30 - Test Systems and Test and Reference Items in GLP (S17E4)

We hear so much about breakthroughs, right? Like
amazing results from all these scientific studies,
stuff that actually has the potential to change
our lives. But I don't know if you've ever thought
about this, but like how do we even know those
results are reliable in the first place? Turns
out a huge part of that comes down to something
that seems kind of basic. How researchers manage
all their equipment and the materials they use
for their experiments. Yeah, you're absolutely
right I mean think about it the whole foundation
of reliable scientific research like everything
from developing new medicines to making sure
that everyday products are actually safe It's
all built on paying really really close attention
to detail every step of the way And that's exactly
where this idea of good laboratory practice or
GLP comes in So for this deep dive, we're going
way deeper than just reading headlines we're
going right down to the nuts and bolts of GLP.
We're going to zero in on what are called test
systems, basically, the tools and the environments
used in research, and then the actual test and
reference items. Two, how are those managed and
kept under control? We've got a ton of information
to work with here from the Code of Federal Regulations.
Like we've got bits and pieces of parts 110,
111, and some other GMP related sections. And
then also some really insightful discussions
with regulatory experts that we found on YouTube.
Now, you might be thinking, hold on, why should
I care about this? I'm not working in a research
lab. Why should I be worried about how they manage
beakers and machines and stuff? But here's the
thing. GLP controls are like the silent guardians
of reliable science. I mean, think about it.
If you're trying to understand the latest health
news, or maybe you work in an industry that's,
you know, affected by these regulations, or even
if you're just curious about, like, how rigorous
scientific discoveries actually are understanding
these GLP principles, it gives you real insight
into why we consider certain research trustworthy
and reproducible. It's like the bedrock of scientific
confidence. Absolutely. Our mission today is
to really pull out the most important parts of
GLP, specifically when it comes to these test
systems and materials. We want to show you how
these little details that you might not even
think about. like how a microscope is maintained
or even just how a chemical sample is labeled,
they're actually fundamental to the integrity
of the entire scientific process. So let's start
at the very beginning. When we talk about test
systems in this whole context of GLP, what are
we actually talking about? So the sources we've
looked at, they don't really give us one perfect
definition of test systems under GLP. But I think
a good way to think about it is it includes all
of the equipment and also the environmental conditions
that are needed to actually do a scientific study.
So we're talking everything from those really
fancy analytical instruments to the rooms where
they store things at specific temperatures. It's
basically all the physical tools and spaces that
are involved in the research. So it's like the
where and the how of the research itself, right?
I guess the main point here is that these systems,
they just absolutely have to be suitable for
whatever job they're meant to do, right? Exactly.
The equipment needs to be able to do its job
accurately and consistently. And the environment,
that needs to be controlled so that nothing messes
with the results. And this connects directly
back to the general principles of good manufacturing
practice, or GMP. At its core, GMP is all about
ensuring quality and preventing things from getting
contaminated during manufacturing. It's kind
of like GLP takes those same really strict quality
principles and applies them to the research phase?
That makes sense. Even in 21 CFR Part 110, which
is all about food manufacturing, you can see
that there's a huge emphasis on keeping facilities
and equipment sanitary, specifically to prevent
food contamination. So it's a similar idea, right?
In research, you got to make sure nothing unwanted
gets into your experiment and messes things up.
Exactly. And 21 CFR 110 .35, just to give you
an example, it specifically says how important
it is to properly maintain and repair buildings,
fixtures, and equipment. So if a piece of equipment
breaks down, or if there's something wrong with
the lab environment, say the air quality is bad,
like it says in 110 .20b6, that could totally
mess up how reliable the study's findings are.
OK. So we know that the research tools and environments
need to be right for the task, and they have
to be kept in good shape. But how do researchers
actually make sure that the equipment they're
using is working the way it's supposed to. That's
where equipment qualification and calibration
come in, right? Right, those are key for making
sure you can trust your test systems. Based on
what we learned from the EAS Consulting Group
video, equipment qualification, that's how you
build up confidence in your equipment, and it
uses a step -by -step approach. Usually it has
four phases, design qualification, which is often
called DQ, then installation qualification or
IQ, then operational qualification, that's OQ,
and lastly, performance qualification or PQ.
Okay, so let's break that down a bit. What is
each of those stages? is mean in practice. Sure,
so design qualification, that's basically confirming
that the design of the equipment is actually
appropriate for what it's going to be used for
in the study. Installation qualification, that's
all about making sure that the equipment was
installed correctly, you know, according to the
instructions from the manufacturer. Then you've
got operational qualification, which is showing
that the equipment actually runs consistently
within the parameters that are set for it. And
finally, you've got performance qualification.
And this is the part where you prove that the
equipment can reliably do what it's supposed
to. to do under normal operating conditions.
So it's like a super comprehensive check at each
stage, from design to actually using it every
day. So it's a very thorough process to make
sure the equipment is up to the job, right? In
the EAS video, they mentioned that this qualification
thing, it should be done for all the major equipment
and then repeated if anything major changes,
like if you move the equipment. It sounds like
they're really controlling things closely. Oh,
absolutely. They even talked about how if you
just move a sensitive instrument a little bit,
like an HPLC system, it could affect how it's
installed or how it works. It really shows how
closely they have to watch everything. And it's
not just a one -time thing. They have to re -qualify
the equipment every so often, or if they do major
repairs, just to make sure it's still working
the way it should. Now, besides qualification,
it's also calibration. So what's the difference
between the two and why is calibration so important
in this whole thing? Well 21 CFR 111 .27 and
that EAS video they both talk about calibration.
Basically it's making sure an instrument is accurate
and precise. How they do it is they compare its
measurements against a standard that's known
to be accurate. They have to do this before they
use the equipment for the first time and then
they do it regularly either based on what the
manufacturer recommends or just how often they're
using it. You can almost think of it like tuning
a music instrument making sure it's hitting all
the right notes. So it's like qualification is
making sure the instrument can play the music
and calibration is making sure it's playing in
tune. Right. I like that analogy. And I remember
the EAS video mentioned that some smaller portable
instruments like pH meters and balances, they
might not need the whole qualification process,
but they still have to be calibrated before every
single use. Exactly. That's because their environment
or how they're set up, it can change often. So
doing a quick calibration helps make sure they're
accurate at that moment. And another important
thing, both the regulations like in 21 CFR 111
.27 and the EAS folks, they emphasized how important
it is to keep log books and they use the to document
all the calibration and maintenance work. It's
all about keeping a really clear record of how
the equipment has been performing so someone
can check it later if they need to. It seems
like documentation comes up a lot in these conversations.
Okay, so we've covered test systems. Now, what
about the actual substances being tested? You
know, the test and reference items, what are
those exactly? The test item, that's simply the
substance that they're studying. It could be
a brand new drug, a new ingredient for food,
any material they're checking out. And the reference
item, that's a substance they already know a
lot about, and they use it for comparison or
as a benchmark to check quality. It could be
a known chemical compound, a placebo, or an older
version of the test item that they've already
tested. You can think of the reference item like
a ruler that you use to measure the test item
against. Okay, so the test item is what we're
trying to learn about. And the reference item
gives as something to compare it to. So if you
don't keep track of these items really carefully,
it seems like you could mess up the whole study.
Oh, absolutely. If you don't know exactly what
your test and reference items are, or if something
happened to them, like maybe their quality got
messed up, then your whole study could be totally
meaningless. This is where those GMT principles
of controlling components and materials come
in, like what's in 21 CFR 211 .80. It's all about
making sure you know exactly what you've got
and making sure it's kept in the right conditions.
And that leads us right into how they handle
and store these items. It's not like they're
just throwing them in a drawer somewhere, are
they? Definitely not. 21 CFR 211 .80A. It says
they need to have written procedures for every
single step of the way. So from when the stuff
comes in to how they store it, how they handle
it during the study, how they take samples from
it, how they test it, and finally whether they
say it's okay to use or if they have to reject
it because it doesn't meet the standards. Those
procedures, they're like a super detailed recipe
for how to manage these important materials.
Written procedures? for everything. It sounds
incredibly detailed. And 211 .80A, it specifically
mentions handling and storing these items in
a way that keeps them from getting contaminated.
What does that look like in a real lab setting?
Well, 21 CFR 211 .80c, it actually gives some
examples like they have to store things that
are in bags or boxes off the floor and they have
to make sure there's enough space between them
so they can clean and inspect properly. This
helps stop things like bugs from getting in or
damage from moisture. And another important point
is in 211 .80 where it says every single container
needs a unique code so they can trace that batch,
what they call the lot. They put a unique code
on every batch. Wow. Why do they need to track
everything so closely? That unique code, that's
how they can tell the whole history of that particular
badge. They can follow it from the moment it
gets to the lab all the way to when they use
it or dispose of it. Like, they can see if it
was quarantined when it arrived, if it was approved
for the study, or if they had to reject it for
not meeting the quality standards. This super
detailed tracking, they also talk about it in
regulations like 21 CFR 111 .370D for dietary
supplements. What it does is it makes sure that
the correct material is always being used. And
if any problems come up, they can trace it all
the way back to exactly where it came from. It's
like each material has its own family tree. So
it's all about being accountable and being able
to retrace your steps if something goes wrong,
right? Like a scientific paper trail, but for
the materials themselves, which takes us right
to the idea of tracking and traceability throughout
the whole research process. Exactly. It's that
coding system plus keeping super detailed records.
That's how they achieve complete traceability
like we saw in 21 CFR 111 .370. You should be
able to basically reconstruct the entire history
of how a product was made and controlled. You
should be able to see where every single ingredient
came from, how it was handled at every step,
and where it ended up. And this ties in directly
with good documentation practices, which we've
talked about before in other deep dives. If your
documentation isn't accurate and thorough, you
can't really say you've got traceability. it's
not enough to just do things the right way. You
have to be able to prove you did them right.
Okay, so let's say you have these test and reference
items. How do you know if they're good enough
to actually use in a study? I'm guessing that's
where quality standards and testing come in.
You got it. 21 CFR 211 .84A is really clear about
that. It says that every single batch that includes
the ingredients, the containers for the drugs,
the closures, like all the materials, they all
have to be tested and approved by the quality
control people before they can be used. And this
isn't just a quick glance. They have to take
samples that represent the whole batch and use
statistically sound methods, just like it says
in 211 .84. They have to be totally sure that
the little bit they're testing actually reflects
the quality of the entire batch. So getting the
right sample to test is crucial. You can't just
test a tiny bit from a big batch and assume the
rest is the same. Nope, you have to be a lot
more careful than that. And the tests themselves,
the methods they use, those have to be established,
validated, and documented, too, to make sure
they're accurate, sensitive, specific, and reproducible.
That's all in 21 CFR 211 .165e. Basically, they
have to prove that the test measures what it's
supposed to and that they can get consistent
results every time they do it. And then 21 CFR
211 .84f and 212 .71a, they make it clear, if
anything doesn't meet those quality standards
that were set beforehand, it's rejected no matter
what. So there's no room for error, like even
if it's almost good enough. Not a chance. Sticking
to those strict quality standards is super important.
If a material doesn't meet the criteria, it's
rejected, period. That's how they protect the
integrity of the whole study. They do have ways
to reprocess materials if they need to, but even
then, the reprocessed stuff, it has to go through
all the same testing and meet all the original
standards before they can use it. So it seems
like documentation is key to this whole thing.
We've talked about procedures and records for
almost everything. Why is docu - documentation
is so essential for GLP. It's simple, really.
Without documentation, without keeping good records,
there's no way to prove that you did all of these
crucial steps correctly. We've already talked
about how important standard operating procedures
are. Those are the SOPs, and they need those
for pretty much everything from managing the
test systems to handling the materials. This
is something we've also seen in our deep dives
on GMP in the past. There's huge emphasis on
SOPs. What they do is they give everyone involved
a really detailed guide to follow step by step.
And the regulations even spell out exactly what
information needs to be documented. Oh, yeah.
For example, 21 CFR 211 .67c says they have to
keep detailed records every time they clean,
maintain, sanitize, or inspect equipment. In
both the EAS Consulting Group video and the one
on good documentation practices, they both said
that these records have to be legible, they have
to be dated, and the person who did the work
has to initial them. And if they need to make
corrections, there's a specific way to do it.
A single line through the mistake, then they
initial it, date it, and explain why they made
the change. That way, the record stays accurate.
It's all about creating a trail. So you can always
look back and see who did what and when they
did it. Exactly. Just like that OS Workshop 2022
transcript mentioned, thorough documentation.
It gives you a history that you can actually
verify. It holds people accountable and it lets
you go back and figure out exactly what happened
in a study, if there's ever a question about
it or if someone needs to investigate something.
Before we finish up, let's quickly talk about
reference standards. We talked about reference
items before, but how do standards fit into the
picture? So the GLP stuff we've looked at today,
it doesn't really go into a ton of cocktail about
reference standards, but the basic idea behind
them is really important for making sure that
test items are high quality and pure. Think about
it this way. To test a substance properly, you
need something that's already been characterized
really well, and you use that as a benchmark.
Remember that Catalano book EXO, the part about
APIs, which are active pharmaceutical ingredients?
It said that reference standards have really
specific requirements for purity. So when you
have well -defined reference standards, you can
be confident about whether your test item meets
the quality standards. It's a really important
concept in analytical chemistry and quality control.
Reference standards are like the gold standard
that you measure your test items against. So
to wrap up this deep dive, what we've learned
is that managing and controlling test systems,
and then the test and reference items too, it's
not just about checking boxes and doing paperwork,
all of these things like meticulously qualifying
and calibrating equipment, carefully handling
and tracking materials, testing everything rigorously
against standards, and then documenting every
single step, all of those things together, That's
what makes for a reliable scientific research
under GLP. It's about making sure the whole process
has integrity from beginning to end. Absolutely.
And for you, the listener, understanding these
core principles, it helps you appreciate how
trustworthy the scientific data is that impacts
our lives. I mean, think about the safety of
the medicines we take, the quality of the products
we use every day. It all comes back to this.
This is why we can be confident in certain scientific
findings. It really makes you think about all
the work that goes on behind the scenes, stuff
you might not even realize is happening, just
to make sure that we can trust the results of
scientific research. So here's something to think
about. These ideas of control and traceability
that we've been talking about, they're used in
science with GLP. But are there other areas of
your life, maybe in things you're interested
in, where accuracy and reliability are really
important too? And in those areas, are there
details that we might not usually think about
that actually make those complex systems more
trustworthy. That's a really interesting question.
And if you want to dive deeper into all of this,
we encourage you to check out the actual regulations
like 21 CFR parts 58, 111 and 211. Or you could
look into industry guidelines like the ICH guidelines
that we talked about. And of course, you can
always reach out to us if you have more questions
about all the little details of the laboratory
practice.