34 - Planning and Preparing for a GMP Audit (S18E2)

You know, when you hear good manufacturing practices
or GMP audits and it's like, ugh. How do we even
wrap my head around all that? Totally. Especially
those FDA regulations, right? Like 21 CFR, part
111 for dietary supplements, or part 211 for
pharmaceuticals. Super detailed. It's a lot.
So this deep dive, think of it as your cheat
sheet. We dug deep into the FDA regulations,
guidance docs, even talked to experts, all to
get you ready for a GMP audit. We really did.
I mean, we're talking the code federal regulations,
like starting with part 110 for general CGMP,
current NIP manufacturing practice. Right. CGMP.
Then all the specific requirements for different
products. So you've got parts 202, 203, 210,
211. 211, yeah, that's the big one for pharmaceuticals.
Exactly. But there's more, 216, 310, 312, 314,
316, 320, 330. We even looked at part 58 for
good laboratory practice, or GLP, how that ties
into GMP. Oh, and grass generally recognized
as safe substances. We covered that, too. Wow.
That's a lot of numbers. It is, but we didn't
stop there. We looked at ICH guidelines. That's
the International Council for Harmonization.
They set those global quality standards for pharmaceuticals,
plus GMP audit manuals, analytical testing guides,
quality risk management, clinical trial handbooks,
even some FDA workshop summaries and videos.
From the FDA and industry experts on YouTube.
Right. OK, so our goal to get you ready for your
GMP audit. to make you feel confident, not stressed,
and to show off how strong your quality systems
really are. So where do we even start with GMP
Audit Prep? First things first, be proactive.
Don't wait till the last minute. Yeah, you can't
cram for this. No, you really can't. It's about
always being ready. And one of the best ways
to do that, audit checklists, super detailed
ones. Checklist, OK. But I beg it's more than
just a quick glance over things. What should
those checklists really focus on? You got it.
They have to go deep. And they have to be based
on the actual GMP regulations. So like if you're
working with food or dietary supplements, you're
looking at 21 CFR parts 110 and 111. But pharmaceuticals,
that's part 211 all the way. OK. So the checklists
help you take those massive regulations and turn
them into actionable items you can check off.
Exactly. Can you give us some examples? Like
what should these checklists be covering based
on the regs? Sure. Think about the facility itself.
Your checklist needs to cover things like sanitary
operations, general maintenance of buildings
and facilities. That comes straight from section
110 .35A and section 211 .58. We're talking walls,
floors, ceilings. Everything needs to be built
and maintained in a way that prevents contamination.
And don't forget ventilation. Section 110 .22
talks about having enough airflow to get rid
of odors and vakers that could, you know, mess
with product quality. Oh, and pest control, too.
That's huge. Makes sense. You want to stop problems
before they even happen. Exactly. And speaking
of preventing problems, let's talk equipment.
Right. The equipment used in manufacturing. Yep,
your checklist has to cover sanitation there,
too. We're talking 110 .35A and section 211 .56B
here. It's not just about wiping things down.
You need a system for properly cleaning and sanitizing
the equipment to prevent contamination. And if
you're using compressed air or other gases in
your process, section 110 .35AG says you need
controls for those. They can't introduce any
unwanted stuff into the product. And here's something
people sometimes forget. Section 110 .80 talks
about Overall, sanitation supervision. Oh, so
someone needs to be in charge, making sure everyone
is following the rule. Exactly. Accountability
is key. What else should our checklists include?
Storage is super important, especially for things
that can grow bacteria. Section 110 .80 stiff
is specifically talks about temperature controls.
You have to make sure refrigerated stuff stays
cold and hot stuff stays hot. And for pharma
equipment. Section 211 .67ab says you need written
procedures for cleaning and maintaining it. And
when it comes to the ingredients, the containers,
the closures, you name it, Section 211 .82bd
is all about handling and storing them right
to avoid contamination. And then there's Section
211 .84ab, which is about testing and approving
or rejecting those mid -materials before they're
used. So every step where something could go
wrong, you have to have a plan for it. Exactly.
And it doesn't stop there. Even those little
things that might seem unimportant can make a
difference. Like what? Well, section 110 .110c
says you have to clean non -food contact services,
too, because even those can be a source of contamination.
And section 110 .110d4 is all about handling
those single -use items carefully so they don't
get contaminated. Then you have section 110 .110d5,
which is about making sure the sanitizers you're
using are safe and effective. And don't forget
about regular maintenance for equipment and finished
food containers. That's section 110 .80b. Wow,
so many details. Right. And during manufacturing...
you have to have controls to minimize microbial
growth and prevent contamination. Section 110
.80B2, talk about that. Oh, and if you're working
with things like batters, braiding sauces, you
know, that kind of stuff. Section 110 .80B has
specific rules to protect them from contamination.
It feels like every little detail matters. They
really do. And we're not even done with the checklist
yet. We're not. What else is there? Let's talk
about the actual production, you know, the operations
themselves. For dietary supplements, section
111 .410c says you have to carefully check all
the packaging and labels before you use them
to make sure they match the master manufacturing
record. Ah, no going rope with the labels. Exactly.
And then section 111 .415 says that everything,
the filling, the assembly, the packaging, the
labeling, it all has to be done in a way that
makes sure the final product meets those quality
standards in that master manufacturing record.
Your checklist should have steps to double check
all of this. Got it. So the checklist isn't just
about physical stuff. It's also about making
sure you're following procedures. Yes. It's all
connected. All right, so the checklists are like
our first line of defense. They keep us on track.
What's the next big thing to focus on for audit
prep? Documentation. It's like the evidence you
present to the auditor. It has to tell the whole
story of your manufacturing process and all the
controls you have in place. For dietary supplements,
section 111 .410 says you have to keep documentation
that lets you trace the complete manufacturing
history of each product, like where it came from,
what happened to it, all the way through distribution.
And those records can't be like scribbled on
napkins. Right, they have to be complete and
easy to find. So what are the specific types
of documents that auditors are going to be like
super interested in, especially for pharmaceuticals
under 21 CFR Part 211? Oh, they're going to want
to see it all, starting with those written procedures
for cleaning and maintaining equipment. Section
211 .67B is all about that. And then they'll
want to see your procedures for handling, storing,
testing and approving or rejecting every single
component container enclosure you use. Section
211 .80A covers that. Makes sense. So they know
you have a plan for everything. Right. But they're
not just going to look at procedures. They want
records, too. Like section 211 .184A says you
need detailed records for everything that comes
into your facility, like the name of the supplier,
the lot number, the quantity, the date it was
received, your internal code. Wow, that is detailed.
It is. Because they want to be able to trace
everything back to its source. And then there's
the testing. Right. All the testing you do on
the materials and the finished product. Super
important, section 211 .184b says you have to
document the results of all those tests and what
conclusions you drew from them. It's not enough
to just do the test. You have to show what you
learned from it. Exactly. And section 211 .192
says that your quality control unit needs to
review and approve all production and control
records before you release any product. It's
that extra layer of quality checking. Okay, so
someone else is double checking your work, making
sure everything is good to go. Makes sense. What
other types of records do auditors want? Well,
section 211 .150 AB says you need procedures
for your warehouse. How you quarantine products,
how you store them. And the same section also
talks about distribution procedures. Then there's
section 211 .165 E, which is all about documenting
how accurate, sensitive, specific, and reproducible
your lab tests are. So they can trust your results.
Exactly. Oh, and remember to document any rejected
products and what you did with them. That's section
211 .165 F. And don't forget about procedures
for keeping those reserve samples, that's section
211 .170. And if you use lab animals, section
211 .173 says you need to keep records for them
too. This is a lot of paperwork. Or, you know,
electronic records. It feels like you need a
record for everything. Speaking of electronic
records, how do those work with GMP audits? That's
where 21 CFR part 11 comes in. If your electronic
systems meet all the rules in Part 11, the FDA
usually considers electronic signatures the same
as handwritten ones, unless a specific regulation
says you need a paper record. But for the most
part, if you're following Part 11, you can use
electronic records instead of paper. That's handy.
Less paper to keep track of. But I bet those
electronic systems have to be super secure. Absolutely.
Auditors are going to want to see things like
audit trails. That's section 11 .10e. What's
an audit trail? It's basically a record of who
did what and when in the system. And it can't
be changed or deleted. It's all about proving
that the records haven't been messed with. And
you need to control who can access the system.
That's section 11 .10d. Only authorized people
are allowed in. So if you're going digital, you
have to prove those records are safe. and can't
be tampered with that's the key Okay, we've talked
about checklist, documentation. What else is
super important for getting ready for a GMP audit?
Training. You've got to have your staff trained
properly. They're the ones who make sure everything
runs smoothly, and they're the ones who are going
to be talking to the auditors. So it's not just
about having procedures written down somewhere.
Everyone needs to know them inside and out. Exactly.
And Thomas Catalano talks about this a lot. Everyone
needs to be trained on the specific procedures
for their job. And auditors will often ask your
staff questions to make sure they understand
those procedures. It's like a pop quiz. Kind
of, but it's all about showing that everyone
knows what they're doing and why. Okay, so we
have our checklists, our documentation, and our
trained staff. That's a good foundation. But
how do we go beyond the basics and be really
proactive about audit prep? This is where you
start thinking ahead, anticipating potential
problems, and fixing them before the auditor
even gets there. It's about being strategic.
Like a chess game. You got it. And one of the
best ways to do that is through risk assessment.
You need to look at your systems and your processes
and figure out where the weak spots are. And
then you come up with ways to fix them. So you're
not just reacting to problems, you're preventing
them. Exactly. And there are some great tools
for this, like cause and effect diagrams, also
called fishbone diagrams, and failure mode in
effects analysis, or FMEA. I remember Jose Rodriguez
Perez talked about FMEA a lot. Right. These tools
help you systematically identify and evaluate
potential risks. It's a huge part of being proactive.
OK, so we're finding the weak spots and fixing
them before they become problems. What else can
we do to be proactive? Mock audits. They're like
practice runs for the real thing. Like a scrimmage
before the big game. Exactly. You do an internal
audit. that's just like a real regulatory audit.
It helps you find any weaknesses in your system,
your documents, your training, everything. And
then you can fix them before the FDA gets there.
Plus, it shows the FDA that you're serious about
quality and that you're always trying to improve.
Makes sense. It's better to find problems yourself
than have the FDA find them for you. Absolutely.
And there's one more thing that can really help
you be proactive. What's that? Knowing what the
FDA is focusing on. How do we do that? Well,
they publish data on what they find during inspections,
like those Form 483 observations. If you look
at those, you can see what kind of problems they're
finding over and over again. So we can learn
from other people's mistakes. Exactly. For example,
we've seen a lot of observations lately related
to the quality control unit, investigations,
procedures. lab controls, and equipment maintenance.
So if you know that those are areas the FDA is
focusing on, you can pay extra attention to them
during your own internal audits and prep. That's
smart. It's like having a little inside scoop.
It is. We've been talking a lot about manufacturing
audits, but are there other types of GMP inspections
people should be ready for? Oh yeah, GMP isn't
just about manufacturing. The FDA also inspects
clinical investigators, sponsors, and CROs. Those
are contract research organizations. So they're
looking at everyone involved in clinical trials.
Exactly. And they have videos about this, like
the ones from the FDA's CITC 2024. The focus
might be a little different, but the main principles
are the same. Data integrity, following procedures,
keeping good records. So even if you're not directly
involved in manufacturing, you still need to
know about GMP. Got it. GMPs everywhere. One
last thing. What about all these changes we're
seeing with how regulatory agencies do things?
Anything else we need to be ready for? Well,
the FDA is doing more and more remote regulatory
assessments. They talked about this in those
CITC 2024 videos, too. Basically, they might
do part of the inspection virtually instead of
coming to your facility. Oh, so like a Zoom audit?
Kind of, so you need to have the technology and
the processes in place to do that, like being
able to share documents electronically, maybe
even giving them a virtual tour of your facility.
It's a whole new way of doing things. It is,
and it takes some extra planning to be ready
for it. Okay, so just to sub it all up for our
listeners, to ace a GMP audit, you need three
things. Good planning, good documentation, and
good training. Couldn't have said it better myself.
And on top of that, you need to be proactive.
Use risk assessments, do those mock audits, and
keep an eye on what the FDA is finding during
inspections. So it's not just about checking
boxes. It's about really understanding the regulations
and being committed to quality. Absolutely. And
if you can do all that, a GMP audit doesn't have
to be so scary. It's definitely manageable. But
it does a big work. It does, but it's worth it.
So here's something for everyone to think about.
You know how manufacturing is getting more and
more complex and the FDA is, you know, always
changing things up. Yeah, it can be hard to keep
up. Well, how can your company create a culture
where you're always ready for an audit, not just
scrambling at the last minute? That's a good
question. Something to think about. It is. And
if you want to learn more about all this, dive
into the Code of Federal Regulations, the ICH
guidelines, all that good stuff. It's all out
there. Great advice. And that's it for this deep
dive into GMP audit preparation. Thanks for joining
us. And remember, being prepared is the best
way to face any audit.