35 – Conducting the GMP Audit Best Practices (S18E3)

Okay, so you know how we all have that medicine
cabinet right or those vitamins and supplements
we take like every single day, right? But like
how often do we actually stop and think about
you know, how that stuff is actually made like
what goes into Ensuring the quality of what we're
putting into our bodies. Yeah, that's a really
good point I mean most people probably don't
exactly so this deep dive is for all those curious
minds out there who want to understand what happens
behind the scenes to guarantee the quality of
these products that we all rely on. Yeah, absolutely.
And today, specifically, we're going to be focusing
on a crucial process, good manufacturing practice
audits or GMP audits for short. And you've been
amazing. You've given us a ton of information
to work with. We've got everything from the official
rules laid out in the Code of Federal Regulations,
parts 110, 111, and 211 to the guidance doc.
straight from the FDA. Plus, we've got insights
from some really interesting pharmaceutical science
books and even some GMP training materials. It's
a lot to cover. Yeah, it is. It's going to be
a deep dive for sure. But that's our mission
today, right, to really dig deep into how these
GMP audits are actually conducted. You know,
we want to understand how they make sure that
quality is basically built into the manufacturing
process from the ground up. Exactly. So we're
going to be looking at the different techniques
auditors use. What are they looking for when
they go into a facility? What are they looking
for when they look at a company's records? How
do they even spot potential problems? And why
is it so crucial for them to stay objective throughout
the entire process? Right. It's like we're getting
a backstage pass to see how the safety and effectiveness
of our health care products are actually protected.
Yeah. Exactly. Okay, so let's jump right in.
Where do these auditors even begin? What are
some of the main strategies or techniques they
use to approach these GMP audits? Well, one of
the most fundamental things they do is they actually
talk to the people who are making these products.
You know, they have these structured interviews
with the personnel, the people who handle, you
know, manufacturing, processing, packing, even
storing the drug products. And this is really
insightful because as 21 CFR 211 .25B points
out, these are the individuals who are directly
influencing the quality of what's being produced.
Makes sense. And talking to them really helps
reveal if the training they receive actually
translates into their daily work and you know
how well they understand what they're doing and
why they're doing it. So it's not just about
you know, checking if the machines are working
properly. It's about understanding if the people
behind those machines actually know what they're
doing and why it's important. Exactly. So what
kind of questions do auditors ask in these interviews
to kind of gauge that understanding? Well, they
might ask someone about their understanding of,
you know, the step -by -step instructions for
a particular task. You know, their standard operating
procedures or their SOPs. They'll want to know
if they've been trained properly on these procedures.
And a really important question is, you know,
what would you do if some something unexpected
happened or if you notice a deviation from the
norm. And their answers to those questions really
help auditors understand the level of quality
awareness within the company. You know, are the
quality procedures just rules on paper or are
they really ingrained in the way people work?
I see. So it's really about that company culture.
You can have, you know, the most perfect procedures
written out, but if people aren't following them
or they don't understand why they're important,
then it's not going to mean much. Right. Now
another key technique we talked about was the
thorough record reviews. And this sounds like
it could involve a lot of paperwork. Yeah, it
definitely can. But it's a really crucial part
of the audit. Meticulously examining the documentation
gives the auditors a verifiable history of the
manufacturing process and of all the quality
control measures that are in place. So think
of it like piecing together a story of how each
product was made and tested. Okay, I like that
analogy. So what kind of documents are they scrutinizing?
What are they really looking at under a microscope?
Well, at the very core, you have the batch production
and control records, which 21 CFR 211 .188 goes
into detail about. These are like the recipe
and the production log book for each specific
batch of medication. Got it. They detail everything
from, you know, the raw ingredients used, the
specific equipment that was involved, to who
performed each step and when it was performed.
And if there are discrepancies or missing entries
in these records, that can be a major red flag.
Right. It suggests that there might have been
issues during manufacturing. that weren't properly
addressed or documented. So it's like a detective
looking for clues. They want that complete and
accurate account of how that particular batch
was made. Exactly. What else are they looking
at in that paper trail? They'll also carefully
examine records related to all the components
that go into the final product. as well as the
containers, the closures, like the bottle caps
and the labels, regulations like 21 CFR, 211
.80, 211 .122, 211 .130, and 211 .184 all outline
what's required in these areas. It's essential
that these materials meet very strict quality
standards and that they're correctly identified
and controlled from the moment they arrive at
the facility until they're actually used. And
it's interesting these records actually have
to be kept for at least one year after the product
or even three years for certain over -the -counter
drugs, according to 21 CFR 211 .180. So that's
a lot of record keeping. Yeah, it is. It really
emphasizes the importance of traceability, knowing
exactly where everything came from and where
it went. Absolutely. So specifically, what are
they looking for in these records about the containers,
the closures, the materials? They're verifying
that... Every incoming shipment of these things
was properly sampled, tested, and then approved
by the quality control unit before it was used
in production. And this is a key point that's
highlighted in 21 CFR 211 .84a. The actual testing
and examination results showing whether the materials
were accepted or rejected based on predefined
quality standards are super important. And that's
mentioned in 211 .184b. This whole process makes
sure that only materials that meet the required
quality standards actually end up in the final
product. Yeah, you definitely want to catch any
problems with the raw ingredients or the packaging
right away. the beginning? Exactly. Before it
even gets to the manufacturing stage. Now what
about the machines and the equipment that are
actually used to make the products? Right. Are
there records for those as well? Oh absolutely.
The procedures for cleaning and maintaining the
equipment and utensils, along with the logs that
document when and how this was done, are all
thoroughly reviewed. Regulations like 21 CFR
211 .67b and various GMP training materials really
emphasize how critical this is. These procedures
need to be incredibly detailed they have to specify
who's responsible for the cleaning the schedules
for when the cleaning happens the exact methods
and materials to be used and probably most importantly
how contamination is prevented right so it's
not just you know a quick wipe down it's a whole
system designed to ensure cleanliness and to
prevent one batch from contaminating another
okay so it sounds like every piece of equipment
basically has its own maintenance and cleaning
history yeah now I also remember our sources
mentioning something about calibration records
yes The records of calibration and maintenance
for all the equipment are absolutely vital. And
this includes the initial qualification process,
which we saw in a YouTube transcript on 21 CFR
111 GMP laboratory overview. And this involves
something called design qualification, installation
qualification, operational qualification, and
performance qualification. Wow, that's a mouthful.
I know, right? DQ, IQ, OQ, and PQ. OK, so can
we break that down a little bit? Like, what does
each of those qualifications mean? Sure. So think
of DQ like verifying that the design of the equipment
is actually suitable for its intended purpose.
OK. IQ is all about confirming that it was installed
correctly. Gotcha. OQ is making sure that it
actually operates the way it's supposed to under
controlled conditions. Right. And then PQ is
proving that it consistently produces a quality
product in a real world manufacturing environment.
OK. So it's like taking it through a series of
tests, basically. Yeah. major equipment should
go through all these stages to ensure that it's
you know properly designed installed working
correctly and that it consistently produces the
desired result right and then after any significant
changes or repairs or even if equipment is moved
it might need to be Requalified and all of that
needs to be documented Wow, and you know even
smaller mobile equipment like pH meters and balances
They need to be calibrated regularly to make
sure they're accurate. Okay Although they might
not require that full qualification process every
time they're used, so it's all about ensuring
that Every tool used in manufacturing is accurate
and reliable. So it's like every piece of equipment
has its own quality passport, basically. Yeah,
I like that. It has to prove its credentials.
Now, what's another key area of records that
auditors really focus on? Another really important
area is how a company handles complaints. Written
procedures for dealing with complaints are mandatory.
And we saw that mentioned in a YouTube transcript
on good documentation practices. Auditors will
review those procedures to see if they're thorough
and to ensure that all complaints are properly
recorded, investigated, and that appropriate
actions are taken in response. And the speed
and the thoroughness of those investigations
and the corrective actions that are implemented
are really strong indicators of a company's commitment
to continuous improvement and to patient safety.
Right. So it's not just about making the product.
It's about being responsive to feedback and making
sure that any issues are addressed quickly and
effectively. Absolutely. So we've talked about
the paperwork. It seems like every step leaves
a trail that these auditors are carefully following.
Right. Now the third major technique we mentioned
with on -site observations. So this is where
the auditors actually get to see what's happening
in real time on the ground, right? Yeah, exactly.
Direct observation of the manufacturing and the
laboratory operations is absolutely crucial.
It lets auditors verify if what's written in
the procedures is actually being followed in
practice. OK. And it lets them identify any potential
that might not be obvious just from looking at
the records. So it's all about seeing the reality
of the manufacturing environment. Makes sense.
So as they're walking through the facility, what
are some of the key things they're paying attention
to? Well, facility design and condition is a
primary focus. You know, auditors assess whether
the layout and the construction of the building
actually help prevent contamination and make
cleaning easier. Right. This includes things
like having smooth, durable, easy -to -clean
surfaces in areas where the product is directly
exposed. You know, sealed openings in the walls
and ceilings, appropriate flooring. And we saw
these details in sources like good design practices
for GMP pharmaceutical facilities. I'll also
check if there's enough space to prevent mix
-ups between different products or materials.
And that was something we saw highlighted in
a YouTube transcript. So the building itself
needs to be designed with quality in mind. Exactly.
What about the actual work that's being done?
What are they observing there? They're looking
very closely at the sanitary operations, including
general maintenance, pest control measures, and
how waste is handled, as required by 21 CFR 110
.35 and various GMP training materials. They
also pay very close attention to hand washing
and sanitizing facilities and practices, referencing
regulations like 21 CFR 110 .372 and 110 .35.
And they'll look for things like, are there easily
visible signs reminding employees about proper
hand hygiene? those are things they'll definitely
be checking. It's interesting how those simple
things can be so critical in this context. What
else are they looking at as they're walking through?
What other details catch their eye? They're also
looking at how materials are handled and stored.
Okay. Auditors want to see that raw materials,
whether they're liquids or powders in bulk, are
stored in a way that protects them from contamination.
And that's something that's emphasized in 21
CFR 211 .84A and CFR title 21110 .PDF. And finally,
they'll assess the ventilation and air control
systems to make sure that things like odors,
vapors, and any potential airborne contaminants
are minimized, and that's in line with 21 CFR
110 .20B6 and 211 .42B. They'll be checking if
fans and air blowing equipment are properly located
and operating correctly, as mentioned in 110
.20B6. And you know, in sterile manufacturing
areas in particular, you can expect especially
intense scrutiny of these systems because the
risk of contamination is so high. Right. So it's
a really comprehensive look at everything, from
the people to the paperwork to the physical environment.
to try to get a complete picture of the GMP compliance.
Now what happens if an auditor sees something
that isn't quite right? How do they actually
go about identifying these deviations and then
figuring out if a company is truly meeting the
required standards? Well, they use a very systematic
approach. They compare everything they observe
and every record they review against the established
benchmarks. And these benchmarks include the
GMP regulations themselves, the company's own
detailed standard operating procedures, and any
predefined acceptance criteria for tests and
manufacturing processes. Okay, so if something
doesn't measure up against those benchmarks,
that's noted as a deviation. Exactly. Any departure
from those established standards is noted as
a potential noncompliance. And it's important
to remember that the observations that auditors
make, such as those documented on FDA form 483,
are potential deviations. They need further evaluation
by regulatory agencies to determine if they actually
constitute a violation. And we saw that highlighted
in YouTube transcripts, like understanding FDA
inspections and data and FDA clinical investigator
training course. So a 483 is more like a notification
of concerns that need to be looked into further
rather than a final judgment. That's an important
distinction to make so that the company then
has a chance to respond to those concerns and
provide more information. Exactly. Now, I thought
this was interesting. A YouTube transcript on
accuracy and precision in bioanalysis mentioned
that Even if test results consistently fall very
close to the acceptable limits, that could actually
raise a red flag for auditors. Right. Because
it could indicate underlying issues with the
testing methods themselves. And that would warrant
a closer look. It's like they're not just looking
for outright failures. They're also looking for
patterns that might point to a problem. Precisely.
They're looking for anything that could potentially
impact the quality, the safety, or the effectiveness
of the product. OK. And as a comprehensive analysis
of FDA form 483 observations points out certain
regulations tend to be cited more frequently
than others and those often relate to the responsibilities
of the quality control unit. 21 CFR, 211 .22D,
the thorough review of production records, 211
.192, and the establishment of very clear written
procedures, 211 -100A. And this kind of gives
manufacturers some insight into areas where maintaining
full compliance can be particularly challenging.
That's really valuable information for manufacturers
to have. Yeah. So they can really focus on those
areas where maybe things are a bit more tricky.
Right. Now, throughout this whole auditing process,
what are some of the critical qualities or practices
that the auditors themselves need to have to
make sure the audit is both effective and fair?
Well, clear communication is absolutely essential,
and Leonard Steinmore discusses this in his GMP
So Quality audit manual. Auditors have to be
able to clearly articulate their findings and
any concerns they have, not just during the audit
itself, but also in the closing meetings. Right.
This ensures that the company being audited fully
understands the observations and they have the
opportunity to ask questions. So it's about being
transparent and open and avoiding any surprises
at the end of the audit. Exactly. What about
the auditor's mindset and approach going into
this? Objectivity is paramount. Now, auditors
have to base their assessments solely on the
evidence and the facts that they gather, sticking
strictly to the regulations and to the company's
own procedures. They need to avoid letting personal
opinions or biases influence their judgment.
And we saw this principle of impartiality emphasized
in numerous sources. Their role is to assess
compliance against those established standards.
It's not to impose their own views or opinions.
Makes perfect sense. It's about sticking to the
facts and the rules. And I've always heard that
saying, you know, if it isn't documented, it
didn't happen. Right. How does that apply to
the auditors and the work that they do? Detailed
note -taking is absolutely crucial for auditors.
Comprehensive and accurate notes form the foundation
of the audit report. You know, they provide the
evidence to support the findings. So whether
it's an observation that's made on the manufacturing
floor, a key point from an interview with personnel,
or specific details from reviewing records, thorough
documentation is non -negotiable. Like you said,
if it's not documented in the auditors' notes,
it's as if they didn't see it or hear it. And
the goal is to really capture all the relevant
information, both positive findings and any areas
of concern. to provide a true and fair representation
of the facility's compliance status. So a GMP
audit is clearly much more involved than just,
you know, ticking boxes on a checklist. It's
a combination of sharp investigative techniques,
a real commitment to objectivity, and a very
meticulous approach to documentation. Absolutely.
And it's all working together to safeguard the
quality of the healthcare products that we all
depend on. Right, and the next time you reach
for a medication or a supplement, you know, take
a moment to think about all those rigorous processes,
including these detailed GMP audits that are
in place to help ensure its safety and its effectiveness.
I think this deep dive has really shed some light
on the best practices in GMP auditing. Now, I'm
curious, what stands out to you as the most critical
aspect of ensuring quality in pharmaceutical
manufacturing? And what other questions do you
have about this really complex regulatory landscape?
We encourage you to keep exploring and digging
deeper into this incredibly important field.
Yeah, it's a fascinating area. It really is.
And there's always more to learn.