MS. OK. I'm not familiar. It's a
mouthful. But basically, liquid chromatography,
the LC part, it's like a really sophisticated
sorting machine. OK. It separates the different
components in that stressed drug sample, and
then the NMR and the MS, those stand for nuclear
magnetic resonance and mass spectrometry. Those
are kind of like specialized microscopes. They
help the scientists determine the structure and
the weight of each of those separated molecules.
So using all of that detailed information, they
can then piece together the sequence of chemical
changes that the drug went through, which is
that degradation pathway. So it's like it's like
molecular forensic science. Exactly. It's like
CSI for molecules. I love that. So now we're
getting into impurity profiling, identifying
like the bad guys. Right. Why is that so important?
Why do we need to know exactly what these impurities
are? I mean, knowing what these impurities are
is. absolutely vital for patient safety. I mean,
some degradants might be harmless, but others
could be toxic. They could reduce how well the
drug works. And the FDA, as you know, they have
very strict requirements for understanding, controlling
these potential impurities in any drug that they
approve. And this is all spelled out in the Code
of Federal Regulations, Title 21, Part 211. And
there are techniques that can be used, like NMR.
petroscopy, which is a technique that we've talked
about in previous deep dives, where you're really
looking at the structure of a molecule. Yeah.
And they use this to figure out, OK, well, what
does this impurity look like? OK. What's its
three dimensional structure? And that is essential
for figuring out if it could be toxic and for
developing really sensitive methods to actually
detect it. and the final product. So it's not
enough to know that it breaks down. You have
to know what it breaks down into. Absolutely.
And if those things are going to cause a problem.
Exactly. You've got to know who the bad guys
are. So I imagine this whole process creates
a ton of data. Oh, yeah. What do they do with
all of that? So this is where it all comes together.
All this data is used to develop what are called
stability indicating methods, or SIMs. You can
kind of think of a sim as, you know, your drugs
report card. It's a specific test. Okay. It's
designed to accurately measure how much of the
good stuff the active drug is present and also
any of those degradants that might have formed.
So are these what they use, like, throughout
the process to kind of keep checking? You got
it. They're essential for ensuring that that
drug product maintains its quality. Okay. And
its purity and its potency. Right. From when
it leaves the factory to, you know, when it's
sitting on the shelf to when it expires. Okay.
And that's important because obviously we want
to make sure that the medicine we're taking is
actually, you know, going to do what it's supposed
to do. Absolutely. So it's good for quality control.
I get it. But how does knowing about how a drug
degrades actually influence how they design the
medicine itself, the formulation? Oh, that's
a great question. So understanding how a drug
degrades is so valuable when you're thinking
about formulating that final product. So for
instance, you know, if they do these forced degradation
studies and they see that a drug is really susceptible
to that hydrolysis, which remember is breaking
down in water, then they're going to probably
choose excipients. Those are those inactive ingredients
that are in the medication along with the drug.
They're going to choose ones that have a very
low moisture content. Oh, OK. And actually, one
of our sources specifically mentions avoiding
putting moisture sensitive drugs in certain types
of capsules. Right. Because those capsules can
actually have a high moisture content. Well,
that makes sense because you don't want the packaging
to break it down. Exactly. You don't want the
delivery system to be part of the problem. And
another example, let's say the studies show that
the drug degrades really quickly in stomach acid.
Oh, OK. So then they might use an enteric coating
as we've talked about. Right. So that the drug
is protected from the acid. Oh, wow. Until it
gets to the intestines where it can actually
be absorbed. Okay. So that's directly preventing
that pH degradation. So it's all about choosing
the right partners for the drug and the right
protection based on how that drug behaves under
stress. Yeah, you can think of it that way. Choosing
the right inactive ingredients and the right
protective measures like coatings, really building
a strong, robust medicine that's designed to
last. So this whole process, it's clearly generating
a ton of data. What do they do with all that
information? Well, all of that data is used to,
it's part of the big regulatory filings. Oh,
OK. The pharmaceutical companies have to submit.
To the FDA. Exactly, to the FDA, right. And those
submissions need to prove to the FDA that the
drug is safe and effective. Right. For however
long. They say it's going to last on the shelf.
So that data interpretation, explaining what
it all means, is crucial. So it's not just about
doing the experiments. It's about explaining
what those experiments mean. Absolutely. And
those agencies, they really scrutinize the data
to make sure the drug is well characterized and
that the right measures have been taken to control
any potential degradation. And that stability
data, which is based on those forced degradation
studies, is a cornerstone of getting a drug approved.
OK. So we've talked about the theory. We've talked
about the process. Can you think of any real
world examples, even if we have to kind of infer
them based on the information we have, where
this deep understanding of degradation actually
led to a better medicine? Yeah. I mean, even
if our sources don't lay it out as like a eureka
moment. Right. We can see how it works, right?
Right. So think back to when we've talked about
crystal size distribution, different crystal
forms of a drug. They can have totally different
stabilities. And so that directly affects how
you're gonna manufacture the drug. So for instance,
controlling the temperature during crystallization,
which is something our OPR and eSource talks
about. That's essential to make sure that you're
only making the most stable form. So you're preventing
those degradation issues. Okay, so basically
by understanding that different forms can degrade
differently, they're controlling the process,
so they only make the best one. Exactly, exactly.
You're picking the winner. And, you know, we've
talked about the soft gel capsules for ditonavir
before, and, you know, that specific formulation.
That was probably chosen to improve the drug
stability and absorption. Okay. Right. So maybe
an earlier version was less stable. Right. Or
it didn't dissolve well. And they had to go back
to the drawing board. And they're like, how can
we make this better? Exactly. And that's where
that soft gel formulation came in. OK. So fine
tuning how the drug is presented to make it more
stable. OK. That makes sense. Are there any other
examples that you can think of where we can see
this in action? Well, going back to oxidation
that we talked about earlier, you know, it's
highly likely that for a lot of drugs that are
susceptible to reacting with oxygen, they've
come up with risk mitigation strategies. And
that's all based on those forced degradation
studies. So they might add antioxidants to the
formulation to kind of neutralize that oxygen,
or they might use special packaging that doesn't
let oxygen in. And even if our sources don't
give us a specific example, you know, this is
standard practice in the pharmaceutical industry,
all driven by that fundamental understanding
of how drugs can degrade. Wow. Okay. And, you
know, similarly with hydrolysis, right? Yeah.
If that's a big concern. Okay. They might use
very specific drying processes in manufacturing.
Okay. Or put those little desiccant packets,
those little... The do -not -eat packets. Exactly.
The do -not -eat packets. Right. In the packaging
to absorb moisture. Oh, wow. And all of this
is because of those forced degradation studies.
So it's like this whole process where you stress
it, you find out how it breaks. You get to know
it. Yeah, you get to know it. And then you use
that knowledge to make it better. Exactly. Exactly.
You're anticipating the problems before they
even happen. Wow. And building in, you know,
multiple layers of protection. This has been
so interesting. I mean, this is like a whole
part of drug development that I, you know, I
never even thought about. The hidden world. Yeah.
So, I mean, what would you say are, like, the
biggest takeaways for our listeners today? I
think the biggest takeaway is that these forced
degradation studies, while they might seem kind
of counterintuitive, like why would you want
to break a drug? Right, exactly. They're actually
a really essential early step in making better
medicines. They really give us those critical
insights into the vulnerabilities of a drug,
and that lets scientists design treatments that
are stable, effective, and safe. So it's like,
you know, that whole thing, what doesn't kill
you makes you stronger. Exactly. You're basically
making the drug stronger. Yeah, you're making
it stronger by by stressing it out. That's really
fascinating. Yeah. It's amazing to think about
all that work that goes into it, like even, you
know, when I'm just taking like a simple over
the counter pain reliever. Right. I never think
about all the steps that it took to get there.
Right. Right. And it's it really speaks to how,
you know, rigorous the science is. Yeah. that
goes behind every single medication, even that
simple pain reliever, it started as a molecule
in a lab. It had to go through this complex manufacturing
process. They had to choose just the right packaging
to keep it safe and stable. It's a whole journey
for that little pill. It is, and that journey
is all about ensuring the quality of the medicines
that... that we all use. Yeah, I'm definitely
going to think about that the next time I take
anything. Yeah. Well, thanks for joining us for
that deep dive today. It was fascinating. My
pleasure. To our listeners, be sure to tune in
next time as we explore. Yes. Another exciting
topic in the world of pharmaceuticals. Until
then. See ya. Bye bye.