82 – Impurity Profiling & Control Strategies (S6E7)

All right, diving in today, and I'm excited about
this one. We're going deep on something most
people probably don't think about much, but it's
really, really important. Impurity profiling
and how those are controlled. It's kind of behind
the scenes, but yeah, super important. Exactly.
And you sent over a really cool collection of
sources, stuff on drug development, the actual
manufacturing processes, and of course, the regulations.
Can't forget those. What we're aiming for today
is to break down, you know, really get to the
nuts and bolts of how companies make sure the
meds we all take are safe. And a huge part of
that is finding and dealing with any impurities.
So we're going to dig into the methods they use,
look at some real world examples, give everyone
listening a good grasp of this whole world that's
kind of hidden within drug production. It's like
you get your medicine, you trust it's going to
work, right? But behind that trust. There's this
whole system making sure what you're swallowing
is exactly what it should be and nothing it shouldn't.
That's a great way to put it. So much goes into
it that we never see. And honestly, kind of scary
to think about what could happen if they didn't
do this. Oh, absolutely. You know, you hear about
those rare cases where there's a contamination
issue. That's why this whole impurity control
thing is not just like an optional extra. It's
really fundamental. It's about safety, plain
and simple. And that's where those regulations
come in. They're the backbone of this whole thing.
They drive the whole process. Totally. And as
we talk about specific examples, you'll see exactly
how those rules shape what manufacturers actually
do. OK, so let's get down to it. How do scientists
even find these impurities, these like tiny little
unwanted bits. I mean, we're talking microscopic
level here. Yeah, it's pretty amazing. Right.
So what are the tools? What are they using? Well,
one that popped up a bunch in what you said,
especially when they were talking about chiral
drugs, was HPLC, high performance liquid chromatography.
Sounds intimidating, but... Super precise. Yeah.
From what I read, it's like the ultimate sorting
machine. That's a good way to think about it.
It's like you have this complex mixture, right,
your drug sample, and HPLC can separate out each
individual component, and not just separate them,
but measure them too. So you know exactly what's
in there, the good stuff, the active ingredient,
but also any impurities lurking around. And with
chiral drugs, it gets even cooler. Which, just
to remind everyone, those are the ones that exist
in two mirror image forms, like our hands, a
left and a right version. Exactly. And sometimes,
only one of those forms is the actual medicine.
and the effective one. The other one could be
totally useless, or even worse, cause problems.
Could even be harmful. Right. So HPLC can tell
them apart. That's why it's so powerful in this
context, that ability to do such specific separation.
So crucial. Makes you realize it's not just about
what's there. It's about the specific version
of it too. Now, another technique that came up
was NMR, nuclear magnetic resonance. Now, I always
picture that as like a way to map out the structure
of a molecule. Is that right? Yeah, you got it.
NMR is fantastic for figuring out that whole
molecular architecture, how all the atoms are
linked up, the whole blueprint. But here's where
it gets even better for impurity profiling. We're
not just using NMR to ID what the impurity is
anymore, but also to say exactly how much of
it is present. So it's about quantifying it.
Exactly. It's becoming super reliable for measuring
those unwanted bits. So you get the ID and the
quantity all in one go. That's amazing. Two birds,
one stone. And often, working hand -in -hand
with NMR, we have mass spectrometry, or MS. I
remember reading that together. They're like
the dynamic duo for unraveling the mysteries
of unknown impurities. They really are. It's
like NMR gives you the blueprint, right? And
then MS comes in, and basically it weighs the
pieces of that blueprint. By looking at those
weights, we can figure out what an impurity is,
even if we've never encountered it before. And
when you use high -resolution MS, you get...
crazy accurate ID. One of the sources you sent
talked about LCHRMS, which is just liquid chromatography
hooked up to high resolution MS. That's a mouthful.
I know, right? But it's incredible tech. And
they used it to identify and measure NDMA in
ranitidine. NDMA, this nitrousamine impurity,
it caused a whole bunch of recalls and investigations.
That was huge news a while back. It was. And
it just goes to show you how powerful and important
this kind of impurity profiling can be. It's
not just science for the sake of science. It
has real -world implications. For sure. For sure.
Now, shifting gears a bit, let's talk about another
kind of impurity that might be lurking. Elements.
For this, it seems ICP -MS is the tool of choice.
Inductively coupled plasma mass spectrometry.
So we're talking about things like detecting
metal residues or other elemental stuff. Spot
on. ICP -MS is the go -to for measuring elemental
impurities in drugs. And these could come from
various sources. Maybe there was a metal catalyst
used during synthesis and some of it stuck around.
Or maybe it's naturally occurring elements that
were in the starting materials. Oh, so it's not
always like contamination in the factory sense.
Not necessarily. Sometimes it's just like inherent
to the stuff they're working with. But the challenge
with ICP -MS is that you often get interferences.
This means one element, or ion, can mask the
signal of another one because they have similar
masses. Like trying to pick out a single voice
in a crowded room. Exactly. A classic example
is argon, which has an atomic mass of 40 interfering
with calcium, which also has a mass of 40. So
how do they differentiate? How do they tell those
apart? Well, they have some clever tricks up
their sleeves. ICP -MS instruments often have
collision or reaction. cells to deal with this
problem. OK, break those down for us. What are
those? Sure. So in a collision cell, they introduce
a low reactivity gas, something like hydrogen,
into the path of the ions. This gas collides
with the ions. And because interfering ions tend
to be a bit bigger or have a slightly different
charge, they lose more energy in these collisions
compared to the analyte ions, which are the ones
we want to measure. And that energy difference
can be used to separate them out. The downside
is that the analyte ions can also lose some energy,
so our ability to detect really, really low levels
might be slightly reduced. Reaction cells, on
the other hand, use reactive gases like ammonia
to selectively react with the interfering ions,
changing their mass so they no longer overlap
with what we're trying to measure. But here,
the challenge is making sure that reaction is
super specific so it only affects the interfering
ion and not the analyte. So a lot of fine -tuning.
Yeah. The choice between these approaches depends
on a bunch of factors, but ultimately it comes
down to which one gets rid of the interference
and still lets them detect the impurity at the
level they need. You know, one of the sources
mentioned that for calcium detection, a reaction
cell using ammonia is way more sensitive than
a collision cell with hydrogen, simply because
it does a better job at eliminating that pesky
argon interference. So it's not just about, does
it work? It's about Does it work best for this
particular analysis? Exactly. Wow, it's amazing
how much complexity goes into just figuring out
what's in these meds, even at that tiny scale.
It's mind boggling for sure. So once you've got
all these fancy tools to pinpoint potential impurities,
what happens next? How do manufacturers actually
control them during the whole manufacturing process?
That's where the rubber meets the road. It's
where the science of chemistry meets the practicality
of engineering. And it's all about designing
processes that build in controls to minimize
the formation of impurities from the get -go
and, of course, remove any that do pop up. So
it's kind of a two -pronged approach. Prevention
and cleanup. You got it. And process optimization
is key here. It's all about tweaking the conditions
to get the best outcome. One of the OPR and D
sources had this great example where they were
making a certain compound and they had this impurity,
they called it bisform impurity D, that was forming
during the synthesis. What kind of tweaks are
we talking about? Well, in this case, they played
around with the amount of DMF, which is a common
solvent, and the speed at which they added another
ingredient, carbonyl imidazole. And by carefully
adjusting those two things, they were able to
dramatically reduce the amount of that pesky
byproduct. It's like a recipe, isn't it? Like,
changing the order you add ingredients or how
much you use can totally change how the dish
turns out. Exactly. And crystallization is another
key player in this control game. It's often thought
of as just getting the drug into a solid form,
you know, those nice little crystals you see.
But it's actually a really powerful way to purify
things, too. There is this really cool example
in one of the sources about how they use different
solvents like IPAC and methanol to improve the
optical purity of a salt form. Remind us again,
optical purity meaning? Right. So that means
making sure you have the right proportion. of
the two mirror image forms. If you only want
the left -handed version, you want to make sure
there's not too much of the right -handed one
mixed in. And what they found was that this particular
impurity, a hemi -salt, was forming and messing
up their attempts to get that pure drug they
were after. But by picking the right solvent
combo, they could essentially dissolve away the
hemi -salt and crystallize out the pure form.
It's like using solubility to do your dirty work.
Neat. So you're not always trying to react the
impurity away. Sometimes you can just kind of
dissolve it away. Yeah. We also saw stuff about
using scavengers to remove specific types of
impurities. Oh, yeah. Scavengers are super useful,
especially when you use metal catalysts in the
synthesis, like palladium, which is pretty common.
You've got to make sure none of that metal ends
up in your final product. And that's where scavengers
come in, these substances that basically grab
onto the metal and pull it out. They just like.
Snatch it up pretty much activated carbon, you
know, like charcoal is a common one. It just
absorbs a bunch of stuff But they also use more
specific chemicals like TMT or L cysteine, which
is an amino acid TMT being oh, right. Sorry two
hundred and four six trimer capitos triazine.
That's a mouthful Tell me about it. But anyway,
the interesting thing they talked about was using
L cysteine because it could avoid having to do
another filtration step to get rid of the activated
carbon and that's important because from a good
manufacturer practice or GMP standpoint, they're
always worried about Potential contamination
from the carbon itself getting into the final
product. You don't want to solve one problem
just to create another Exactly. So even the choice
of scavenger isn't just about whether it works
or not It's about all these other factors like
practicality and safety. Absolutely makes sense
Now another technique that sounded super cool
almost futuristic was continuous flow chemistry
Oh, yeah, that's definitely a hot area in pharma
manufacturing instead of doing reactions in big
batches They use this like mini chemical factory,
a network of tubes where they pump the reactants
through. Yeah, kind of. And because of that,
they can control all those reaction parameters
super precisely. Temperature, pressure, how long
the ingredients are reacting. And that fine -tuned
control can really cut down on those unwanted
byproducts, leading to a much purer product right
from the start. One of the articles you shared
mentioned using continuous flow for making these
complex molecules where timing is everything.
Because if the timing's off, you get the wrong
stuff. Exactly. And that precision is what helps
them avoid those impurities that might pop up
if the reaction isn't perfectly timed. It's fascinating.
So much more control than just dumping everything
in a big vat and hoping for the best. And then
to make sure things are on track... They're these
in -process monitoring techniques, right? Absolutely.
They're like having little checkpoints along
the production line. Techniques like thin -layer
chromatography or TLC, which is a quick and easy
way to check what's in a mixture, gas chromatography
or GC, which separates things based on how easily
they evaporate, and even NMR can be used to monitor
the reaction as it's happening. This way, scientists
can see right away if any impurities are starting
to form and make adjustments to the process before
things get out of hand. It's all about keeping
a close eye on things. Makes total sense. All
right, we've covered a lot of different methods,
and it's been super interesting. But let's bring
it back to the real world for a second. Those
OPRND sources you sent over had some great case
studies that really show how this all comes together.
Let's talk about them. OK, so remember that enantiomeric
purity upgrade we were talking about earlier,
where they had that hemi -salt forming and messing
things up? Oh yeah, the one where they figured
out the right solvent combo. That's the one.
They didn't just stumble on that solution, it
was systematic. They really dug deep into understanding
the chemistry, the properties of the drug, and
the impurity. And they even used NMR to confirm
the structure of that hemi -salt, which helped
them figure out which solvents to use. It's a
great example of how this isn't just trial and
error. It's about using analytical thinking to
guide the process. Totally. And the one about
using L -cysteine to remove palladium, that was
a good one, too. They specifically chose L -cysteine
over activated carbon, because remember, they
were worried about carbon contamination. and
needing an extra filtration step. It really highlights
how GMP considerations are woven into every decision
they make. It's not just about the chemistry
working in a lab setting. It has to be safe and
reliable for large scale production. Can't cut
corners when people's health is on the line.
Exactly, and then there's that other example
where they tweaked the synthesis to reduce that
bis -form impurity D. They started with a method
that used a lot of DMF, which was a pain to remove,
not very practical for large -scale production,
but by changing the rate they added one of the
reactants and optimizing the solvent system,
they got the impurity levels way down consistently.
That kind of process refinement, it's crucial
for making sure you have a drug product that's
high quality batch after batch. Consistency is
key. Definitely. And it's so clear that all these
methods, all these control strategies, they're
not just some theoretical stuff. They're directly
tied to meeting those strict safety standards
set by regulatory agencies all over the world.
Couldn't agree more. And even though we didn't
get into the nitty gritty details of those regulations
today, it's important to remember that they drive
everything in this field. They're not guidelines.
They're requirements. And if manufacturers don't
identify and control impurities properly, the
consequences can be serious. We're talking about
the effectiveness of the drug and, even more
importantly, patient safety. So these efforts,
all these details we've been talking about, they're
the foundation for making sure the medicines
we all depend on are as safe as they can be.
Well said. So as we wrap things up, what are,
like, the big takeaways, the things you really
want people to walk away with from this deep
dive into the world of impurity profiling and
control. I think the main thing is I hope they
have a better appreciation for the complexity,
how much goes into making sure our meds are pure.
It's not just one thing, it's layers and layers.
You've got these incredible analytical tools
to find even the tiniest amounts of unwanted
stuff. And then you've got this whole science
of designing and controlling the manufacturing
process to prevent those impurities in the first
place. place or get rid of them efficiently.
And those real -world examples, those case studies
we talked about, they really bring it all home,
show how these principles are put into action
day in and day out to make sure the medicines
that people rely on are safe and effective. It's
been a real eye -opener for sure. And I believe
everyone has something to think about, a question.
With all the amazing advancements in technology,
both in the analytical tools and in manufacturing
itself, how do you think our ability to find
and control impurities, even at those incredibly
tiny levels, is going to evolve in the future.
And how might that impact drug safety? What about
developing totally new kinds of therapies? It's
exciting to think about. There are so many possibilities.
Right. It's a fascinating area for sure. Thanks
for joining us for this deep dive. My pleasure.
Always fun to geek out about this stuff.