44 - Preparing for Regulatory Inspections (S19E6)

Okay, so you know, you guys sent in a ton of
stuff about inspections, regulatory inspections
and how to get ready for them. So that's what
we're going to be looking at today. It's a big
one. It is a really big one. And we're going
to try to help you kind of wade through all this
material and get ready for your next inspection.
So. Absolutely. Pharmaceutical and dietary supplement
industries. This is for you. Yeah, we've got
a lot to cover today. I mean, the listener sent
in a really interesting mix of sources we've
got. the CFR, the Code of Federal Regulations,
with all the detailed legal stuff. I mean, we're
talking multiple parts here covering everything
from how you make your products to clinical trials
and beyond. And then to give us that more practical
kind of on -the -ground perspective, we've got
transcripts from YouTube videos by some really
reputable folks like ES Consulting. And even
the FDA themselves weighing in. Then, to round
it all out, We've got excerpts from some key
books on GMP quality auditing, risk management,
and even those internationally recognized ICH
guidelines. Nice. It's a lot. It is a lot. So
I think our mission today should be to take all
of this and distill it down to something really
usable for everybody listening, like actionable
advice that they can use. Absolutely. Should
he get ready for these inspections and feel...
Really confident. I think that's the key takeaway
here Like how do we take all this dense information
right and turn it into something that people
can actually implement in their day -to -day
Exactly. So we're gonna focus on the most important
stuff first. We got to talk about documentation
Yes, it is like the foundation. Absolutely of
everything the backbone right and then of course
the people involved Yeah, got to make sure everyone's
properly trained will train staff is critical
and knows their stuff. Absolutely and then we
want to talk about you know, mock audits and
why those are so important. Yeah, these are like
your fire drills. Right, exactly, like you don't...
You practice before the real thing hits. Right,
you don't want to wait till the real inspection
to figure out what you're doing. Right, exactly.
And then a big one is transparency. Oh, huge.
And communicating effectively. Being open and
honest with the agencies. With the inspectors,
yeah. It builds trust. Right, and then finding
those gaps, those weaknesses in your systems
before they do. Proactive is the name of the
game. Exactly. And then what to expect when they're
actually there. Yeah. How to handle that interaction
smoothly. And then finally, you know, inspections
happen, you get the report, and then what? Well,
that's where the real work begins. Using those
results to make your system even better. Continuous
improvement. That's the heart of GMP. Right.
OK, so even in just glancing through this material,
there are some details that are pretty fascinating.
Oh, absolutely. There are some real gems in here.
Yeah. Like, for instance, You wouldn't think
something as simple as where you put fans in
your facility would matter that much. But CFR
Part 110, it actually lays out some pretty specific
requirements. It's all about preventing contamination.
Makes sense. And then EAS Consulting, they had
a really interesting point about reviewing lab
data. It's not just about one person checking
it at the end. Right. They were advocating for
like a multi -layered approach. Different people
checking at different stages. Multiple sets of
eyes. More eyes the better and it makes sense
when you think about it. Catching those errors
early on can save you a lot of headaches down
the line. For sure, for sure. Those FDA case
studies. Oh, those are always enlightening. Yeah,
those are fascinating. They really show you how
important it is to have your documentation in
order. Yeah. I mean, some of those applications
were delayed or even rejected because the paperwork
was incomplete. Wow. Or poorly organized. So
even small things can have a big impact. Absolutely.
The devil's in the details, as they say. All
right, so let's start with the big one, documentation.
Like I said, it's the foundation. Yeah. And the
thing is, it's not just about having documentation
for the sake of having it. It's about the why
behind it. Think of it like this meticulously
kept records. They tell a story. Oh, okay. They're
the story of your commitment to quality. Okay.
And it starts with the basics like CFR Part 110
points out. Your buildings, your fixtures, they
have to be in good repair and clean. Right. Sanitary
conditions to prevent your products from getting
contaminated. Adulterated. Exactly. It's all
about having a system in place. And that system
needs to be documented every step of the way.
OK. So it's really about having a system and
proving that you have a system. Exactly. You
have to be able to demonstrate that you're in
control. OK. That you're following a plan. And
that plan is designed to ensure quality. And
so that's where the documentation comes in. That's
where the documentation comes in. It's your proof.
OK. So let's get specific then. Like, CRFAR Part
2 .11 talks about equipment. Right. It's not
enough to just clean your equipment. You have
to have a written procedure. Absolutely. You
need to spell out exactly how it's done, who's
responsible, and how often you do it. Right.
And this is to prevent contamination. Exactly.
It's all about minimizing the risk of something
getting into your product that shouldn't be there.
And I'm guessing this is the same kind of thing
that Blazner talks about in his book. Oh, absolutely.
Blaisner really emphasizes the importance of
written procedures for production and process
control. He argues that these procedures are
your guarantee that every product you make meets
the required standards. The identity, strength,
quality and... Purity. Exactly. And these aren't
just suggestions. These procedures need to be
carefully reviewed and approved. By quality control.
By quality control. Exactly. To make sure that
every step is scientifically sound and consistently
followed. OK. So it's not just like some random
person writing this down. This has to be vetted.
Absolutely. It has to be a control document.
All right. So we've got our building. We've got
our equipment. What about when the product's
all made? Where do we put it? Warehousing. That's
another area where documentation is key. CFR
Part 211, it's very clear you need written procedures
for how you store your products, the conditions,
the temperature, humidity, all of that. Right.
And even how you rotate your stock. OK, so that
things don't expire. Exactly. You don't want
to end up with expired materials or products
that have degraded because they weren't stored
properly. So this is all about preventing loss
and waste as well. Absolutely. It's about protecting
your investment and ensuring the quality of your
products right up until they reach the customer.
Okay, so Bleisner also mentions that these records
have to be readily available. Oh, yeah. You don't
want to be scrambling when the S -vector shows
up. Right. They ask for a document. You need
to be able to pull it out quickly and easily.
It makes sense. Okay, so now we're talking about
like the history of the product, like how it
was made. Traceability. That's the key word.
Okay. CFR Part 111. It specifically requires
you to be able to trace the entire journey of
your dietary supplements. Okay. From beginning
to end. From raw materials to finished product.
you need to know where everything came from and
where it went. And this is all documented? All
documented every step of the way. So how do we
actually do that? Like how do we keep track of
all this information? Well think of it like a
recipe. You know when you bake a cake, you follow
a recipe. In pharmaceutical manufacturing, that
recipe is called the master production and control
record. Okay. It lays out every single ingredient,
every step. every parameter. So it's incredibly
detailed. Incredibly detailed. It's the blueprint
for making your product. Wow. And then each time
you make a batch of the product. You create a
batch production record. Okay. And that record
documents everything that happened during that
specific production run. So it's like a log book
for that particular batch. Exactly. And it shows
that you followed the master recipe and it also
documents any deviations that might have occurred.
Okay. So if something unexpected happened. You
write it down. You write it down and you explain
why it happened and what you did about it. Okay,
so it's not just about following the rules, it's
also about explaining when you didn't follow
the rules. Exactly, and why and what you did
to correct the situation. Okay, so these records
are really important. Absolutely, it's there.
You're proof that you're operating in a controlled
and consistent manner. Okay, so we've talked
about the product itself. Let's go back to those
raw materials and how we control those. Material
control and traceability, another critical area.
And again, documentation is key. Okay. CFR Part
211 requires you to have written procedures for
everything you do with your components and containers.
Okay. So like receiving them, storing them, testing
them. All of that. Every single step needs to
be documented. Okay. So you have to have a procedure
for literally everything. Pretty much. And for
dietary supplements, CFR Part 111 adds another
layer of complexity. Oh, how so? Well, they require
you to have a unique identifier for every single
lot of incoming ingredients. Okay, so even within
a shipment? Even within a shipment, every lot
needs to be individually identifiable. Wow, that's
pretty intense. It is, but it's necessary for
traceability. Yeah. You know, if there's ever
a problem, you need to be able to track it back
to the specific lot of material. Okay, and then
what about storing these materials? Like, how
do we make sure they're not contaminated? Again,
CFR Part 111. has you covered. Okay. You need
documented procedures for how you receive and
hold your raw materials. This includes everything
from the conditions in your warehouse to how
you prevent mix -ups and contamination. So it's
all about protecting the integrity of your ingredients.
Exactly. You're building quality in from the
very beginning. Okay. And then what happens if
you get a shipment of materials and some of it's
bad? Rejects. Rejects. Yeah, that's covered too.
Okay. CFR Part 111 requires you to have strict
procedures for identifying, holding, and controlling
any rejected materials. Okay, so this would include
components, packaging labels. Anything that doesn't
meet your standards. And why is that so important?
Well, you want to make sure that those rejected
materials don't accidentally end up in your product.
Right, so you need to keep them separate. Separate
and clearly identified. Okay, so you don't want
to mix good stuff with bad stuff. Exactly, you
need to have a system in place, a quarantine
system to prevent any mix -ups. Okay, so this
is all about containing the problem. Containing
the problem and preventing it from spreading.
Okay, makes sense. All right, so now let's move
on to the lab. Ah, the lab. the heart of quality
control. Right. So what kind of documentation
do we need there? Well, the EAS consulting group,
they had a lot to say about this in their video.
They really emphasize the need for strong systems
to control and review all of your lab data. OK,
so making sure it's accurate and precise. Exactly.
You want to be confident in your data. Right.
And they really stress the importance of having
multiple layers of review. Oh, interesting. So
not just one person checking the data. No, not
just one person. The analysts who generates the
data, they review it, of course. But then their
peers review it, and then a supervisor reviews
it. OK, so it's like a triple check. Exactly.
It's about building in those checks and balances.
Makes sense. And what's the thinking behind that?
Well, it's not just about catching errors. It's
about fostering a culture of shared responsibility.
Everyone understands that data integrity is critical.
And everyone has a role to play in ensuring that
data is accurate and reliable. OK, so it's a
team effort. Absolutely. And the EAS Consulting
Group also talked about the importance of managing
that data appropriately. Okay, so what does that
mean? It means eliminating transcription errors.
So being careful when you're copying data from
one place to another? Exactly. And it means tracking
the data throughout its lifecycle. Okay, so knowing
where it is, who has access to it. Exactly. And
then finally it means archiving the data securely.
Okay, and are there any specific requirements
for how long you have to keep lab data? Yes,
there are. And they vary depending on the type
of data. Okay. But for example, serious adverse
events related to dietary supplements. Those
records have to be kept for at least six years.
Wow, that's a long time. It is, but it's important
to have that historical data available if you
ever need it. Okay, so we've got EES Consulting
talking about this. What about the other sources?
Well, the PCB transcript, they also touched on
lab documentation. Okay. They emphasize the need
for a second person to review and sign off on
all lab records. So, again, that idea of multiple
checks. Exactly. Two sets of eyes are better
than one. Right. And then what about ES Consulting?
Do they have anything else to add? Yes, they
did. They talked about the importance of having
separate tracks for investigating out -of -specification
results. Okay, so when a test result doesn't
meet the expected specifications. Exactly. They
said you need to have separate procedures for
analytical investigations. Okay. and microbiological
investigations. Because the approach is different.
Exactly. You're looking for different things.
Okay, so we've talked a lot about the what of
documentation, but what about the how? Ah, the
practicalities. Yeah, like, are there any best
practices that people should keep in mind when
they're creating and maintaining these records?
Oh, absolutely. And the Advancing Health Transcript,
they had some great advice on this. Okay, I'm
ready. First, they emphasize the importance of
legible handwriting. Oh, that's a big one. You
don't want your records to be unreadable. Right.
And they also said you should always include
your printed name and the date along with your
signature. OK, so it's clear who wrote what and
when. Exactly. And 3D signatures, they are very
clear about this. You should always sign and
date every single entry personally. OK. and you
should include your credentials if appropriate.
OK. So if you're a chemist or a quality control
manager or whatever. Exactly. You want to make
it clear what your qualifications are. OK. And
they also cautioned against using date stamps.
Yeah. They said that date stamps can be problematic.
How so? Well, because they don't provide that
personal accountability. Right. So someone could
just stamp a bunch of documents without actually
reviewing them. Exactly. It's better to handwrite
the date and sign your name. OK. So it's more
about that personal touch. Exactly. It shows
that you were actually there. Yeah. And that
you reviewed the information. Okay. And then
what about timeliness? Like how soon after something
happens should you document it? Ideally immediately.
Okay. But certainly within 24 hours. Okay, so
don't let things pile up. No. Don't wait until
the end of the week to try and remember everything
that happened. Right. And then what about this
idea of verifiability? Ah, yes. Every entry you
make in a record has to be verifiable. Okay,
so what does that mean? It means that there has
to be a source document that supports your entry.
Okay, so you can't just make things up. No, you
need to have evidence to back up what you're
writing. Okay, and that source document could
be what? It could be a lab report, a batch record,
an observation you made during an inspection.
Okay, so anything that can prove that what you're
writing is true. Exactly, and it's important
to keep those source documents organized and
accessible. Right, so you can easily find them
if you need them. Exactly. And then what about
making copies of documents? Ah, yes, that's something
that happens all the time. It does. And the Easy
Global Training Transcript? They had some good
advice on this. Okay, let's hear it. First of
all, they said that copies need to be legible.
Okay, so no blurry faded copies. No, you want
to be able to read the information on the copy?
Right. And they also said that you shouldn't
introduce any errors during the copying process.
Okay. So be careful. Be careful, double check
your work. And they also recommended a page numbering
system. Yeah, they said you should use a system
like page X of Y. Okay, so it's clear that you
have all the pages. Exactly, and they were very
clear about this. You should never eliminate
pages from a document. Okay, so even if there's
a mistake on a page. Even if there's a mistake,
you have to keep the page. And why is that? Well,
because it's a record of what happened. OK. You
can't just erase history. Right. You can't pretend
it didn't happen. Exactly. And they also talked
about the importance of a log book. OK. So this
is a separate document. Yes. A log book is used
to capture the signatures and initials of everyone
who's interacted with the product. OK. So it's
like a chain of custody. Exactly. It shows who
had access to the product and when. OK. So if
there's ever a question about who did what, you
can look it up in the log book. Exactly. It's
a valuable tool for traceability. Okay, so we've
talked a lot about documentation, and that's
great, but documents are just pieces of paper
if you don't have the right people to create
them, review them, and follow them? Absolutely.
People are just as important as the paperwork.
Okay, so let's talk about personnel training
and qualifications. All right. So this is where
things get really interesting. OK. Because as
CFR Part 2 -12 and one of our Season 2 transcripts
point out, it's not enough to just have procedures
written down. Right. You have to have people
who are qualified to carry out those procedures.
OK. So you need a skilled and knowledgeable team.
Exactly. You need people who understand the regulations
and who have the experience to apply them in
a real world setting. And how do you make sure
you have those people? Well, it starts with hiring
the right people. Okay, so looking at their education,
their background, their experience. Exactly,
but it doesn't stop there. Right, because things
change. Things change and people need to stay
up to date. So ongoing training is crucial. Absolutely.
You need to have a robust training program that
covers all aspects of GMP. And one of our Season
6 transcripts pointed out that the competence
of your personnel directly impacts the quality
of your product. Absolutely. It's a direct link.
So if you have well -trained people... They're
more likely to have high -quality product. And
if you have poorly -trained people... You're
more likely to have problems. Right. And those
problems can lead to... Recalls of warning letters,
all sorts of bad things. Okay, so training is
not just a nice -to -have, it's a must -have.
It's a critical part of your quality system.
And how do the inspectors assess whether your
people are properly trained? Well, they do it
through interviews. OK. So they'll actually sit
down with your employees and ask them questions.
Exactly. And they'll be listening for certain
things. Like what? Well, they'll be listening
to see if the employee understands the procedures.
OK. If they can explain them in their own words.
Right. And they'll also be looking to see if
the training has actually translated into the
employee's daily work practices. OK. So it's
not just about knowing the theory. It's about
applying it in practice. Exactly. And they might
ask the employee to describe what they would
do if they encountered an unexpected situation.
Okay. So they're really trying to gauge the depth
of the employee's understanding. Exactly. They
want to know if the employee can think critically
and solve problems. And this all goes back to
those written procedures we talked about earlier.
Absolutely. Those procedures are the foundation.
And the training is what brings them to life.
Exactly. It's the bridge between the theory and
the practice. OK, so we've talked about documentation.
We've talked about training now. Let's talk about
how to proactively identify any gaps in your
quality system before the inspectors find them.
Yes, the art of the mock audit. OK, so what exactly
is a mock audit? Well, it's basically a simulated
inspection. OK, so you're pretending to be the
inspector. Exactly. You're putting yourself in
the inspector's shoes, and you're looking at
your operations with a critical eye. And why
is this so important? Well, As Steinborn points
out in one of the book excerpts, internal audits
are an invaluable tool for self -assessment.
They allow you to step back and evaluate your
own compliance with the regulations and your
own internal standards. So it's a chance to find
your own weaknesses before someone else does.
Exactly, and to fix them before they become a
problem. And one of our Season 6 transcripts
mentioned that mock audits can help you identify
potential deviations from both the regulations
and your own procedures. Absolutely. It's a chance
to see if you're actually following the rules
that you've set for yourself. And I'm guessing
that this proactive approach is really important.
It's critical. You don't want to wait for the
FDA to tell you that you're doing something wrong.
Right. You want to find it and fix it yourself.
Exactly. It's about being proactive and taking
ownership of your quality system. Okay, so mock
audits are a great way to find those gaps, but
how do they fit into the bigger picture of GMP?
Well, mock audits are a vital part of the continuous
improvement cycle. They provide you with feedback
on how your systems are actually working. And
you can use that feedback to make changes and
improve your operations. So it's not just about
finding problems. It's about using those problems
to make things better. Exactly. It's about learning
from your mistakes and constantly striving to
improve. And the PECB transcript we looked at,
they talked about the importance of investigating
discrepancies? Yes. They said that you should
investigate any unexplained discrepancies or
failures to meet specifications. Okay, so if
something goes wrong, you don't just shrug it
off, you try to figure out why it happened. Exactly.
You dig deep, you find the root cause. And then
you put measures in place to prevent it from
happening again. That's the essence of corrective
and preventative action. OK, so mock audits can
be a great way to test your ability to investigate
and correct problems. Absolutely. You can use
mic audits to simulate different scenarios. OK,
so you might stage a mock recall or a mock contamination
event. Exactly. And then you can see how your
team responds. OK, so it's like a fire drill.
Exactly. You're practicing for the real thing.
OK, so we've talked about preparation. We've
talked about finding those gaps now. Let's talk
about what happens when the inspector actually
shows up. All right, so now we're in the hot
seat. Right, so what's the most important thing
to keep in mind during an inspection? I would
say transparency and communication. Okay, so
being open and honest with the inspector. Exactly,
don't try to hide anything. Right, because they're
gonna find it anyway. They will, and it will
look a lot worse if you try to cover it up. Okay,
so be upfront and be honest. Exactly, and the
Advancing Health transcript, they emphasize the
importance of maintaining honesty and accuracy
in all your reporting. Okay. So don't fudge the
numbers. Don't try to make things look better
than they are. Right, just tell the truth. Tell
the truth and be prepared to back it up with
documentation. And they also talked about this
idea of being willing to be monitored and audited.
Yeah, yeah, that's important too. Okay, so don't
be defensive. No, don't be defensive, be cooperative.
Okay, so the inspector is not your enemy. No,
they're there to help you improve your operations.
Okay, so you should view the inspection as an
opportunity. An opportunity to learn and grow.
Okay, and what if the inspector does find some
issues? Well, then they'll issue you a Form 483.
Okay, and what is a Form 483? It's basically
a list of the inspector's observations. Okay,
so it's not a formal finding of a violation?
Not necessarily. The FDA will review the 483
and decide whether to take further action. Okay,
so it's like a warning? It can be seen as a warning,
but it's also an opportunity to correct the issues.
OK, so what should you do if you receive a 483?
Well, the FDA's own clinical investigator training
course materials, they have some excellent advice
on this. OK, I'm listening. First of all, they
recommend that you submit a written response
to the 483. OK, so you don't just ignore it?
No, you don't ignore it. You take it seriously.
And why is it so important to respond? Well,
it shows the FDA that you acknowledge the observations.
and that you're committed to taking corrective
action. OK, so it's about demonstrating that
you're taking it seriously. Exactly. And it also
gives you a chance to provide any additional
information or context that might be helpful.
OK, so you can tell your side of the story. Exactly.
And the training materials, they lay out some
specific elements that should be included in
your response. OK, let's hear it. So first of
all, you need to address each observation individually.
OK. And for each observation, you need to state
whether you agree or disagree. OK. If you agree,
then you need to outline your plan for corrective
action. Okay, so your CAPA plan. Exactly, and
your CAPA plan should include any actions that
you've already taken. Okay. When those actions
were completed and your plans for future actions.
Okay, so you need to be specific. E -specific
and include realistic timelines. Right, you can't
just say you'll fix it someday. No, you need
to have a concrete plan with deadlines. And you
also need to explain how you'll verify that your
actions were effective. Absolutely. You need
to be able to prove that you fixed the problem.
Okay, and what about if you disagree with an
observation? Then you have the right to present
your own evidence and rationale. Okay, so you
can challenge the inspector's findings? Yes,
but you need to do it respectfully and professionally.
Right, so no yelling or name -calling. No, stick
to the facts and present your case clearly and
calmly. Okay, and how long do you have to submit
your response? The FDA recommends 15 business
days. Okay, so that's about three weeks. Yes,
and it's important to meet that deadline. Why?
Well, because if you submit your response late,
it might not be considered during the FDA's review
process. OK. So they might already be writing
you a warning letter. Exactly. So don't delay.
Get that response in as soon as possible. OK.
And what happens if you don't submit an adequate
response? Well, the training materials are very
clear about this. Uh -oh. Failure to respond
adequately can lead to further regulatory action.
OK. So that's bad. That's bad. It means more
scrutiny, more inspections, more problems. OK.
So. take the 483 seriously and respond appropriately.
Absolutely. It's not something you want to brush
off. Okay, so we've covered preparation, documentation,
training, self -auditing, communication regarding
potential findings. What about the actual interaction
with the inspector during the inspection itself?
Ah, the main event. Right. What are some key
things to keep in mind? Well, the understanding
FDA inspections and data transcript had some
good insights on this. Okay, let's hear it. They
emphasize that FDA inspections are designed to
look at all aspects of your manufacturing operations.
OK, so they're not just focused on one specific
area? No, they're looking at the big picture.
OK. And they're particularly interested in your
quality system. Right, because that's the foundation
of everything. Exactly. Your quality system is
what governs all of your operations. OK. And
they also mentioned that the FDA typically doesn't
do paper audits before they come on site. That's
right. They're coming to see your operation in
person. Okay. They want to observe your processes,
they want to talk to your employees, they want
to see how things are actually done. So it's
not just about checking boxes? No, it's about
understanding how your system functions in the
real world. Okay, and how do they decide which
facilities to inspect? Well, they use a risk
-based approach. Okay, so they're more likely
to inspect facilities that have a history of
problems. Expert.