132 – Quality Control in Continuous Manufacturing (S9E12)

All right, welcome back, everyone, to the Deep
Dive. We're diving into a topic today that's
pretty central, I think, to a lot of the changes
we're seeing in pharma. Yeah, it really is. We
talked a lot on the show about how medicines
are made, and a lot of those conversations, we
tend to touch on the older, kind of traditional
batch processes. Right, right. The way things
have always been done, but. Sort of the tried
and true, yeah. There's this big, I don't know
if you'd call it a sea change, but there's this
big shift that's happening towards continuous
manufacturing. Definitely. Yeah, it's a big deal.
And with that, so many questions come up about
like, how do you make sure that the quality of
the medicines that are being made in this new
continuous way are just as good, just as safe
as the ones that we're used to? Yeah, that's
really the million dollar question, right? I
mean, you're changing the entire paradigm of
how you're making these very important products.
Absolutely. And so there's a lot of scrutiny
on how do you make sure that the quality is maintained.
For our listeners, you know, some of you are
really deep in the weeds of pharmaceutical manufacturing,
but a lot of you are just tuning in because you're
curious. Yeah, yeah. And maybe you've heard this
term, continuous manufacturing. Uh -huh. You
just want to wrap your head around like, OK,
what does this mean for the quality of the medicines
that I might eventually end up taking? Yeah,
absolutely. And I think the good news is that
there are a lot of really smart people thinking
about this problem. That's good. And that's what
we're going to talk about today, right? Yeah,
yeah. So for those who maybe need just a little
refresher. Right? The difference between continuous
and batch is, you know, used a good analogy before,
like making a big pot of something. That's batch,
right? Right. You do all these steps, you mix
it all up, and then you test it at the end. Continuous
is more like an assembly line where things are
just flowing continuously. Yeah. And so when
we talk about quality and continuous manufacturing,
it's a whole different ballgame. Right. It is.
It is. So today, we're really going to focus
on three key things. We're going to talk about
real -time release testing, which is this really
exciting area. So wait, hold on. Real -time release
testing, so like you're testing it as it's being
made? Exactly. That's wild. Exactly. So that's
a huge change from waiting till the end to test
it. Right. Then we're going to talk about P .E.
process analytical technology, which is really
the workhorse of real time release testing. It's
all the fancy sensors and instruments that allow
you to measure things in real time. And then
we'll talk about dynamic process monitoring,
which is how you use all that data from PAIT
to actually control the process and make sure
that it's running smoothly. So we're talking
about a lot of technology here. We're talking
about a whole different way of thinking about
quality. We are, and that's what makes this so
fascinating. Yeah, absolutely. Because it's not
just about doing the same things we used to do,
but faster. It's about doing them differently.
Right. And using technology to actually improve
the quality. OK, so let's go back to basics for
a second. Like, how was quality traditionally
checked, I guess, in the context of batch manufacturing?
Yeah, so traditionally, and this is still done
in many cases, you make your batch, your big
pot, you've cooked it up, you let it cool, and
then you take a sample of that batch. Okay. You
send it off to a lab and you do all sorts of
tests. You test for identity, for potency, for
purity. All the things that are gonna make sure
it's safe and it does what it's supposed to do.
Exactly, exactly. You wanna make sure there's
no contaminants, it has the right amount of the
drug, all of those things. Okay. And so that
batch... is essentially on hold. Oh, right. While
you're waiting for those test results to come
back. And that's kind of where the time lag comes
in, right? Exactly. And that's fine if you're
doing batch manufacturing, because everything's
kind of stop and start anyway. Right. But when
you move to continuous, you can't afford to have
those hold times. Right, right. Because you're
trying to keep this flow going, you can't just
put everything on pause. Exactly. Imagine an
assembly line just stopping every few feet because
you're waiting for a quality check. It would
completely defeat the purpose. So that's what
makes this whole shift in quality control so
crucial. It is. And I think one of the key things
we see in a lot of the sources is this idea of
a structured approach to pharmaceutical development.
Okay, what does that mean? It's essentially this
idea that you're thinking about quality from
the very beginning of the process. Oh. And not
just tacking it on at the end as an afterthought.
So, drug development from discovery to market.
talks about this. And it really emphasizes that
quality needs to be built into the very design
of the manufacturing process. So it's not just
about checking the quality at the end. It's about
designing a process that's inherently going to
produce high quality. Exactly. It's like, you
know, when you build a house, you don't just
hope that it's going to be safe at the end. Right.
You build it with safety codes in mind from the
very beginning. You have the inspector come in
and check things along the way. Exactly. And
that's really the mindset shift that we're seeing
with Continuous manufacturing. That's fascinating.
Okay, so this built -in quality that sounds Great
in theory, but how does it actually work in practice?
Well, that's where this concept of real -time
release testing, RTRT, comes in. Right. We touched
on that earlier. Yeah. So instead of waiting
till the very end to test the quality, you're
doing it continuously throughout the process.
So you're basically taking measurements as the
drug is being made. Exactly. You're monitoring
things like the concentration of the drug, the
particle size, moisture content, all those critical
quality attributes. But how do you actually take
those measurements in real time? That's where
PILOT comes in. Process analytical technology.
And this is really a suite of tools, a toolbox,
if you will, of various analytical techniques.
So we're talking about things like spectroscopy,
which uses light to analyze the chemical composition
of a material, or chromatography, which can separate
and identify different components of a mixture.
And then there are all sorts of sensors that
can measure things like temperature, pressure,
flow rate. So you're basically building these
sensors right into the manufacturing equipment.
Exactly. And the beauty of Payt is that it allows
you to do all of this in real time without having
to stop the process. Right. Because you can't
take a sample out and send it off to the lab
if you're trying to keep this continuous flow
going. Exactly. So Payt gives you this continuous
stream of data about what's happening in the
process. So you're essentially watching the process
unfold in real time, kind of like a live feed.
Yeah, that's a great analogy. And if something
starts to go wrong, you can catch it immediately
and hopefully correct it. Precisely. And that's
really the power of PAIT, right? It's not just
about measuring things. It's about using those
measurements to control the process. OK, so how
does this real time monitoring and control actually
work in practice? What are you looking for? So
you're looking at those critical quality attributes,
the CQAs that we mentioned earlier. Right, the
things that are essential to make sure that the
medicine is safe and effective. Exactly. So things
like... Potency, which is the amount of the active
ingredient. OK. Purity, making sure there's no
contaminants. Right. And then things like particle
size and moisture content, which can affect how
the drug dissolves and is absorbed in the body.
And all of these things can be monitored and
controlled in real time using tape. Exactly.
So you set up these control limits for each CQA.
So basically a range that's acceptable. Right.
And as long as the measurements are staying within
those limits, you know your process is running.
smoothly and if they start to drift outside of
those limits that's when the alarms go off and
you know you need to take some action so it's
like having these built -in safety nets all along
the way exactly and that's a huge shift from
the traditional approach where you only find
out about problems at the very end right when
it's potentially too late exactly yeah and so
with continuous manufacturing and Pate you're
really moving towards this idea of preventative
quality control okay so you've got all these
sensors all this data coming in right That must
be a lot to handle, I imagine. It is. And that's
where data analytics comes in. And increasingly,
artificial intelligence. Oh, yeah. We've talked
about AI a lot on the show. And for good reason,
right? Because these systems can handle huge
amounts of data and actually make sense of it
in a way that humans just can't. So you're using
AI to analyze all this data coming from the sensors
and help you make decisions about the process.
Exactly. So for example, AI can be used to identify
trends in the data that might indicate a problem
is developing. Oh, wow. So even before it actually
becomes a problem. Exactly. So you can take corrective
action before things go out of spec. OK, that's
really powerful. It is. And this is an area where
AI is really starting to shine in pharmaceutical
manufacturing. So all of this new technology,
this new way of thinking about quality, what
does it mean for the traditional quality control
methods? Are they all just going to disappear?
It's a good question. And I think the answer
is, it's not a black and white situation. Some
traditional methods are definitely being adapted
for use in continuous manufacturing. OK. So for
example, dissolution testing, which is a very
common test to see how quickly a drug dissolves
in the body. Right, right. That's now being done
in line. as the drug is being made. Oh, wow.
So you don't have to take a sample out and do
it offline. That makes sense. And content uniformity,
which is making sure that each tablet or capsule
has the same amount drug. Right. That can also
be monitored in real time now. So it's not just
that these tests are being done faster. It's
that they're being integrated right into the
manufacturing process. Exactly. And that's a
really important point. OK, so are there any
traditional tests that are still going to be
necessary? even with all this new technology?
I think so. There are certain tests that are
really hard to do in line, like stability testing,
where you have to see how the drug holds up over
time. You can't really accelerate that. And the
regulators are still going to want to see those
results, right? Yeah, absolutely. And then there's
final release testing, where you do this really
comprehensive analysis of the finished product
to make sure it meets all the specifications.
So it's not a complete replacement. It's more
like an evolution. Exactly. It's about using
the best tools for the job, whether they're traditional
or new. Okay, so we've talked a lot about the
technology, but what about the regulations? Right.
Are the regulators on board with this whole continuous
manufacturing thing? Yeah, that's a really important
question. And I think the answer is... Increasingly,
yes. Good. So the FDA, for example, has been
very supportive of continuous manufacturing.
Good to hear. They see the potential benefits,
not just for efficiency, but also for quality.
OK. Because if you're doing things right, continuous
manufacturing can actually lead to more consistent
products. Right, because you have so much more
control over the process. Exactly. And so the
FDA has been putting out guidance documents and
working with companies to help them implement
continuous manufacturing in a way that meets
all the regulatory requirements. So it's not
like they're just letting anything go. They're
still holding companies to those same high standards.
Absolutely. And if anything, the standards are
even higher in some cases. OK, why is that? Because
continuous manufacturing can be more complex.
Right, right. And so you need a really robust
quality management system in place to make sure
that everything is under control. And that's
something that comes up in our sources a lot,
right? Yes, definitely. The importance of a quality
management system or QMS. Yes. And that's basically
the framework that ensures that all aspects of
quality are being addressed. OK. So it covers
things like documentation, training, deviation
handling, risk management. So it's not just about
the technology. It's about having the right.
systems and procedures in place as well. Exactly,
and that's something that the regulators are
really focused on. Okay, so what about the starting
materials? Right. The raw ingredients that go
into making the drug. Yes, the quality of the
starting materials is absolutely crucial. And
in continuous manufacturing, it's even more important
because any variability in the starting materials
can have a ripple effect throughout the whole
process. So you're basically amplifying any problems
if you're not starting with high quality materials.
Exactly. And so there's a lot of emphasis on
having a really good understanding of your supply
chain and making sure that your suppliers are
meeting all the quality requirements. OK, so
we've talked about a lot of different aspects
of quality control in continuous manufacturing.
Right. But I think it's important to circle back
to one of the main reasons why companies are
so interested in continuous manufacturing in
the first place. Yeah. And that's the potential
for faster cycle times. Exactly. So how does
all of this we've been talking about, how does
it contribute to that? So if you think about
the traditional approach with batch manufacturing,
there are all these hold times built into the
process. Right. You're waiting for test results.
You're transferring material from one step to
the next. Right. Right. All of that takes time,
but with continuous manufacturing, you're eliminating
a lot of those whole times. Okay, how so? Well,
for one thing, you're doing a lot of the testing
in real time, so you don't have to wait for those
results. Right, right. And because the process
is continuous, you're not having to stop and
start all the time. So the material is just flowing
smoothly from one step to the next. Exactly.
And that can lead to some pretty significant
time savings. Okay, so what are some of the real
world benefits of these faster cycle times. I
think one of the most important is that it can
potentially lead to faster delivery of medicines
to patients. Right, because if you can manufacture
the drug faster, it can get to the people who
need it sooner. Exactly. And that can be a huge
benefit, especially for patients with serious
illnesses. Absolutely. And I imagine there are
also cost savings involved, right? Definitely.
So if you can manufacture the drug faster, You're
using your equipment more efficiently. You're
potentially reducing your inventory costs. Right,
because you're not having to store as much material
for as long. Exactly. And so all of that can
contribute to lower manufacturing costs, which
can ultimately benefit patients as well. OK,
so we've talked a lot about the theory and the
technology. Right. But are there any real world
examples of companies actually doing this? Yeah,
that's a good question. And I think the answer
is it's still early days. OK. Continuous manufacturing
is really just starting to gain traction in the
pharmaceutical industry. OK. But there are definitely
some companies that are leading the way. OK,
like who? Well, I'm not going to name any specific
companies, but there are some big names out there
that are investing heavily in continuous manufacturing.
And they're starting to see some really promising
results. OK, like what kind of results? Well,
for example, some companies are reporting that
they've been able to reduce their manufacturing
cycle times by as much as 50 percent. Wow, that's
huge. It is. And that's not just a theoretical
number, that's real world data. That's really
impressive. Yeah. And it really shows the potential
of continuous manufacturing to transform the
way that we make medicines. So it's not just
about making things faster. It's about making
them better. Exactly. And that's what's so exciting
about this field. OK. So to wrap up today's deep
dive, I think it's safe to say that continuous
manufacturing is here to stay. I think that's
a pretty safe bet. And it's really changing the
way that we think about quality control. It is.
And it's all about be more proactive, more data
-driven, and more focused on building quality
into the process from the very beginning. And
ultimately, that's all good news for patients,
right? Absolutely. Because it means that we're
going to have access to safer, more effective
medicines that are produced more efficiently.
That's what it's all about. And so as we see
more and more companies adopting continuous manufacturing,
it's going to be really interesting to see how
this field continues to evolve. Especially with
AI and all those advancements that we talked
about. Exactly. And so as we wrap up, here's
a question for our listeners to ponder. As continuous
manufacturing becomes more sophisticated and
we start to rely more and more on AI to monitor
and control the process, what's the role of human
oversight? How do we ensure that we're not just
turning everything over to machines? It's a really
interesting ethical question I think that we
need to be thinking about. Definitely food for
thought. And a good place for us to leave it
for today. Thanks for joining us on the Deep
Dive. Yeah, thanks everyone.