20 - Quality Risk Management: A Proactive Approach (S15E6)

All right, diving right in today. We're talking
about something really important, especially
when it comes to things like pharmaceuticals
and dietary supplements, quality risk management.
You got it. Or as everyone calls it, QRM. Yeah,
that's it. And we're really looking at this as
like a proactive way of thinking in manufacturing
to make sure that all the things we need to be
safe and effective actually are. Right. It's
not just about checking off the regulatory boxes,
but really kind of fundamentally changing the
way we think about. potential problems. Like,
how can we tackle these things before they even
become a problem? Right, get ahead of them. Exactly.
And so today, in this deep dive, we're going
to really be exploring some of those core principles
of QRM and some of the practical tools that people
use. We're going to be looking at things like
regulations, like 21 CFR parts, 110, 111, and
211. Big ones. Yep, the big ones. And some industry
guidelines as well, like ICH Q9, which is kind
of the big one when it comes to quality risk
management. Yeah, kind of the the Bible, so to
speak. Yes, exactly. So basically, we really
want to give listeners an idea of how manufacturers
are ensuring the quality and safety of their
products using this whole framework of QRM, which
is super important. Exactly. So to get us started,
I guess the first thing we need to do is define
it. Right. For someone who's never heard this
term before, what exactly is quality risk management?
Yeah, that's a great question. At its core, Quality
Risk Management, or QRM, is really a systematic
process. It's how we can assess, control, communicate,
and review risks to the quality of a drug product
throughout its entire life cycle. Okay, the whole
thing. The whole thing. So from its initial development...
all the way through post -market, when it's actually
with the patient. Wow. And yeah, ICH Q9, which
is an international guideline on quality risk
management, really lays out this framework for
us. And one of the most interesting things about
QRM is that it really emphasizes being proactive.
OK, interesting. So it's not just about reacting
to. problems when they happen, but it's about
identifying those potential issues and mitigating
those risks before they ever occur. So almost
like predicting what could potentially go wrong.
Exactly. And using scientific understanding and
data to do that. Got it. And it's not meant to
be a separate activity either. It really needs
to be integrated directly into the pharmaceutical
quality system. OK, so it's woven into the whole
fabric of how things work. Exactly. It's not
an add -on. It's fundamental to how quality is
managed. So if we have this really systematic
approach to looking ahead and trying to identify
potential problems and really integrating it
into how everything functions, what are some
of the principles that guide QRM? Right. So ICH
Q9 highlights two really key principles that
underpin QRM. The first one is that the evaluation
of risk should be based on scientific knowledge,
experience with the process, and ultimately it
links back to patient protection. Right, because
that's the whole point at the end of the day.
Exactly. So we're not just going off of gut feeling
or, you know, just assumptions. We're really
basing it on evidence and data. Yeah. And always
with the patient as the main focus in mind. Right.
So data -driven decisions. Absolutely. Absolutely.
And then the second principle is that the level
of effort, formality, and documentation All of
that is in proportion to the level of risk. So
it's not a one size fits all. Exactly. It's really
scaling the response to the level of concern.
Right. Because we don't want to be spending tons
of time and resources on a small issue, but we
want to be putting a lot of effort if it's a
big risk. Right. Prioritize. Exactly. Prioritize
the highest risks. OK. So that makes a lot of
sense. You really want to be smart about how
you use your resources. Exactly. OK, so now that
we've kind of got an idea of what it is and the
principles that guide it, how does this all work
in practice? Right. So the risk management process,
it generally follows several stages, which are
outlined in ICH Q9. And those are risk assessment,
then risk control, then we move on to risk communication,
and finally risk review. Got it. All right, so
four main stages. Exactly. Exactly. And let's
start with risk assessment. Okay. That's where
we identify and analyze those potential risks.
to quality. And really, it's a three -part process.
OK, so let's break that down a little bit. What
are those three parts? OK, so the first part
is hazard identification. This is where we're
asking what might go wrong. So we're really brainstorming
all those potential things, those hazards, that
could impact the quality of the product. That
could be anything from the equipment to the people.
Exactly. So like you said, equipment, people,
maybe the equipment hasn't been cleaned properly.
Maybe there's an issue with the environment.
Maybe there's the possibility of mix -ups, maybe
with the raw materials, or even the labels on
the product. And then we also think about deviations
from the manufacturing process itself. And actually,
regulations like 21 CFR Parts 110, 111, and 211,
they highlight a lot of these areas where hazards
could occur. Things like sanitation, proper material
handling, all of those are really important.
So the regulations actually point to some of
the potential concerns. They do. They do. They
give us a good starting point for what to look
for. OK. So that's hazard identification. Then
what's the next step in the risk assessment process?
So once we've identified those hazards, then
we move to risk analysis. OK. And here we're
asking, OK, what's the likelihood of that harm
actually occurring? OK. And if it does occur,
how severe would the impact be? Right. So how
bad could it be? Exactly. And sometimes we even
consider detectability, which means, could we
catch it before it causes a problem? Oh, right.
So this involves looking at historical data like,
have we seen this before? Right. Have we had
issues before? Exactly. Also, theoretical analysis,
you know, kind of thinking through what could
happen. Right. And then getting expert opinions
from people who really understand the process.
Right. The people who are actually doing this
day in and day out. Exactly. Exactly. And even
stakeholder concerns. So really getting input.
from a variety of sources to understand what
the potential impact could be. So you're not
just, you know, sitting in a room by yourself
coming up with this stuff. You're really going
out there and trying to get a comprehensive view.
Right. Because we want to be as thorough as possible.
Right. And then the third part of risk assessment
is risk evaluation. OK. So here we're comparing
the risk against some predetermined criteria.
So is this risk, is it acceptable? Or is it unacceptable?
Based on those predefined criteria. Exactly.
And this helps us to prioritize, you know, which
risks do we need to address most urgently? Right.
Triage. Exactly. Exactly. So we can focus on
the most important ones first. OK. So so we've
identified our hazards, we've analyzed the risks,
and then we figured out which ones are the most
important to address. Right. So what happens
next? So the next stage is risk control. OK.
And this involves two main strategies. So we
have risk reduction and then we have risk acceptance.
OK, so two sides of the same coin. Yeah, exactly.
So risk reduction, that's all about taking actions
to lower the probability of that harm happening.
OK. Or the severity of the impact if it does
happen. Oh, if it does happen, it's not as bad.
Exactly, exactly. So some examples, we might
improve cleaning and sanitation procedures. Which
is super important. Very important. Yeah. And
actually, it's mandated in regulations like 21
CFR 110. OK. The design of the equipment is important
too so we can clean it easily. We might separate
work areas physically so we don't mix things
up. And that's something that's highlighted in
21 CFR 211 and also by... Experts like Leonard
Steinborn, who we've talked about before. Right,
right. And then, of course, proper material handling
and storage. Always important. Very important.
Again, that's covered in 21 CFR 110. So lots
of different things we can do to reduce risk.
So these are very concrete things that we can
do to minimize those chances of something happening.
Exactly, exactly. Now, sometimes, you know, we
might do all we can to reduce a risk, but we
just can't get it any lower. Right, right. or
maybe the cost of reducing it further just doesn't
make sense compared to the benefit we get. So
in those cases, we might formally accept the
risk. Okay, interesting. So you're not ignoring
it, but you're saying, we acknowledge that this
is a risk and we've thought about it, and this
is why we're okay with this level of risk. Exactly.
Okay, that makes sense. Yeah, so we've documented
it, we've thought about it, we've made a decision.
Right. And then finally, we have the last two
stages, which are risk communication and risk
review. Okay. So risk communication is all about
making sure everybody knows about these risks
and what we're doing about them. So everyone's
on the same page. Exactly. And then risk review
is about checking in on those risks regularly.
OK. So it's an ongoing process. We want to make
sure our risk control measures are actually working.
Right, because things change. Exactly. Things
change all the time. So it's a continuous cycle
of assessing, controlling, communicating, and
reviewing. So you're always kind of keeping an
eye on those risks. Always. Always. OK. So earlier,
you mentioned that there are some specific tools
that manufacturers use to help them with QRM.
Right. Could you tell us a little bit more about
those? Yeah. So ICH Q9 NX1 actually gives us
a whole bunch of different tools and techniques
that we can use for risk management. OK. And
these range from Very basic stuff. Okay, like
you know drawing flowcharts, right? Right to
map out a process or using checklists, right
to gather data all the way to some more advanced
techniques Okay, so let's talk about those more
advanced techniques here. Yeah, so one very common
and very powerful tool is FMEA failure mode and
effects analysis. And we've talked about FMEA
before with Mike Lay Brown, who's an expert in
this area. But basically, FMEA is a systematic
way to identify potential failures in a process.
or in a piece of equipment. And then to analyze
the effects of those failures and figure out
what might be causing them. So it's really looking
at all the different things that could go wrong
and then what would happen if they did go wrong.
Exactly. Exactly. And then another really popular
tool, especially when we're focusing on hazard
prevention, is HACCP, Hazard Analysis and Critical
Control Points. Okay. And this one's mentioned
in ICH Q9 NX1. Okay. And also in regulations
for food manufacturing, like 21 CFR 110. Got
it. But basically HACCP is all about identifying
those really critical points in a process. The
points where we absolutely have to have control
to prevent a hazard. So it's like, if these things
go wrong, we're in big trouble. Exactly. So we
really need to make sure that these points are
controlled. Exactly. So we want to focus on those
make or break points. Got it. And then we have
some other tools, like risk ranking and filtering,
which helps us to prioritize risks if we have
a lot of them. Right. So when you're overwhelmed,
you need to kind of figure out which ones are
the most important. Exactly. There's also fault
tree analysis, which is a kind of a visual way
of showing how different things could lead to
a failure. Okay. And then there's hazard operability
analysis or HAZBUP, which is a very structured
way of identifying hazards and operational problems.
Okay. So there's lots of different tools, and
the key is to choose the right tool for the job.
Right, and it depends on what you're looking
at and the kind of information that you have
available. Exactly. Okay, so that's a great overview
of some of the tools. Now let's bring this back
to the actual manufacturing floor. Right. How
does all of this get applied in practice? Yeah,
so QRM really has a big impact on manufacturing.
First of all, it helps us to make better decisions.
Okay. So by doing these risk assessments, manufacturers
can be more proactive about how they design their
processes, what equipment they choose, and how
they allocate their resources. Right, because
if you understand where the risks are, then you
can put your resources where they're most needed.
Exactly, exactly. And that includes things like
equipment qualification and validation, which
are so important. Right, making sure the equipment...
works properly. Right, and we've talked about
this before, but the risk assessment can actually
determine how rigorous the qualification process
needs to be. Okay, so not every piece of equipment
is treated the same. Exactly. It depends on the
risk it poses to the product. Got it. And then
another really important thing is that QRM fosters
a culture of continuous improvement. Okay. By
always looking for areas where we can improve
and then monitoring those changes, we're constantly
getting better. So it's not just a one -time
thing. It's an ongoing process. Exactly. It's
a cycle of planning, doing, checking, and acting.
Right. That makes sense. Yeah. And then of course,
QRM is essential for regulatory compliance. Oh,
OK. So it aligns with the expectations of GMP.
Good manufacturing practices. Yes. Good manufacturing
practices for pharmaceuticals and dietary supplements.
And the regulations, like 21 CFR Parts 210 and
211 for pharmaceuticals and 21 CFR Part 111 for
dietary supplements, they don't always use the
term QRM, but they definitely imply it. Okay.
Like they require a risk -based approach in many
areas, like equipment qualification, process
validation, change control, and handling deviations
in corrective actions. So it's not just a good
idea. It's really part of the law. Exactly. It's
not optional. Got it. And then finally, the principles
of QRM. they can be applied to everyday practices
on the manufacturing floor. Okay. So, for example,
with sanitation, we can have risk -based cleaning
procedures. Okay. So instead of just cleaning
everything the same way, we identify high -risk
areas and focus on those. Right. So it's more
targeted. Exactly. More targeted. And that's
outlined in 21 CFR 110. Okay. And then with material
management, we assess the risks associated with
raw materials, with suppliers, and storage conditions.
Right. Even equipment maintenance can be prioritized
based on risk. And James L. Vesper, who we've
talked about before, he emphasizes that calibration
schedule should be risk -based too. Okay. So
we can see that QRM really permeates every aspect
of manufacturing. Yeah, it really does seem to
touch everything. It does. It really does. And
even in a lab, we apply QRM principles to method
validation. Right. So that the tests we use to
check the quality of the product are reliable.
Okay. And also to how we qualify and calibrate
lab equipment. Okay. Which is in regulations
like 21 CFR Part 111 and other GMP guidelines.
Got it. And when we need to make changes, QRM
helps us to assess the potential impact of those
changes, which we call change control. OK. And
when we have rejected materials, QRM helps us
to figure out what to do with them. Right. And
that's outlined in regulations like 21 CFR 111
.425 for dietary supplements. So QRM is really
about thinking ahead and making sure that everything
is done in a way that minimizes risk. Exactly.
Exactly. It's about being proactive. systematic
and data driven. Got it. Let's think about a
hypothetical example. So imagine a manufacturer
is making multiple products using some of the
same equipment. OK. And they do a risk assessment
and realize there's a potential for cross contamination.
OK. So using QRM, they might decide to buy dedicated
equipment for some of the products. OK. Or they
might implement stricter cleaning procedures
between batches. Right. And that way, they're
mitigating the risk. Got it. And another example,
let's say a manufacturer is choosing a new supplier
for a raw material. OK. They do a risk assessment
and they find out that the new supplier might
have some quality issues. OK. So what do they
do? Well, they might need to do more testing.
Exactly. They might implement stricter testing
requirements for the raw materials from that
supplier. Got it. And that aligns with regulations
like 21 CFR 211 .84. OK. So those are just a
couple of examples of how QRM can be used in
practice. Yeah, those examples really help to
kind of see how it all comes together. Exactly.
It's not just theory. It's actually happening
in real life. Right, so as we wrap things up,
what would you say are some of the key benefits
of taking this proactive approach with QRM? Yeah,
so the benefits are huge. First of all, it leads
to better quality and safer products. Which is,
of course, the most important thing. Absolutely.
Absolutely. It also improves efficiency because
we're focusing on the things that matter most.
Right. So you're not wasting time and resources
on things that aren't as important. Exactly.
And of course, it helps us to comply with regulations,
which is really important for any manufacturer.
Right. Keeps you out of trouble. It does. It
does. So QRM is really not just a burden. It's
actually a really valuable way of doing business.
It is. It really is. It's about making sure that
the products we use are safe and effective. And
that's something we should all care about. Absolutely.
This has been a really fascinating look at quality
risk management. It has. And it's so clear that
it's not just a bunch of rules. It's really a
fundamental framework for making sure that products
are of the highest quality and safe for people
to use. So to wrap things up, I guess we'll leave
listeners with this thought. Think about all
the products that you use every day, from food
to medicine to everything in between. The principles
of identifying risks and mitigating them, which
is what QRM is all about, are probably at work
behind the scenes to make sure that those products
are safe and effective. Absolutely. And it makes
you wonder what other areas of our lives could
benefit from this kind of thinking. That's a
really good question. Something to think about.
It is. It is. Well, this has been a great Deep
Dive, thanks for joining us. Yeah, thanks for
having me. And we'll see you next time. See you
next time.