How does an expert FDA investigator conduct a manufacturing inspection? While each inspection and each investigator is different, what thought processes might they use as they walk through a facility?

At the 48th annual International GMP Conference held in early March 2024 at the University of Georgia in Athens, Georgia, FDA national expert pharmaceutical investigator Simone Pitts provided a rare glimpse into the approach and thought processes an expert FDA investigator goes through when conducting inspections of manufacturing facilities.

“Normally during inspections,” she said, “there are certain things that we are definitely going to cover. We only have a short period of time, so we are going to be looking at the quality system and probably be looking at analytical data from the laboratory to make sure product going out the doors meets your specifications.”

Pitts presented three case studies that centered around deficiencies in cleaning programs, tablet and packaging operations, and microbiology labs. Following are the remarks she made, in her own words.

Cleaning Programs

“During the walk-throughs, we will walk around the facility and check various pieces of equipment to make sure that they are clean, especially if they are stated or tagged as being clean. We like to look at them and make sure they are actually clean.

We are going to look in those hard-to-clean places, those hard-to-reach places, and make sure your cleaning validation is based on the worst-case scenario.

We are going to spot-check equipment tagged as clean to make sure it is, and to make sure that the firm is doing its due diligence. If you say you have an effective cleaning program in place, we are going to verify that you do.

We will look in tanks, blenders, what have you, the hard-to-clean places – for example, agitator bars and baffles if there are any. Then there is the discharge – the discharge valve is usually at the bottom of the tank. So those are the places where you can possibly have residues that get stuck and get left behind.

If there is not a robust cleaning system which can hit those target-rich places that we are going to check, then you are probably going to have issues such as residues being left behind. The residue could either be from cleaning agents that are being used, or it could be the API itself, depending on the nature and the structure of the API. If you don’t have a robust cleaning process, those residues can be left behind.

The biggest concern with that is going to be cross-contamination. So, the next product that is coming behind that – what is going to be the impact on that product? If you don’t have an effective cleaning program, and if the process leaves residues behind, then the next product will probably be contaminated with the previous product. Cleaning is big. Cleaning is a big ticket item for us to double-check when we are on manufacturing facility inspections.

You need to identify the residues. If there is a residue left behind, the biggest thing we want to know is what is it? And what is the impact going to be for maybe the current batch and for future batches that have been manufactured?

During a recent inspection, a piece of equipment was labeled as clean. The tank was labeled as clean. But looking inside the tank, it wasn’t. There were white spots inside the tank. And when asked about the white spots, the firm said, ‘We are not exactly sure what they are.’ When you say that to an investigator, of course the ears go up, your spider sense starts tingling. You’re like, ‘Well, if you don’t know what it is, I definitely don’t know what it is, so maybe we should find out what it is together.’

As part of the written procedures, are there instructions for disassembling a piece of equipment? Because if you don’t have proper instructions instructing personnel on how to clean, then they are not going to know how to clean. We like to see in the SOPs descriptors of how to disassemble something, how to clean it properly, then how to reassemble and make sure everything is in good working order before moving forward.

If an issue arises, what was the CAPA plan? How are you going to ensure that this does not happen again? Where do you see the problems and how do you fix those problems and mitigate any issues moving forward so it does not happen again? And then also as part of that, what is your CAPA effectiveness check?

Tablet and Packaging Operations

As part of the inspection process, we are going to look at packaging and labeling if the firm packages and labels products. And as part of that process, we are going to make sure that everything is validated from beginning to end. Are all the pieces of equipment that are identified on that packaging line calibrated? Specifically, if they have weight checks, there is going to be a weight check on the line. So, is that a calibrated piece of equipment?

There may be tablet counters. Is the tablet counter calibrated? And has everything that is part of that inspection line been validated as one integral unit? It can have empty bottles, blister cards, whatever is coming through – are they going to be filled appropriately with the correct number of tablets, capsules, or what have you?

Then is it going to go maybe through a weight check system to make sure it has the proper number of tablets or capsules in there. Then is it going to be labeled properly? And if it’s labeled properly, is there is an expiration date? And however that date is going to be coded on there, is it going to be stamped on the label? If it’s a blow-fill-seal system, is it already part of the manufacturing process? Those are all types of things that we are going to look at on inspection.

If a firm has numerous deviations for broken tablets, the FDA investigator is thinking, ‘There is something wrong.’ Perhaps the machine is dropping tablets too hard or there is too much force. Or you go back and look at the manufacturing process. If you are looking at the manufacturing process, maybe the compression force for the tablets is not strong enough or it is not meeting specification. Maybe the tablets are too soft, and with manipulation they are breaking during packaging.

When we see things like that, those are the things that we are starting to think about – where in the process could things go wrong? You immediately think, go back to the process itself. Could it be something in formulation? Are there compression issues? Is the right amount of the material in there to make sure it makes a complete tablet that is meeting specifications?

If that doesn’t end up being a problem that has been identified, what is going on in packaging? Are they packaging the product like they are supposed to and getting enough tablets? Is the bottle maybe too large and they are having too much movement during shipping?

You start to think of the many and multiple things that could possibly go wrong – what could possibly have happened. In one case it was that they did not validate the packaging line properly and that pretty much was the problem. Normally when we are on inspection, we ask for your validation protocols and your validation reports. That is what we are going to look at.

We are going to make sure that the firm set its criteria for what it needs to meet, and that the validation report is the summary showing that those criteria were met. Then we will look for failures or look for inadequacies.

Microbiology Laboratories

Whenever a firm receives microbiological media, the proper protocol is to evaluate that media. You need to do some sort of testing to make sure that the media that you purchased can support growth. Because if it can’t support growth, then it’s useless – it can’t be used for routine laboratory analysis. It can’t be used for surface sampling or any sampling. If the medium isn’t able to support growth, there is no point in using it.

If you don’t have a validated micro method and the right controls in place, and if you are testing product to meet a specification that is microbiologically based, then you are not going to get a valid result.

Therefore, the firm doesn’t know if product going out the door is safe for consumption. Is it going to have a large microbial growth load in it? And if it does have a large microbial growth load, what is that going to look like for the patient? Are there going to be any safety concerns?

If the patient is immunocompromised, how is that microbial organism going to fare for them? Is it going to make them sicker? Is it going to compromise them even more? You need to have a validated method in place. The USP chapters discuss how to validate an alternative microbial method.

Right now, a big trigger for the agency is Burkholderia cepacia, which is a particularly nasty bug. It likes to hang out in the water systems. FDA is stressing more and more the USP chapter 60 for B. cepacia. We require all firms to follow and test according to USP chapter 60.

We like to stress that the ability of microbiological testing to detect objectionable organisms should be tested and must be established and validated.

We also stress that if a drug product is contaminated with microorganisms, a firm just cannot say, for example, as part of a deviation, ‘Well, we did the investigation and we say that it was only this one lot or this one partial lot of product that was affected, so we are going to release the other half. We are just going to contain and then reject the other half.’

You can’t do that. You can’t really say, ‘Well, it is here, then it is not over here. It is here, so it is not here.’ Microbial growth is not uniform. They are nasty little bugs. They appear and they hide. You don’t see them for a little while and then they appear again.

Quality Unit

What is the role of the quality unit? The quality unit comprises QA, which is quality assurance, and QC, which is quality control. There must be a comprehensive quality system in place that has oversight of the manufacturing operations. When I say manufacturing operations, that means from incoming materials, how it is being received, the manufacturing process, process validation, SOPs in place, finished product out the door, analytical testing, stability testing. Everything should have quality oversight, including the selection of vendors.

Who are they selecting to purchase and receive materials from? If they are using contract manufacturers, then there needs to be oversight for contract manufacturing. If they are using contract testing laboratories, there needs to be oversight over the contract labs. The key takeaway is quality has the ultimate responsibility for products going out the door, and the lack of a quality unit or an ineffective quality unit is no excuse.”

FDA Investigator Profiles

Simone Pitts’ insights into the thought processes of an FDA investigator help provide an approach one could use to perform a self-assessment of a manufacturing facility, prepare for an inspection, and train company auditors. Each investigator has his or her own approach and areas they tend to focus on.

Having background on the inspection tendencies of a specific FDA investigator inspecting your facility, including which quality systems they cite most, can help facilitate preparations and interactions during the inspection.

Redica Systems provides profiles of FDA investigators with a variety of useful information. For example, here is some of the information in our profile of Simone Pitts: