107 – FDA & ICH Guidelines Overview (S8E2)

OK, so think about it. You go to the pharmacy.
You pick up a new prescription, right? You've
got that little box, maybe a bottle of pills
or something. Yeah. But like, have you ever thought
about how many steps it took to get to that point,
you know, for that medicine to get into your
hands? It really is a fascinating process when
you start to peel back the layers. I mean, there's
so much cutting edge science involved and years
of research and just an incredible amount of
hard work from so many people. Right. And then
there's this whole other side to it that most
people probably don't even think about. This
whole framework of regulations, all these rules
that have to be followed. Yeah. I mean, it's
a whole hidden world, really. But it's absolutely
essential to make sure that everything is done
properly and safely. Yeah. And I mean, for good
reason, right? These rules are really there to
protect our health. I mean, that's the bottom
line. It's to make sure that every single medicine
that we take is safe and that it's actually going
to work. Exactly. It's all about making sure
that the medications people are taking are effective
and that they're not going to cause any harm.
So in today's deep dive, we're going to sort
of take a journey into that hidden world. We're
going to explore some of the most important guidelines
that govern the development of new medicines.
And specifically, we're going to focus on those
coming from the FDA, the Food and Drug Administration
here in the U .S., and also the ICH, the International
Council for Harmonization. Now, I know this might
sound like some pretty dry acronyms, but trust
me, once we start to unpack the ideas behind
them, it's really going to become clear why these
guidelines are so vital for all of us. And that's
really our goal today, right, to kind of demystify
some of these maybe seemingly complex regulations
and to show how they actually have a real impact
at every stage of how a drug is made, you know,
starting from that initial discovery in a lab
all the way through to the point where it's actually
being manufactured and ultimate ending up in
our medicine cabinets. Exactly. We really want
to sort of pull back the curtain on this whole
process. So we're going to focus on the core
principles that underpin these guidelines, you
know, the big ideas of safety and quality. We're
also going to take a look at some of the key
documents that are involved. And of course, we
have to talk about the FDA's role in all of this,
how they oversee the whole process. Right. The
FDA plays a crucial role in making sure that
everything meets those standards. Yeah, absolutely.
And then we'll touch upon how countries are working
together to try to harmonize these roles on a
global scale. Which is a huge undertaking, but
incredibly important for bringing new medicines
to patients worldwide. For sure. OK, so maybe
let's start with the basics. You know, why do
we even need all these guidelines in the first
place? Like, what's the fundamental reason for
all of this? Well, it's pretty straightforward
when you think about it. Both the FDA and the
ICH guidelines, they all share this one fundamental
goal, and that is protecting public health. That's
the foundation of everything. OK, makes sense.
And they do this by setting these really strict
standards to ensure that medicines are safe.
They actually work to treat the conditions they're
designed for and that they are made. consistently
to a high level of quality. It's really a universal
commitment to making sure that people are going
to benefit from the medicines that they take.
So it's not just like someone in an office somewhere
just like coming up with rules randomly, right?
No, not at all. These are really grounded in
science. Exactly. They're not just arbitrary.
I mean, these guidelines, they're really built
on a solid base of scientific principles, and
they reflect just the vast knowledge and experience,
really, that's accumulated over decades of pharmaceutical
research and development. Yeah. I mean, you think
about it, they've probably learned a lot over
the years. Oh, absolutely. And these guidelines
have evolved. They've learned from successes,
but also from some of the past failures that,
unfortunately, have happened in the industry.
But. always with that aim of preventing any potential
harm to patients and making sure they're truly
benefiting from the treatments that they receive.
That makes a lot of sense. OK. So now let's talk
about kind of the key players here. OK. We've
mentioned the FDA and the ICH. Can you give us
just a little bit more background on sort of
who they are and what their specific roles are?
Yeah. So the FDA, like you said, is the regulatory
authority here in the United States. It's a government
agency and they have a lot of responsibilities.
I mean, I think about food, cosmetics, tobacco.
All sorts of things. But in terms of like drug
development, their main job is to oversee the
entire life cycle of a medicine. Okay. From the
very beginning to the end. like the earliest
testing. Yeah, so you're talking like the preclinical
testing, then the clinical trials where you're
actually testing it in humans. And then even
like the manufacturing process, right? How the
drug is actually made on a large scale. Yeah.
And then ultimately they decide whether or not
a drug can actually be sold on the market here.
So they really act as like. A gatekeeper, I guess
you could say. Right. They're the ones making
sure that only medicines that meet these incredibly
rigorous safety and efficacy standards are actually
available to patients in the U .S. Okay, so that's
the FDA sort of like the National Guardian of
our medicines here in the United States. So what
about the ICH? You said it's an international
body. How does that fit into the global picture?
Okay, so the ICH stands for the International
Council for Harmonization of Technical Requirements
for Pharmaceuticals for Human Use. Wow! A mouthful.
It's a mouthful. But it's a really, really important
organization. What they do is bring together
regulatory authorities. So like, you know, the
FDA, but from different countries, right? And
also the pharmaceutical industry from all over
the world. So you've got the U .S., Europe. Japan
and others all coming together. Okay. And their
main goal is to try to harmonize the technical
requirements for pharmaceutical products. So
harmonize. What does that mean practically speaking?
Well, basically it means they're trying to create
like a more consistent set of guidelines that
everybody can follow. So for example, they work
on things like, you know, what kind of testing
do we need to do to prove that a drug is safe?
What are the standards for its quality and what
kind of evidence do we need to show that it actually
works? Makes sense. And the idea is that if we
can all sort of get on the same page with this,
if we can have these common standards, then it
can really reduce a lot of unnecessary duplication
of effort. Right. Because otherwise, you could
have companies doing one set of tests for the
US, another set for Europe, another set for wherever
else. Right. So the idea is to streamline that.
make it more efficient on a global scale. And
I guess ultimately if it's more efficient that
could potentially mean getting new medicines
to patients more quickly. Exactly. I mean if
pharmaceutical companies don't have to jump through
a million different hoops in each country then
theoretically they can develop and you know make
those new medicines available to patients all
over the world much faster. So it's really about
making the international process more efficient,
but without cutting any corners when it comes
to safety or quality, right? Yeah, absolutely.
It's finding that balance, right? You want to
be sure that the process is streamlined and efficient,
but of course, never at the expense of patient
safety. Yeah, that's a really important point.
OK, so I think now we've got a good sort of overview
of kind of the why behind these guidelines and
who the major players are. Let's get into some
of the specifics, starting with safety. So what
are some of the key safety requirements that
the FDA and the ICH focus on? Well, I think it
goes without saying that safety is like the top
priority, right? I mean, it's absolutely paramount.
And it's addressed right from the very beginning
of drug development. I mean, before a drug is
ever given to a human, even before it goes into
clinical trials, it goes through a ton of testing.
Right. And that's called preclinical study. Preclinical,
so before the clinic. Before it gets anywhere
near humans, right. And these preclinical studies
are just crucial. I mean, they're really the
foundation for understanding how safe a drug
might be. And so what kinds of studies are we
talking about here? Is this all like happening
in a lab? Yeah, so initially it's all lab work.
It's a combination of what we call in vitro and
in vivo methods in vitro in vivo Those sound
very scientific they do but they're actually
pretty simple concepts Okay, break it down for
us. So in vitro literally means in glass Okay,
so it refers to studies that are done in test
tubes or with cell cultures Okay, so in a controlled
environment outside of a living organism exactly
and then in vivo means in living organisms. OK.
So those studies involve testing in living creatures.
Like animals? Yeah, most often as animal models.
OK. For instance, in cancer drug development,
one of the sources we looked at, the Anti -Cancer
Drug Development Guide, talks about using certain
mouse models, like the L1210 and P388 leukemias.
OK. And they've been historically used to see
if a potential cancer drug actually has any effect
on the cancer cells. OK, so they're testing these
drugs on animals to see how they interact with,
like, a living biological system. Exactly. So
what are they looking for? What kind of information
are they trying to get from these preclinical
studies? Well, they're looking for a whole range
of potential safety issues. OK. And they're trying
to understand how the drug is absorbed into the
body. Where does it go once it's in the body?
You know, we call it distribution. How does the
body break it down? It's metabolism. And then
how does the body get rid of it? How is it eliminated
or excreted? And that's often referred to as
ADME, those four processes together. ADME, okay,
got it. But they're also looking for any signs
of toxicity or harmful effects, of course. So
they're trying to see if the drug is damaging
any organs or systems in the body. Exactly. For
example, they might use ex vivo preparations.
Ex vivo. Now there's another one. Okay, so ex
vivo means like they take tissues or organs out
of an animal, right? Okay. And they study them
in a lab setting. So they're outside of the body,
but they're still like living tissues. So for
example, they might use like perfused guinea
pig hearts to see if a drug might cause this
heart rhythm problem called QT prolongation.
QT prolongation? That sounds serious. It is serious.
It's basically a change in the heart's electrical
activity that can be really dangerous. One thing
that's important to note here is that sometimes
the concentrations of the drug that are needed
to see these effects in these models, they might
not actually reflect the levels that a patient
would experience in their body. So it might not
be a realistic scenario. Exactly. So that's something
that scientists always have to consider when
they're interpreting the results of these preclinical
studies. You know, just because something happens
in a lab dish at a really high concentration
doesn't necessarily mean it's going to be a problem
for a patient. Right. Because the dose that someone
would actually take is probably much lower. Yeah,
that's the key. So we have to be careful about
drawing conclusions from these early studies.
It's all part of the process, but it's not the
whole picture. Makes sense. OK, so. What happens
after these initial preclinical studies? What's
the next step in figuring out if a drug is safe?
So the next step is to do more in -depth studies
called toxicology studies. Okay. And these are
specifically designed to really try to identify
any potential adverse effects that the drug might
have. Okay. And to figure out what doses would
be safe to use when they actually start testing
the drug in humans. So they're still working
with animals at this point? Yeah. Typically,
okay, and they're looking at how the drug affects
different organs and systems in the body, you
know over different periods of time Okay, and
a range of doses because that's important right
to see how the effects change as the dose increases
makes sense so they're really trying to understand
the full spectrum of potential ways a drug could
be harmful that's the goal and a really critical
part of ensuring safety is understanding how
the body actually processes the drug, you know,
what we call is metabolism because it's really
important to know if the drug might interact
in a dangerous way with other medications that
a patient might be taking. Right. Drug interactions.
Exactly. And this is a big one. You can have
two drugs that seem perfectly safe when they're
taken on their own, but if you take them together,
they can interact and cause all sorts of problems.
So that's something that they have to study very
carefully. Absolutely. There's a book called
Drug Interactions in Pharmaceutical Development.
And it really emphasizes just how critical it
is to understand these interactions. And they
actually give this really interesting example.
This interaction between Jimfribrazil, which
is a cholesterol -lowering drug, and rapaglinide.
which is a diabetes medication. OK. And when
you take these two drugs together, the effect
on blood sugar levels was much stronger than
expected just based on how each drug worked individually.
So the combination was much more potent than
either drug on its own. Yeah. And it really highlighted
how important it is to investigate these mechanisms
very, very thoroughly. And luckily now, you know,
we've got these in vitro approaches. So these
lab based studies that are actually designed
to try to predict these potential drug interactions
before they even happen in people. Oh, wow. So
they're trying to anticipate these interactions
in the lab to prevent them from happening out
in the real world. That's the goal. It's all
about trying to be proactive. That's really amazing.
It seems like there are a lot of checks and balances
in place to make sure that a drug is going to
be safe before it even gets to the point of being
tested in people. Yeah, absolutely. There are
a lot of steps involved, and it's a very rigorous
process. And actually, the FDA has rules in place
to prevent companies from making claims about
a drug's safety or effectiveness before it's
been thoroughly reviewed. Yeah, I can see why
that would be important. You wouldn't want companies
making promises that they can't keep or giving
people false hope. Right. Exactly. So they have
to wait until the FDA has given them the green
light. Yeah. And there's actually a book that
we looked at called FDA Regulatory Affairs. And
it mentions specifically that you can't promote
an investigational drug as safe or effective
before it's gone through the whole FDA review
process. I mean, that would be incredibly misleading
and could actually put people at risk. Right,
because people might make decisions about their
health care based on information that's not actually
accurate. Yeah. OK, so that gives us a good overview
of the safety requirements. Let's switch gears
now and talk about quality. What are some of
the main aspects of quality that these guidelines
address? OK, so. When we talk about quality in
pharmaceutical development, it's all about consistency.
It's about making sure that every single badge
of a drug is manufactured to meet this very specific
set of standards. And it's also about making
absolutely sure that it's free from any kind
of contamination. Of course, that's super important.
Yeah. And a really important part of this is
what we call good manufacturing practices, or
GMP. GMP. Yep. I'm sure you've heard that term
before. Yeah, definitely. I've seen it on like
drug labels and stuff, but I'm not really sure
what it actually entails. Right. Well, GMP is
basically this whole system of regulations and
guidelines that cover every single aspect of
the manufacturing process. Wow. It's really comprehensive.
OK. It covers like everything from the raw materials
that are used to make the drug to the facilities
and equipment that are involved, even to the
training of the people who work in those facilities.
So everyone involved has to be Properly trained.
Yeah, absolutely Everyone has to know exactly
what they're doing and it's all about having
these very very detailed procedures Written down
and document it Okay to ensure that both the
active ingredient in the medicine what we call
the API or active pharmaceutical ingredients
Okay, and the final drug product that patients
receive are both of the highest possible quality
So it's like a really, really detailed instruction
manual for how to make drugs correctly. That's
a great way to put it. OK, can you give us some
specific examples of what GMP looks like in practice?
Absolutely. So for instance, one thing that GMP
requires is very detailed, written procedures
for how to clean and sanitize all of the equipment
that's used in manufacturing. OK. And even for
the cleaning agents themselves, the chemicals
that they use to clean the equipment. So it's
not just wiping things down with a wet rag. No,
it's much more specific than that. And one of
the sources that we looked at, validated cleaning
technologies, talks about how important these
procedures are. And the reason is that it's crucial
to prevent any kind of cross contamination. So
you don't want any residue from one drug ending
up in another drug. Exactly. Or even contamination
between different batches of the same drug. Yeah,
I can see how that would be a big problem. Yeah.
So what else? OK, so another thing that GMP covers
is how all of the components containers and closures
are handled and stored. So like the vials and
the bottles and the caps and all that? Exactly.
Okay. And there are strict rules about how they
have to be handled and stored to prevent contamination,
to prevent mix ups, and also to prevent any kind
of degradation of the materials themselves. You
know, you want things expiring or getting damaged.
Yeah, of course not. So where are all these rules
actually written down? Well, a lot of them can
be found in Title 21 of the Code of Federal Regulations,
specifically Part 212. OK, so the CFR. Yeah,
like the Bible of Federal Regulations. So it's
everything down to how you clean the machinery
and how you store the packaging that's regulated
to make sure the final product is safe and effective.
Exactly. And another really important part of
GMP is documentation. They have to keep meticulous
records of everything. Okay, like logs and stuff.
Yeah, detailed logs of every step of the production
process. And this is super important because
they have to be able to review those records
to make sure that every single step was carried
out according to the approved procedures. Okay.
And also to look for any deviations or unexpected
events that might have happened during manufacturing.
You know, did something go wrong? Did something
not go according to plan? They need to document
all of that. And there's another source. the
certified pharmaceutical GMP professional handbook
that really stresses just how critical this record
review process is. So it's like a constant checking
and double checking to make sure everything is
done right and that if there are any problems
they're caught and dealt with immediately. Yeah
and that's really the essence of GMP. It's all
about having systems in place to prevent errors
and to ensure the quality of the final product.
Okay. Now, I've also heard the term quality by
design or QBD. How does that fit in with GMP?
Yeah, so QBD is a really interesting concept.
It's kind of like the next level of quality assurance.
It's a more proactive approach. Okay. Instead
of just, you know, testing the final product
to see if it meets the standards, QBD is all
about understanding and controlling the entire
manufacturing process from the very beginning.
So you're trying to design a process that will
consistently produce a high quality product.
That's exactly it. And one of the sources we
looked at, Comprehensive Quality by Design, goes
into a lot of detail about this. It talks about
how important it is to understand the critical
quality attributes of a drug. OK, so what are
those? So those are basically the characteristics
of the drug that are really important for its
safety and efficacy. You know, things like its
purity, its potency, its stability. OK. And QBD
is all about figuring out what those critical
quality attributes are and then designing a manufacturing
process that will consistently produce a product
that meets those specifications. So it's like
a more holistic approach to quality control.
Yeah, exactly. It's not just about checking the
boxes at the end. It's about building quality
into the process from the very beginning. OK,
so how do they actually do that? How do they
build quality into the process? So one of the
key elements of QDD is something called the design
space. And that's basically the range of operating
conditions for the manufacturing process that
have been scientifically proven to consistently
produce a product that's of acceptable quality.
So they figure out the sweet spot, the conditions
where everything works perfectly. Exactly. And
then they put in place a control strategy to
make sure that the process stays within that
design space. You know, they're constantly monitoring
things and making adjustments as needed. OK.
And regulatory agencies, like the FDA, are now
really pushing for this QBD approach. So they
want to see companies implementing these more
sophisticated quality control systems. They do,
because they see it as a much more robust way
to ensure quality. OK, so that's QBD. Now let's
talk about impurities. We touched on that earlier
when we were talking about the API, the active
ingredient itself. But how did the FDA and ICH
guidelines address the issue of impurities in
the final drug product, the one that patients
actually take? Yeah. So controlling impurities
is a huge part of ensuring drug quality and safety.
And there's an ICH guideline, Q3BR, that specifically
deals with this. And one of the books we looked
at, Safety Evaluation of Pharmaceuticals and
Medical Devices, goes into detail about this
guideline. And it lays out what types and levels
of impurities are considered acceptable in new
drug products. OK. So there are limits on how
much of any given impurity can be present in
the final product. OK. So they're not saying
that there can be absolutely zero impurities,
just that they have to be below a certain level.
Exactly. It's impossible to have absolutely zero
impurities. OK. but they have to be controlled
and monitored very carefully. And there are even
guidelines for specific types of impurities that
might pose a particular risk. So they're looking
at the specific properties of those impurities
to determine how much of a risk they pose. Yeah.
For example, the FDA has issued guidance on how
to assess and control what are called DNA reactive
impurities. DNA reactive impurities? What are
those? So those are impurities that have the
potential to damage DNA. Okay, that sounds pretty
bad. It can be. They're considered mutagens,
meaning they can cause mutations. OK. And those
mutations can potentially lead to cancer. Oh,
wow. So that's a serious concern. Yeah. So it's
really important to control those very carefully.
And even our own source, the Season 3 Preclinical
Development and IND Enabling Deep Research Source
text, that talks about how important it is to
control these DNA reactive impurities. Okay.
So these are really tightly regulated. They are.
And another one of our sources gives a really
good example of how companies go to great lengths
to control even very specific impurities. Okay.
It's from the FDA's Office of Pharmaceutical
Quality, and it talks about how a company very
carefully controlled the formation of this impurity
called aniline dimer during the synthesis of
their API. Okay. And they had to do that to ensure
the safety of the final product. So it's really
amazing how much attention they pay to detail.
I mean, they're looking for even tiny amounts
of these impurities. Yeah, they have to. It's
all about making sure that the drug is as pure
and as safe as possible. You also mentioned earlier
the physical attributes of the API, things like
its crystal structure are important for quality.
How are those aspects addressed in the guidelines?
Right. So this might seem a little bit technical,
but it's actually really important. So the physical
form of the API can actually have a big impact
on how the final drug product performs in the
body. Okay. So, for example, something called
polymorphism, which is basically how the molecules
are arranged in a crystal structure. Okay. That
can actually affect things like how soluble the
drug is, how stable it is, and even how well
it can be processed during manufacturing. Wow.
So it's not just the chemical formula of the
drug. It's how the molecules are actually arranged
that matters. Exactly. And there's another source
that we looked at, Season 6 Drug Manufacturing
and Process Development Transcripts. And it talks
about how process chemists really have to control
the specific solid form of the API. Okay. Because
they need to make sure that it's consistent and
that they can reproduce it reliably on a large
scale. So it's the same every time. Right. Consistency
is key. And they actually give an example from
the FDA's Office of Pharmaceutical Quality where
controlling the solvent form during the crystallization
process led to a much better yield impurity of
the API. So they tweaked the process to make
the API better. Exactly. They figured out a way
to make it more pure and to get more of it from
the same starting materials. That's really cool.
It seems like they're constantly trying to optimize
these processes to make the drugs as good as
they can be. OK, so we've covered a lot about
safety and quality. Now, how does the FDA actually
get involved in this whole process? It's not
like they just show up at the end and say, OK,
thumbs up or thumbs down. Oh, no, not at all.
They're involved from the very beginning. OK.
The companies that are developing the drugs,
they're called sponsors. OK. And they interact
with the FDA throughout the entire process. There
are all sorts of meetings that they have, both
formal and informal, where they discuss their
development plans. They can ask specific questions,
get feedback from the FDA, get guidance on their
regulatory strategy. So it's really a back and
forth conversation between the people developing
the drug and the FDA. Exactly. It's a dialogue.
And those interactions can be incredibly valuable
because they can help to avoid any surprises
down the road. Okay. For example, a company might
have a pre -IND meeting before they even submit
their investigational new drug application. Okay.
And they'll talk about their pre -clinical data
and their plans for clinical trials. So they're
getting feedback before they even officially
submit their application. Yeah, they're trying
to make sure that they're on the right track.
Okay. So those early interactions with the FDA
are really important. Makes sense. And then,
of course, there's also the whole manufacturing
side of things. I would imagine the FDA plays
a big role in that as well. Yeah, huge. So the
FDA has the authority to inspect manufacturing
facilities, to do audits. OK. And they can do
this both before a drug is approved and also
periodically after it's already on the market.
OK. And the whole point of these audits is to
make sure that the facilities are following those
GMP regulations that we talked about earlier.
OK, so they're checking to see if the companies
are actually doing what they said they were going
to do. Exactly. And they're making sure that
they're consistently producing high quality products.
OK, so it's not just about, you know. doing things
right at the beginning, but it's about maintaining
those standards over time. Yeah, it's an ongoing
process. Yeah, let's talk about the actual applications
that the companies have to submit to the FDA.
What are the key regulatory documents in the
drug development process? Okay, so the first
big hurdle is the IND. the investigational new
drug application. OK. And this is what they have
to submit before they can even start testing
the drug in humans. OK. And the IND includes
a ton of information, all the preclinical safety
data. detailed plans for the clinical trials,
and then this whole section on chemistry, manufacturing,
and controls, what they call CMC. CMC. And one
of our sources, the Season 3 Preclinical Development
in IND Enabling Deep Research Source Text, talks
about how important the CMC section of the IND
is. OK. Basically, they have to provide the FDA
with assurance that they can actually make the
drug consistently and to a high enough quality
standard. OK. So it's not just about like having
a recipe in a lab notebook. They have to show
that they can actually scale up the process.
Exactly. OK. And they call it phase appropriate,
meaning that the level of detail that's required
in the IND actually increases as the drug moves
through the different phases of clinical trials.
So in the early phases, when they're just starting
to test the drug in a small number of people,
they don't need as much information as they do
later on when they're doing larger trials. Yeah,
exactly. It's kind of a tiered approach. OK.
So the IND is basically asking permission to
start testing the drug in people and showing
the FDA that it's safe enough for those initial
studies and that they can actually make it to
a decent standard. That's a good summary. And
then once the clinical trials are completed,
assuming everything goes well.