88 – Risk Management in Process Scale-Up (S6E13)

Okay, so you're listening to this deep dive because
you want to learn a little bit more about how
to manage the risk when you're scaling up a chemical
process, right? Yeah, that's a... a really important
step in the whole drug development process, moving
something from the lab to the plant. Absolutely.
And there's a lot that can go wrong. And I think
we both know from looking at all this OPR &D
literature that people really do encounter all
kinds of interesting and sometimes scary situations.
Oh, yeah. You don't want to be the one calling
your boss in the middle of the night because
the reactor's on fire. No. Absolutely not. So
the point of today is to kind of go through some
of these things and talk about how we can identify
the risks, but also what we can do to either
prevent them from happening or have a plan B,
a contingency plan, if something does go wrong.
And I think a good place to start would be to
just kind of highlight some of the key risks.
You know, what are some of the things that can
happen? Because I think a lot of people when
they think about scaling up, it's just, oh, we're
just making more. But it's not just about making
more, right? No, not at all. You can get a very
different reaction outcome when you move from
a small scale to a large scale. And I think a
lot of that has to do with the fact that you're
changing the equipment. You're going from something
that's maybe a round bottom flask with a stir
bar in it to a huge reactor that has a completely
different type of agitation and different ways
of heating and cooling. And so the way that the
heat is distributed in the reaction mixture can
be very different. Yeah, and that was one of
the things that really jumped out at me when
we were going through some of these OPRD papers
was just how many times people mentioned unexpected
behavior. whether it was the formation of some
kind of impurity that they hadn't seen before
or the reaction just not going to completion
or and this is one that I was kind of fascinated
things like crystallization where at a small
scale it crystallizes beautifully but then you
get to a big reactor and all of a sudden you've
got this gooey mess you know yeah and crystallization
is so important for purification right so if
you can't control the crystallization then you're
gonna have a really hard time getting a pure
product absolutely Do you have any specific examples
from OPR &D that come to mind of a situation
like that? Yeah, actually there was one where
they were making this It was a corral benzo something
or other. I don't remember the exact name, but
the interesting thing was that on a small scale
they could remove this protecting group and everything
was fine, but when they tried to do it on a larger
scale the protecting group just wouldn't come
off. So they were stuck with this intermediate
that they couldn't convert to the final product.
And they had already presumably done all the
work to develop this synthetic route. Right?
So to have it fail at that late stage, because
of something that seems so simple, I mean, removing
a protecting group, you wouldn't think that that
would be the make -or -break step. Right. And
that's the thing with scale -up, is that you
have to look at every single step in the process
and really think about how it's going to behave
when you change the scale. Because even something
that seems trivial can become a major problem
when you're dealing with large quantities. So
it's not just the main reaction, it's every single
step along the way. The work -up, the purification,
everything. Exactly. You got to think about it
all. And it's not just the chemistry, either.
It's the engineering, too. Like, how are you
going to mix this reaction mixture? How are you
going to heat it or cool it? What kind of reactor
are you going to use? All of these things can
affect the outcome. Oh, yeah. The choice of reactor
is huge. You know, you've got batch reactors,
continuous flow reactors, and each one has its
own pros and cons. And then there are all kinds
of different designs within those categories.
So, yeah, I mean, it's a whole discipline in
itself. just figuring out the right equipment.
It really is. And you know, another thing that
we see a lot in OPRND is problems with impurity
formation during scale up. You know, maybe you
get a little bit of an impurity in the lab and
it's not a big deal, but when you scale up, that
impurity can become a major problem because it
might be toxic or might be difficult to remove.
And it seems like there are a lot of different
reasons why you might see an increase in impurities
when you scale up. I mean, sometimes it's just
that you're starting with different raw materials
or you're using a different solvent, and that
can have a big impact on the purity of the product.
Oh, absolutely. I mean, even something as simple
as the order of addition can make a difference,
you know? If you add things in a different order
on a large scale than you did on a small scale,
you might get different impurities. And then
there's always the issue of controlling the temperature,
right? because if you have a large reaction mixture,
it can be hard to keep the temperature uniform
throughout the whole thing. And if you have hot
spots or cold spots, that can lead to the formation
of unwanted byproducts. Yeah. And controlling
the temperature is especially important for exothermic
reactions where you're generating a lot of heat.
If you can't remove that heat fast enough, the
reaction can get out of control and... Well,
you don't want to be around when that happens.
Yeah, safety is a huge concern when you're scaling
up. I mean, you're dealing with much larger quantities
of chemicals. So the potential consequences of
an accident are much greater. For sure. That's
why it's so important to do a thorough risk assessment
before you even start scaling up a process. You
need to identify all the potential hazards and
then figure out how you're going to mitigate
them. What does a risk assessment actually involve
in the context of process chemistry? Well, it
starts with identifying the hazards. You know,
what are the chemicals that you're using? What
are their properties? Are they flammable? Are
they toxic? Are they corrosive? And then you
need to think about the process itself. What
are the temperatures and pressures involved?
What kind of equipment are you using? Are there
any potential sources of ignition? Once you've
identified the hazards, then you need to assess
the risks. You know, how likely is it that something
will go wrong? And if something does go wrong,
what are the potential consequences? So you're
looking at both the likelihood of a problem occurring
and the severity of that problem if it does occur.
Exactly. And then based on that risk assessment,
you can start to develop mitigation strategies.
You know, how are you going to reduce the likelihood
of a problem? And if a problem does occur, how
are you going to minimize the consequences? And
those mitigation strategies can take many different
forms. It could be anything from changing the
process to using different equipment to implementing
safety procedures. Right. And it's important
to remember that there's no one -size -fits -all
solution. the best mitigation strategies will
depend on the specific process and the specific
hazards that you're dealing with. Absolutely.
And that's why it's so important to have a good
understanding of both the chemistry and the engineering
involved, because you need to be able to think
critically about the process and identify potential
problems before they occur. Yeah, and you need
to be able to work with the engineers to come
up with creative solutions, because sometimes
the best way to mitigate a risk is to change
the process altogether. And sometimes it's as
simple as using a different solvent or changing
the order of addition. But the key is to be proactive
and to think about these things before you start
scaling up. Absolutely. An ounce of prevention
is worth a pound of cure, as they say. That's
definitely true in the world of process chemistry.
So let's talk a bit more about some of the specific
strategies that can be used to mitigate risks
during scale up. You mentioned earlier that sometimes
you might need to develop an alternative synthetic
route. Can you give us an example of that from
the OPRND literature? Sure. There was this one
paper where they were trying to make this myed
ketone, and their initial synthetic route involved
isolating these liquid enones, which were really
difficult to handle on a large scale. And then
they had to distill these bromo ketones, which
are pretty nasty compounds to work with. So they
had a couple of steps in there that were inherently
risky just because of the nature of the materials
they were dealing with. Exactly. So what they
did was they went back to the drawing board and
they came up with a completely new synthetic
route that avoided those problematic intermediates
altogether. So they essentially redesigned the
synthesis to make it more scalable from the get
go. Exactly. And that's often the best approach
if you can do it because if you can design out
the risk then you don't have to worry about mitigating
it later on. And that was one of the things that
I found really interesting when we were looking
through these papers was how often people would
talk about designing for scalability right from
the beginning. It's not just about coming up
with a synthesis that works in the lab, it's
about coming up with a synthesis that can be
readily translated to a larger scale. Right,
and that means thinking about things like the
availability and cost of raw materials, the ease
of purification, the stability of the intermediates,
and the overall safety of the process. So you're
essentially trying to anticipate potential problems
and address them before they even arise. Exactly.
It's a lot like playing chess, you know? You're
trying to think several moves ahead and anticipate
your opponent's moves. That's a great analogy.
And it highlights the fact that process chemistry
is as much about strategy and planning as it
is about technical expertise. Absolutely. And
that's why it's such a challenging and rewarding
field to work in. Definitely. So you mentioned
catalyst deactivators earlier as a way to manage
impurity formation. Can you elaborate on that
a bit more? Sure. So as we discussed, when you
scale up a reaction, you sometimes see an increase
in the formation of impurities. And one reason
for that can be that the catalyst is too active.
So it's not just catalyzing the reaction you
want, it's also catalyzing other side reactions
that lead to impurities. Exactly. And one way
to address that is to use what's called a catalyst
deactivator. This is a substance that binds to
the catalyst and reduces its activity. So you're
essentially making the catalyst less efficient?
but in a controlled way, so that it still catalyzes
the main reaction, but is less likely to catalyze
side reactions. Exactly. And by fine -tuning
the amount of catalyst deactivator that you use,
you can optimize the selectivity of the reaction
and minimize the formation of impurities. It's
a bit like putting a leash on a very energetic
dog. You still want the dog to be able to run
and play, but you don't want it to run wild and
get into trouble. That's a great analogy. And
there was a good example of this in one of the
OPRND papers, the one of about the synthesis
of Dunpezel. They were doing a hydrogenation
reaction and they found that they were getting
a lot of impurities when they scaled up. Presumably
because the hydrogenation catalyst was also catalyzing
other unwanted reactions. Exactly. So what they
did was they added a catalyst poison to the reaction
mixture. And by carefully controlling the amount
of poison that they used, they were able to suppress
the formation of those impurities and get a much
cleaner product. So they were able to essentially
tame the catalyst and get it to do what they
wanted it to do. Exactly. And it's a really powerful
technique because it allows you to fine -tune
the selectivity of a reaction without having
to completely redesign the process. So it's a
very elegant solution. And it highlights the
fact that process chemistry is often about finding
these clever little tweaks that can make a big
difference. Absolutely. It's all about understanding
the subtleties of the chemistry and finding ways
to manipulate it to your advantage. So we've
talked about designing for scalability. We've
talked about catalyst deactivators. What are
some other strategies that can be used to mitigate
risks during scale up? Well, one really important
strategy is to use in process controls or IPCs.
What are those exactly? So IPCs are basically
measurements that you take during the process
to monitor how things are going. So you're essentially
keeping a close eye on the reaction as it's happening.
Exactly. And the goal is to catch any problems
early on before they have a chance to get out
of hand. What kind of things are you measuring?
It depends on the process, but some common things
that you might measure include temperature, pressure,
pH, and the concentration of reactants, products,
and impurities. And how do you actually take
those measurements? There are all sorts of different
techniques that can be used, but some common
ones include spectroscopy, chromatography, and
spectrometry. And are these measurements typically
done manually, or are they automated? It depends.
For some simple measurements, you might be able
to do them manually. But for more complex measurements,
or if you need to take measurements very frequently,
it's usually best to automate the process. And
I imagine that the use of automation is becoming
increasingly common in process chemistry, as
it is in so many other industries. Absolutely.
Automation is a great way to improve efficiency
and reduce the risk of human error. So you mentioned
that the goal of IPCs is to catch problems early
on. What happens if you do detect a problem?
Well, the first thing you need to do is try to
figure out what's causing the problem. And once
you know what's causing the problem, you can
start to think about how to fix it. And sometimes
the fix might be as simple as adjusting the temperature
or the pressure. Right. But sometimes it might
be more complicated. You might need to change
the solvent or the catalyst or even the entire
process. And I imagine that those decisions are
not always easy to make. especially when you're
under pressure to get the product out the door.
Absolutely. But it's important to remember that
safety and quality always come first. So if you
detect a problem, you need to take the time to
investigate it properly and make sure that you're
addressing the root cause. That's good advice.
So we've talked about designing for scalability.
We talked about catalyst deactivators. We talked
about IPCs. Are there any other important strategies
for mitigating risks during scale up? Well, one
thing that we haven't really talked about yet
is contingency planning. Right. That was one
of the things on our list. What is contingency
planning exactly? So contingency planning is
basically about thinking about what could go
wrong and having a plan in place to deal with
it. So you're essentially preparing for the worst
case scenario. Exactly. And the goal is to minimize
the impact of any problems that do occur. What
are some common things that people plan for?
Well, some common things that people plan for
include equipment failures, power outages, and
raw material shortages. So you're thinking about
things that are outside of your control. Right.
Because even if you do everything right, sometimes
things just go wrong. And it's important to be
prepared for those situations. What are some
examples of contingency plans? Well, for example,
if you're worried about an equipment failure,
you might have a spare piece of equipment on
hand. Or if you're worried about a power outage,
you might have a backup generator. You're essentially
creating redundancies in your system so that
if one part fails, you have a backup. Exactly.
And that's really important, especially when
you're dealing with a large scale process. Because
if something goes wrong, it can have a huge impact
on production. Absolutely. So contingency planning
is all about being proactive and thinking about
what could go wrong before it actually happens.
Exactly. And it's an important part of any risk
management strategy. So we've talked about a
lot of different strategies for mitigating risks
during scale -up, but I think it's important
to emphasize that there's no one -size -fits
-all solution. The best approach is going to
depend on the specific process and the specific
risks that you're facing. Absolutely. And that's
why it's so important to have a good understanding
of both the chemistry and the engineering involved,
because you need to be able to think critically
about the process and identify potential problems
before they occur. Right. And you need to be
able to work with a team of experts, including
chemists, engineers, and safety professionals,
to develop a comprehensive risk management plan.
Exactly. Because scaling up a chemical process
is a complex undertaking, and it requires a team
effort to do it safely and effectively. And it's
a really important part of the drug development
process because it's the bridge between the lab
and the market. Absolutely. And if we can do
it right, we can bring new medicines to patients
faster and more efficiently. and hopefully without
any explosions along the way. That would be ideal.
Well, this has been a fascinating deep dive.
I've learned a lot about the challenges and the
rewards of process scale up. It's been my pleasure.
Thanks for joining me. Anytime. So for everyone
listening, I hope this has given you a better
understanding of the complexities of moving a
chemical process from the lab to the plant. And
I hope it's inspired you to think critically
about the risks involved and the strategies that
can be used to mitigate them. Because at the
end of the day, it's all about bringing new medicines
to patients safely and efficiently. And that's
a goal worth striving for. So until next time,
keep on learning, keep on innovating, and keep
on diving deep.