99 - Analytical Methods in Formulation Testing (S7E9)

ever stop to think, like really think, about
how a pill or a liquid medicine, whatever you
or someone you know might take, how it always
seems to be just the right dose. Not too strong,
not too weak, and it works the same way every
single time. But how do we actually know that's
gonna happen? How do they make sure? So that's
a great question. Today, we are diving deep into
a world that, honestly, most folks probably don't
think too much about, but is so crucial. analytical
methods in formulation testing. You know, those
tests and checks that scientists do to make sure
every single dose of medicine is exactly what
it should be. Now, looking at all the stuff you
sent over, especially that transcript, what was
it called? 99 analytical methods in formulation
testing. I think it was from season seven, episode
nine. Yeah, that's the one. It's obvious this
whole area is like... the bedrock of pharmaceutical
quality. So our mission in this deep dive is
to break it all down, you know, make it clear
how these methods work, but more importantly,
why they matter so much for the medicines we
depend on. OK, let's unpack this. Absolutely.
So. To start with, we've got to understand that
analytical methods are really the foundation
for making sure any drug, like whether it's a
pill, a capsule, an injection, whatever, has
the right identity, we'd be 100 % sure what that
substance actually is. Right. And then, of course,
its strength, or what we call potency, which
basically means the exact amount of the active
ingredient in it. And of course, there's the
whole quality thing. Does it meet all the standards?
Is it pure? Meaning, does it have any nasty contaminants
in it? Makes sense. So we'll be looking at some
of the key techniques that scientists use, both
when a new drug hits the market for the first
time and then... you know, how they keep checking
it over time to make sure it stays stable and
effective. Okay. And a really important part
of this whole thing is of course the industry
standards. Those super strict rules and the expectations
set by those regulatory bodies like the FDA,
they're the watchdogs making sure drug companies
are doing everything right to keep patients safe.
So basically we're talking about the science
that makes sure every medicine you pick up from
the pharmacy is safe and it actually does what
it's supposed to do. Precisely. And by the end
of this deep dive, hopefully everyone listening
will get a much better grasp on, you know, the
hows and the whys behind drug quality and why
all these processes are in place to protect us
as patients. So let's kick things off with the
big question. Why are these analytical methods
so essential? It all boils down to quality and
performance. Okay. Making sure that every single
batch of a drug that's made Every single one
consistently meets the exact specifications.
It's not enough to just be kind of close. Each
unit, every tablet, every milliliter has to be
right on the money. So it's about total consistency.
Like no matter when you buy that medicine, whether
it's today or year for now, that first pill is
going to be identical to the last one. Exactly.
And there are several pieces to this. First,
there's verifying the amount of the active ingredient,
you know, the stuff that actually makes the medicine
work. Like if a bottle says 500 milligrams, you
better believe scientists are making sure there's
exactly 500 milligrams in there, plus or minus
a tiny, tiny bit. Got it. Then there's the checking
for. You know, anything that shouldn't be there.
Things that might form as the drug gets older,
or maybe got in there accidentally during manufacturing.
We call those degradation products and impurities.
Ah, so like making sure there's nothing harmful
lurking in there, right? Right, or if something
is there that it's below a safe level. And the
third part is making sure the physical stuff
is right too. So like, if it's a cream, does
it spread easily? If it's a pill, is it hard
enough to swallow, but will it also dissolve
properly in your body? That's called dissolution
testing. Interesting. So it's not just about
the chemicals themselves, but how the medicine
is actually put together, you know, its form
and how that might affect how it works in the
body. Yeah, absolutely. All this testing is basically
to guarantee that a drug will do its job properly
throughout its whole shelf life. Because if it
breaks down too quickly or it doesn't dissolve
properly, it's not going to work as well. Makes
perfect sense. So when does all this testing
actually happen? I'm guessing it's not just one
big test at the end. No, you're right. It's a
multi -stage process. One critical stage is what
we call product release testing. So these are
the tests that are done on every single batch
of a drug before it can leave the factory. end
up on the pharmacy shelves. Think of it as the
final quality control check, like the last hurdle
before it gets to the patients. The gatekeeper.
Exactly. So this is where they confirm that the
product meets all those standards we talked about,
identity, strength, quality, and purity. And
what kind of tools these scientists use for these
tests? I know the transcript we have for this
episode doesn't go into a ton of detail about
the specifics, but I've seen some of the other
materials you shared, and it seems like they've
got a pretty amazing arsenal of techniques. Oh,
absolutely. You're right. The transcript might
not list every single method, but there are some
key ones that are used all the time in pharmaceutical
analysis. OK. Chromatography, for example, is
a big one. Chromatography. Yeah, especially techniques
like HPLC, which stands for High Performance
Liquid Chromatography, and GC, which is gas chromatography.
Basically, these methods separate out all the
different molecules in a sample. Like, think
of it as sorting them by size or some other property.
Yeah. And that lets us identify and measure them.
Wow. HPLC is particularly amazing because it
can separate really complex mixtures, like think
about all this stuff in a pill. It has incredible
resolution, which means we can spot even tiny,
tiny amounts of impurities. Wow. GC is especially
helpful for those volatile compounds, the ones
that easily turn into a gas. Huh, interesting.
And then there's spectroscopy. Spectroscopy?
Yeah, like UV vis spectroscopy. infrared spectroscopy
or IR for short NMR which stands for nuclear
magnetic resonance and that one gives us all
kinds of information about the structure of the
molecule. And then there's mass spectrometry,
which is hinted at in pharmaceutical analysis.
These techniques basically use different types
of light or magnetic fields to identify and measure
different substances based on how they interact.
Okay. It's kind of like giving each substance
a unique fingerprint. That's incredible. I mean
the level of detail and precision they can achieve
is mind -boggling. It is. But sometimes those
good old -fashioned methods are still really
important. Oh really? Like what? Like titration,
for example. That's a classic technique that's
been used for ages to figure out the exact concentration
of a solution. OK. And then there are all those
physical tests we mentioned earlier, like for
tablets. There's the dissolution test, hardness
test, and something called a friability test,
which basically measures how easily a tablet
will crumble. So think of everything. They try
to. Yeah. All of these tests together, all these
different techniques, give a really complete
picture of whether a drug is good to go before
it ever reaches a patient. So that product release
testing is really like that final safeguard to
make sure that every medicine that makes it out
there meets the strictest standards. But once
it's made and it passes all those tests, how
do we know it's going to stay effective over
time? Doesn't it like degrade or go bad eventually?
Well, that's where stability assessment comes
in. OK. So stability testing is all about figuring
out how a drug changes over time and under different
conditions. Think about it. Medicines can be
exposed to all kinds of environments. It might
get too hot or too cold, too humid, or even be
exposed to sunlight. Right. So stability testing
tries to mimic all those different conditions,
but in a controlled way. So they're basically
putting the drugs through, like a science -backed
version of accelerated aging? Kind of, yeah.
So they store the drug under all these different
stress conditions, harsher than normal, and also,
under those ideal conditions, the ones you see
on the label, like store at room temperature
for long periods of time. OK. And then... at
set times, maybe every few months or so, they
pull out samples and test them using those same
analytical methods we talked about earlier. And
that's how they know how long a medicine will
last, right? Exactly. The stability tests help
determine the shelf life. which is that expiration
date you see on the bottle. And they figure out
the best way to store it too. Like, does it need
to be refrigerated or kept away from light, things
like that. That makes sense. Oh, and it's worth
mentioning that there are internationally agreed
upon guidelines for this whole stability testing
thing. You know, like the ICH guidelines mentioned
in season three, the process of new drug discovery
and development, and season five, safety evaluation
of pharmaceuticals and medical devices, international
regulatory guidelines. ICH stands for the International
Council for Harmonization of Technical Requirements
for Pharmaceuticals for Human Use. That's a mouthful.
It is. But basically, it means that scientists
all over the world try to follow the same rules
for drug development and quality. That's good
to know. So it sounds like there's a very well
-defined rule book for all of this. But who exactly
sets these standards for analytical methods and
all the testing? Well, in the U .S., a lot of
it comes down to the FDA. The Food and Drug Administration.
Yep. And other countries have their own regulatory
agencies, too. These agencies are responsible
for public health, so they have very, very strict
rules for how analytical methods are used in
drug testing. They don't mess around. I bet.
So one thing you mentioned was this process called
validation in the context of these analytical
methods. What exactly does that mean? So method
validation is all about proving that a specific
testing method does what it's supposed to do.
OK. It has to produce results that are accurate
and that can be reproduced every time. Right.
And that means proving several things. First,
accuracy, meaning that the method actually gives
you a result that's close to the real value.
So if there are actually 500 milligrams in that
pill, the test better say it's close to 500 milligrams.
Right. Then there's precision, which means if
you test the same sample over and over, you should
get pretty much the same result every time. So
it's like hitting the bullseye every time is
accuracy, and then precision is like all the
arrows being really close together. Yeah, that's
a good way to put it. Yeah. And both are crucial
because if a drug is inaccurate, meaning it's
consistently giving the wrong dose, or if it's
imprecise and varies a lot from dose to dose,
that could have serious consequences for patients,
right? Absolutely. And then there's specificity,
which means that the test can accurately measure
just the thing you're interested in without being
thrown off by anything else that might be the
mixture. OK. And sensitivity, which is super
important for drugs that are given in low doses,
as mentioned in season seven formulation and
analytical development for low dose oral drug
products. Right. Because in those cases, you
need to be able to detect even tiny, tiny amounts
of impurities. Got it. And lastly, there's robustness,
which means that the method still works even
if there are slight changes in the conditions.
OK. So it's not enough to just have a test that
seems to work, you got to prove it. You got to
prove it. Prove it with solid evidence that it's
reliable and it's going to give you the right
answer every time. And all of this is regulated
by those good manufacturing practices or GMP,
which are highlighted in season six, the Certified
Pharmaceutical GMP Professional Handbook. GMP
regulations are basically the rule book for making
medicines. Okay. And they require the use of
these validated analytical methods and they require
super detailed documentation of every single
step of the testing process. Everything has to
be recorded and traceable, no cutting corners.
So there's no room for error. Not really. And
then there are also those pharmacopias like the
European Pharmacopia, the Japanese Pharmacopia,
and the United States Pharmacopia, mentioned
in Season 8, merged U48. What are those exactly?
So those are like official books, essentially,
that lay out standard methods for testing lots
of different drugs and substances. and they provide
a baseline for quality testing. And there's this
initiative called ICHQ4B that's trying to make
sure these pharmacopias are all compatible with
each other, which would make things a lot easier
for everyone, especially for companies that want
to sell their drugs in different countries. It's
really incredible when you think about it, all
the layers of checks and balances that are in
place to ensure the quality of our medicines.
But I'm guessing that developing these really
robust and reliable analytical methods is no
easy feat. especially with all the complex drugs
out there these days. Oh, you are absolutely
right. It's a huge challenge, especially when
you're dealing with formulations that are really
complex, like, you know, combination drugs that
have several active ingredients in them, or when
you have a totally new drug that no one's ever
tested before. So, like, what kinds of challenges
do scientists face when they're trying to develop
these methods? Well, selectivity is a big one.
Selectivity. Yeah. So remember how we talked
about how a test has to be able to pick out the
specific ingredient you're interested in without
getting confused by anything else that's in there?
Well, that can be really tricky, especially when
you've got all these other inactive ingredients
in the mix, what we call excipients. And then,
of course, there might be some degradation products
forming over time, too. So you've got to make
sure your test can ignore all that stuff and
just focus on the active ingredient. Right. So
like separating the wheat from the chaff. Exactly.
And then there's sensitivity, which we mentioned
before. If you're working with a drug that's
given in very small doses, you need a test that
can pick up even the tiniest amounts of impurities.
So that could be a big hurdle, too. OK. And then
there's the stability of the analyte itself.
The analyte. Yeah, that's just the fancy scientific
term for the thing you're trying to measure.
Right. So some analytes could be. quite unstable
once they're in a solution. Like they might start
to break down before you can even measure them.
Oh, that doesn't sound good. Not at all. If that
happens, your results are going to be all over
the place. Right. So what can scientists do to
get around these challenges? Well, it often starts
with a lot of trial and error, honestly. They
have to tweak and refine the testing method until
they get it just right. OK. And luckily, there
are always new and better analytical techniques
being developed. Technology is constantly evolving,
which helps a lot. And of course, once they think
they have a good method, they have to validate
it, remember. I've got to prove it works. Exactly.
They have to show that it's accurate, precise,
specific, sensitive, and robust. But the work
doesn't stop there. Even after a method's been
validated and is being used routinely, they have
to keep monitoring it just to make sure it's
still performing as expected. It seems like a
lot of work, but it's clearly essential. It's
amazing to see how much goes into ensuring the
quality of our medicines. And it's not just about
testing the final product, is it? I know from
some of the other stuff we've been looking at
that these analytical methods are used much earlier
in the drug development process, too. Absolutely.
They're really crucial throughout the entire
process, from the very early stages of discovery
all the way through to postmarket surveillance.
For example. In those pre -clinical studies,
the ones that are done in animals before a drug
is ever tested in humans, analytical methods
are used to measure how much drug is in the animal's
blood or tissues. So they're figuring out, like...
how the drug moves through the body. Right, how
it's absorbed, distributed, metabolized, and
excreted. We call that pharmacokinetics, which
we discussed in season two basic pharmacokinetics
and season three basic pharmacokinetics. Okay.
And then later on when scientists are trying
to figure out the best way to formulate a drug,
like whether to make it into a pill, a capsule,
an injection, or something else. They use analytical
methods to test things like the solubility of
the drug, which is discussed in Season 6 Handbook
of Solubility data for pharmaceuticals. And then,
of course, they have to test how stable those
different formulations are. And even in clinical
trials, when a new drug is being tested in people,
they use these analytical methods to measure
the drug levels in the patient's bodies, which
helps them understand how the drug is working
and whether it's safe and effective. So it's
really a continuous process. Wow, that's fascinating.
It really highlights how vital analytical methods
are to the entire pharmaceutical industry and
ultimately to public health. I mean, every time
someone takes a medicine and it works, it's partly
because of all this incredible scientific work
that's happening behind the scenes. These methods
are the unsung heroes of drug safety and efficacy.
I couldn't agree more. They're the guardians
working tirelessly to make sure that all those
medicines out there are consistently safe, effective,
and top -notch quality. So let's wrap things
up with some key takeaways for our listeners.
What are the most important points you want them
to remember? Okay, so the big picture is that
analytical methods are absolutely essential for
making sure that all drug products, everything
from pills to injections to creams, have the
right identity, the right strength, the right
quality, and are free from harmful impurities.
And this isn't just a one -time check at the
factory. It's an ongoing process that starts
when a drug is first made and continues throughout
its shelf life. those strict industry standards
and the oversight from those regulatory agencies,
plus all the work that scientists are doing to
develop better and better analytical methods,
all of that comes together to protect patients
and make sure that the medicines they rely on
are safe and effective. And that brings us to
our final thought for you, our listener. Think
about all those incredible new medicines that
are being developed these days. Things like biologics
and nanomedicines, which are mentioned in season
three pharmacokinetics and pharmacodynamics of
biotech drugs and season seven nanoparticles
for drug delivery. These are incredibly complex
therapies and they're pushing the boundaries
of what's possible in medicine. But how do you
think those analytical methods we've been talking
about today are being adapted to make sure these
new treatments are safe and effective? How do
you ensure the quality of something that's so
cutting edge and so intricate? It's definitely
something to ponder, isn't it? Absolutely. It's
a huge challenge, but it's one that scientists
are tackling head on. And if you're interested
in learning more about this fascinating field,
there are tons of resources out there, like from
the FDA or the ICH. But for now, we'll leave
you with this question. What do you think is
the single most important aspect of ensuring
drug quality through analytical testing? We'd
love to hear your thoughts. Thanks for joining
us on this deep dive. We'll see you next time.