Making Sense of Cleanroom Regulations
Airborne particle monitoring is a core part of contamination control in sterile manufacturing. Cleanroom teams need to understand how regulations apply to classification, routine monitoring, electronic records and internal risk assessment.
Watch the webinar, Making Sense of Cleanroom Regulations, led by Nicole Aguilar, MSc, Global Product Manager, for a practical review of cleanroom requirements in pharma and biopharma environments.
In this webinar, you’ll learn:
- Why airborne particulates matter in sterile manufacturing
- How cleanroom classification differs from routine monitoring
- How ISO 14644-1, EU GMP Annex 1 and FDA cGMP connect
- Why 21 CFR Part 11 matters for electronic records and signatures
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Hi, everyone. My name is Kyran Page with Beckman Coulter Life Sciences. I'll be moderating today's webinar, and I'm happy to welcome you to this webinar presented by Nicole Aguilar. Nicole is an expert in the field of air particle science, and she holds a master's degree in chemistry with a specific focus on aerosol science from the University of Denver.
She's also a member of the International Organization for Standardization Technical Committee 209. And there, she works to develop and communicate consensus position on ISO 14644.
Nicole has worked with Beckman Coulter Life Sciences for the last six years as a technical specialist and later product manager supporting customers using air particle counters like the MET ONE 3400+.
If you have any questions during Nicole's presentation, please feel free to use the question and answer function to the right of your screen. With that, I'll hand over to Nicole to start the presentation.
Thank you for that introduction. As Kieran noted, my name is Nicole Aguilar. I am a global product manager at Beckman Coulter. And today, we're going to be going through, a presentation webinar on really how do we make sense of cleanroom regulations.
You may have heard many different acronyms, such as ISO, EU GMP, FDA cGMP, and 21 CFR Part 11. Today's goal is for you to leave with a clear understanding of what each standard does and how they all fit together.
As noted, I do work for Beckman Coulter Life Sciences, and we are a proud partner or OpCo of Danaher Corporation since 2011.
So first, just going right into it. This is an outline to show where we're going to be moving throughout the story in this presentation. So first, why do we even care about airborne particles in pharma, biopharma specifically?
Current cleanroom regulations, had mentioned some terms earlier like ISO 21 CFR Part 11. We're gonna go into classification versus routine monitoring as well as data integrity aspects, so FDA 21 CFR Part 11. And then looking more into internal regulations or I should say standards and procedures and guidance documents that you have at your own facilities.
So let's set the stage. What actually keeps this audience up at night? And, really, it's the primary concern in a sterile manufacturing environment is not dust. It's the presence of viable microorganisms that can contaminate drugs.
So a patient receiving an injectable has no barrier between them and that vial. So at the end of the day, what we truly need to measure is a living organism.
And the most frustrating part of this all is that technology is extremely limited today in order to be able to measure, characterize, provide an identification of viable accounts in real time. So I want to emphasize that all of those attributes in real time.
It is important to note that there is technology that is up and coming today and is being discussed in technical committees for implementation that do allow viable particle counting in real time. However, there's still a lot of hardships in implementing this newer technology.
With that being said, because of these challenges, particle counters are used as surrogates in this case. We may not be able to count and characterize microbes in real time just yet, but we can count the total airborne particle instantly and continuously. And in that case, it's an indirect measurement, and we're using particle counting as a proxy.
And you may ask yourself, how does this proxy work? Why does it work? Viable particles are everywhere. They originate from personnel, your clothing, skin, even breathing, for example.
And people really are the dominant source of contamination in a cleanroom. And microorganisms, they don't just float around naked. They actually ride on skin cells or droplets. So when particle counts go up, the probability of viable contamination also goes up with them.
So moving forward, the entire premise of this presentation is that we have guidance documents, regulations for classification, monitoring, even data integrity, and all of these guidance documents were really built on measuring particles as a proxy for microbial risk.
So after just setting the stage of why do we care about air particle counting, the last slide I really ended on the point that people are the source of contamination.
So let's look at this a little bit more. Instead of thinking, hey. We are the main source of contamination. How does that look? We really cannot maybe be a strong source of contamination. Let's look at some of the numbers back in the envelope calculations.
Every hour, up to 3,000 cells are shed from one square centimeter of skin. For reference, one square centimeter is about the size of your pinky fingernail.
Given that, that's about 1,000,000 cells per hour. Now cells alone would just be particles. Right? But we also had mentioned that cells carry microbes or individual particles carry microbes. Your skin has a healthy skin microbiome. It's a complex community, fungi, bacteria, viruses. That is completely normal and healthy.
But it also brings you to the fact that 100,000 skin cells with bacteria are shed per hour. If you look at the two people or the image on this slide, they're having an ordinary day-to-day conversation, talking to one another, breathing, moving in a small space. Although they're doing something completely ordinary, they are also contaminating that space at this point in time.
And all of these statistics that you see right here, these numbers, these are people that are standing still. This is someone who is not moving. So imagine someone in a cleanroom moving, talking, gowning up, making adjustments, really exposing a microbe to or exposure to an open vial or product.
And this is why cleanroom design is so important, and it emphasizes gowning and airflow. It's extremely important the number of people that you have in a critical zone. You are not just trying to stop contamination. You're really trying to manage the source because you are the source, and you can never fully switch it off.
So let's take these statistics, these numbers, and instead of treating it like an academic problem, let's see a real world problem.
In 2012, nearly 800 people across 20 states developed fungal infections linked to contaminated vials produced by a compounding facility.
So the CDC reported that 64 of 753 patients died across nine states.
These steroid injections were given for back pain, simply routine procedures. Patients went in for pain relief, and then they contracted fungal meningitis.
You can see a map here on the slide. This map does show how far the contamination or infections had spread. They were not localized. So one facility contaminated or contamination reached up to 20 states.
It's important to note that the entire problem with microbe contamination couldn't be seen by the naked eye. It was invisible at the point of use, which is exactly why at the point of manufacturing, we need to have a controlled process environment where you are monitoring microbial contamination.
So moving into these regulations and standards that we'll be talking about, it's important to note that all of these grades and limits, these numbers exist to prevent situations like we see here.
So next, we're just gonna go into the current cleanroom regulations. I've hoped at this point, I've convinced you why airborne particle counters and particles are important to monitor and classify clean rooms in pharma, biopharma specifically, or just sterile manufacturing. With that being said, it's important to remember that you are the main source of contamination. At the end of the day, you are someone that not only provides that contamination, but should be someone that's enforcing procedures to help control that contamination.
So before going into any regulations or standards, I want to go into the umbrella or the framework. So the framework being Good Manufacturing Practices, so GMP.
This framework covers personnel, premises, equipment, containers, and documentation. The underlying concept is to produce a high-quality product consistently.
And what this image on the right is really getting at is that GMP is not just a single requirement. It's an entire vocabulary. It's a framework. So you're gonna see words such as compliance, quality control, audit, documentation. If you work in a space similar to this, these words are in your daily life.
And here's the connection that I want to make moving forward. So if we look at the second bullet, it's notes that both EU GMP and FDA cGMP reference ISO 14644 for the methodology of cleanroom classification.
That is a lot of acronyms, so I want to take a step back for a second.
We mentioned good manufacturing practices. It has this framework. And under this framework, we have regulations and we have standards.
So the in this case, ISO 14644, this is a published set of standards that is done by voluntary consensus. So this is done by the International Organization for Standardization. It is a nongovernmental body. Basically, the output of this documentation is a consensus among technical experts and industry participants.
You will also hear terms such as EU GMP and FDA cGMP. These are regulations issued by government authorities.
And as you can see that these regulators didn't write their own method for referencing or cleanroom classification. What they did is they referenced or pointed to ISO specifically. So one thing I want you to take from this slide is that ISO is a method. It tells you how to count particles, locations, sample volumes. It's technical. Whereas the regulation is more, gives you obligation. What is your expected outcome?
And the last bullet point is that the success of GMP compliance relies heavily on the people implementing it. When you think back to earlier in the presentation shedding numbers, it's especially true that both people are the ones enforcing it, and they're the primary source of contamination.
So let's go into a little more specifically into the introduction of ISO 14644. So ISO 14644 is a multipart standard. It is a family of separately published documents that share a common desire in mind. So in this case, ISO 14644 is very specific to cleanroom and associated control environments. The dash one or part one is one of those separately published documents where the focus of part one is to ensure that clean rooms are meeting specific requirements regarding size, counting, and testing locations and frequencies. This allows you to classify clean rooms. Please pay attention or make note of that word classification because we're going to come back to that.
So it specifies cleanroom or air cleanliness within a specific environment. I want to note that classification is a snapshot in time. It is not looking at the process as a whole. It is looking at the room in a snapshot state.
The particle populations that you'll be seeing, and we will show ISO tables, a little bit further in the presentation, are really distributions based on threshold particle sizes ranging from 0.1 microns to 5 microns.
So going into a little more about the details and what it looks like to classify a cleanroom, you probably have often seen, tables that reference ISO class numbers. So right here, there is a reference to a table that is actually in ISO 14644. This slide, once again, is gonna give you scope of that statement. This is what it looks like in practice. So you have rows on this table, which are classes one through nine, class one being the cleanest class. You have columns which show particle thresholds. So you see it through, 0.1 micron in size all the way up to 5 micron in size.
And each cell is your maximum allowable concentration in particles per cubic meter that are allowed in that specific space.
Now I want you to notice a couple things. You may see some blanks, for example. So there are some empty cells that are on the smaller particle end for cleaner classes, and then you might see some on the higher end, empty cells as well, closer to the 5 micron end. Those blanks are intentional, and that's because at very low concentrations, sampling and statistical limitations make classification very unreliable. And at 5 micron and above, particles are heavy enough that they physically just drop out of the sample tubing.
So collection efficiency in this case also drops at those higher sizes. So rather than ISO publish limits for instrumentations for numbers that they can't defend, it is to remove those and have statistically or risk assessments to really show the contamination control in those areas.
So it's important to note that when you are classifying a room, you are not just specifying a room's classification based on any particle size for any class, this table constrains you to which combinations you can actually be classified at.
It is also important to note that your results are only as trustworthy as the instrument you use. The technology should be properly calibrated, robust, and consistent with the relevant standards. We will discuss this later in the presentation.
So I had pointed out earlier to really hold on to that word classification, and the words classification and the term routine monitoring are often used interchangeably. And they are genuinely different activities.
They have different purposes, different sampling locations, different governing documents. So classification, as I noted before, is a snapshot in time. It's about certifying a cleanroom's state. It's the assessment of the room itself.
It tells you that that room met its limit the day you tested it under the state of how many personnel and equipment that you tested it in. It says nothing about that room and what will happen in its state two days from now or three months later.
So classification is very important, and it demonstrates that the cleanroom as a whole complies with its intended air particle concentration class. The key phrase once again, as a whole, you're proving the entire room's performance, not one favorable location.
Now I think what we I really want you to draw from this slide is the last statement at the bottom, that both EU GMP Annex 1 and the FDA cGMP state that classification is done to method defined in the ISO 14644-1.
This is a bridge and showing you that both of these regulatory bodies are pointing documentation. Once again, ISO, very method oriented and technical where these regulatory bodies are relying on that method development.
So let's look take a little bit or let's look into a little bit the EU GMP Annex 1. So the table on the right we looked at is the ISO 14644 classification table. And I had mentioned that the EU GMP Annex 1 is a regulation. It's governed by a regulatory body. It's I also noted that this EU GMP Annex 1 or just reference Annex 1 here on out, does reference ISO 14644.
However, these two tables have one job. They look similar in a way and also have some major differences that I want to point out. So ISO 14644 references class numbers. Whereas Annex 1 uses an entirely different vocabulary, it uses grades. So Grades A, B, C, and D.
Same underlying principles, different naming systems, basically.
So walking through the Annex 1 table on the right side, you will see grade a and grade b. Those are outlined. It's important to note that grade a and grade b must comply with ISO Class 5 requirements in an at rest state.
So I'm trying to show you similarities between the Annex 1 as well as the ISO 14644 guidelines.
Grade C must comply with the ISO Class 7 at rest, and grade d must comply with ISO Class 8 at rest.
I also want you to notice the phrase that I keep using, which is at rest. So if you look at the Annex table on the right, you'll see at rest and in operation. There are different states of what the cleanroom is in, and that's because Annex One is very specific to sterile manufacturing or pharmaceutical biopharmaceutical sterile manufacturing of drugs.
At rest, your room is certified.
The in-operation state is completely different. Personnel are in the room, and instruments and equipment are being used. Annex 1 requires risk to the patient and product to be assessed not only in the at-rest state, but also during operation, when personnel movement and interaction can increase the risk of microbial contamination.
It is important to note that ISO 14644 is intended for a broad audience. It applies not only to FDA-regulated facilities, but also to environments such as hospitals, semiconductor facilities, and aerospace facilities. Annex 1, by contrast, is specific to sterile manufacturing activities, such as gowning, filling vials, and masking.
So looking at cleanroom classification, that's a definition that we held on to before. Now looking at routine monitoring. Routine monitoring means that you're taking daily life or daily processes consideration while you're looking and monitoring air particle cleanliness. So compared to that classification, classification might happen once or twice a year. There is a different rhythm of sampling that happens with classification versus routine monitoring.
Routine monitoring is continuous. It really depends on the processes and personnel that are on in a day-to-day basis that are at play.
Data from routine monitoring can be used to trend overall cleanroom contamination level.
So monitoring does something very different than classification does. Classification is a snapshot in time. You can't use those data points to really trend and look at changes in background or air particle concentrations over time.
Whereas for routine monitoring where you have more frequent sampling at various different locations, the individual can start seeing trends, and these could be early mornings for example, catching a degrading HEPA filter or maybe gowning practices are drifting a little bit and you start to see particle concentrations rising.
A third difference is really to underline is that monitoring sampling locations are focused on contamination risks. So this is what's really happening at play.
Contrast to classification, classification has fixed locations. It's distributed out the methodology is distributed throughout the room, basically, where classification deliberately samples everywhere more often.
So a simple way to kind of remember this is classification is something alright. You can ask yourself, is the room capable? Whereas monitoring generally asks the question, is my product at risk right now at this point in time?
So we showed the relationship between, FDA cGMP, EU GMP, and ISO 14644. This is EU GMP Annex 1 snapshot just going into a little more detail. So it's important to note that Annex 1 really does provide guidance on designing and controlling facilities, equipment systems, and procedures for manufacturing sterile products.
What also makes Annex 1 different than ISO 14644 is that it does expect ongoing routine monitoring, so not just periodical classification or certification. So this is something that we had talked about previously between classification versus routine monitoring.
Annex 1 also does assign grades to different activities. So we had mentioned at rest versus in operation.
Annex 1, once again, was written for a manufacturing sterile product environment, where ISO 14644 is more of a general guidance.
Another difference is that Annex 1 does require viable monitoring, and it also does use quality risk management principles to ensuring that the final product is free of contamination. So quality risk assessment looks at different processes, personnel that's happening within the room, where instrumentation is placed, different practices. Whereas ISO 14644 is very technical, and it's a more of a method development to be referenced.
Next, I want to look into ISO 21501-4. So once again, this is an international standard, by the ISO committee. Once again, it's a consensus or, method that's really developed by a group of subject matter experts or industry and or industry participants. So the purpose of ISO 14644 is to provide a calibration procedure and verification method for particle counters. So your particle counters are used for your classification and routine monitoring methods, for example.
It's important to note that ISO 14644 does actually reference ISO 21501-4, and it specifically states that the particle counter should have a valid calibration certificate.
Frequency and method of the calibration should be based upon accepted practice in ISO 21501. Therefore, ISO 14644 does hand off the calibration procedure verification method to ISO 21501-4.
So what does that mean in the sake of all of these regulations and ISO standards that I haven't mentioned today?
Let's trace the entire chain. Annex 1 and FDA cGMP point to ISO 14644. ISO 14644 then points to ISO 21501-4, which means ISO 21501-4 isn't a nice to have. It's really pulled into regulatory expectation by reference.
Therefore, any user manufacturer that is buying or qualifying instrumentation, if their instrument is not calibrated per ISO 21501-4, there is a gap in your classification and routine monitoring data.
So we went over cleanroom regulations. We heard terms and phrases such as EU GMP Annex 1, ISO 21501-4, ISO 14644, as well as the FDA cGMP.
Next, we're going to go into the FDA 21 CFR Part 11. It's important to note that this is a completely different requirement. It has nothing specifically to do with air particle counting, but everything to do with your data and how to make sure that it's accurate and reliable over time.
So let's take a look at a typical process and what you would see in a routine environmental monitoring program. So this is just an intro to two one 21 CFR Part 11.
Consider a factory-floor diagram with five touchpoints representing manual steps. In a routine monitoring program at a large biopharmaceutical facility, multiple technicians may use several airborne particle counters to collect more than 3,000 samples per month through a highly manual, labor-intensive process that is susceptible to human error.
So looking at our five touch points of data, touch point one, you have someone that's ensuring your technician, someone that's taking the sampling, ensuring that you have the correct SOPs in hand. You're reading. You're understanding those SOPs. Touch point two is that you are manually typing each and every sample and location name into your sampler.
It could be a sampler. It could be something more of like a LIMS system, some sort of facility monitoring system. Nonetheless, someone is manually entering. I want to point out that you could have up to 10 different technicians at multiple different factories using multiple different air particle counters.
That's multiple touch points per day on various units by various users.
Sample or touch point number three is manually configuring the counter. So entering things such as sample time, number of samples, results averaging, making sure that you have multipliers and factors for the volume or units that you're using.
Touch point four is that the user is really taking that printout, that data printout, and they're making photocopies. And the reason for that is that printers and a lot of the counters that are used out there are thermal, so the printouts fade over time. So your raw data literally disappears. So it's important to make photocopies of those.
Last but not least, touch point five, which is manually transcribing the results, typically in an electronic format one by one.
I want to highlight that this is five opportunities for error multiplied by 3,000 samples per month.
One mistyped location, incorrect multiplier, or incorrect sample time or volume can undermine the reliability of your documentation. Is the record reliable? Is it accurate? An auditor may look at the process and ask, 'How can you demonstrate that this sample was truly taken at this time and location?'
And that's where 21 CFR Part 11 comes in. 21 CFR Part 11 is a section within the code of federal regulations established by the US FDA.
It does outline a process for creating, managing, and maintaining electronic records. So it's not just about storage. It's really that full life cycle. It's how a record is created, who can change it, whether the changes are traceable, from what value to which value, and how a signature is bound to those changes or records.
It helps ensure that organizations follow good business practices and that electronic records and signatures are accurate, authentic, reliable, and confidential. These four concepts are worth emphasizing. Accuracy: does the record reflect what actually happened?
Authenticity, can you prove who created it? Reliability, is it complete? Is it consistent? And confidentiality, is it protected from an unauthorized user?
So this is a gap that we typically see today in a monitoring, program. Right? We saw the five touch points before. The five touch points are very manual and labor-intensive.
Today, increasingly, manufacturers, users, those that are looking or doing classification, routine monitoring are looking at more streamlined automated processes. And because that's becoming more and more important, so is 21 CFR Part 11.
Next, I just wanna go into internal regulations. So, really, this is just focusing on a specific company's internal standards, regulations, guidance, and practices. Right? Every company has slightly different take on data integrity and and security.
So larger corporations, for example, take data integrity and security very seriously. They have very different IT infrastructure than than a smaller facility might. Put it in perspective, a data breach one data breach can cost up to $4,880,000.
Every piece of digital equipment must be evaluated for cyber risk and security. So your digital exposure really needs to be assessed much earlier in the process and not later in the process once the process has already been implemented.
So for example, that network particle counter that you have deployed, is is that something that an unauthorized user can have access to? Can they have access to the data? Can they have access to the instrumentation and start actually manipulating not only the data but the settings on the instrument?
What I want to know is that digital equipment does make your process easier, but it does expose you to risk or your company to risk at the same time. So with that being said, just a point of caution or suggestion is really to make sure that your IT and security teams are involved with every new project that you have to know the risks and mitigations early. Any new instrument technology or instrumentation or technology that you are evaluating for your routine monitoring or classification program should be discussed with IT and security systems to ensure that everyone has a clear idea of how 21 CFR Part 11 is applied, whether it's making sure authorized users, networking, what happens to the data after it has been produced, is it going to a shared network, so on and so forth.
And lastly, just looking at internal regulations risk assessment. So one thing I did point out, which was a main difference between EU GMP Annex 1 and ISO 14644 is that EU GMP Annex 1 does rely heavily on quality risk assessments.
The standard of your cleanroom usage is driven by your risk assessment. Your risk assessment determines how you actually operate within your process, product, or facility.
The bottom line is that risk assessment combined with trending information, let's say routine monitoring, may lead for a user or facility setting up criteria or standards that are tighter than the ISO 14644 or EU GMP criteria.
And when I say below those regulatory limits, I mean, they're tighter, stricter because as you're trending data and that data, which typically is trending normally, all of a sudden starts to trend higher, now you have an alert or you're being proactive rather than reactive getting trending that is basically at what the threshold would be for ISO or e l EU GMP Annex 1 guidelines.
Quality is achieved through consistent performance, not simply by meeting pass-or-fail criteria. A room that barely meets the thresholds may technically pass, but a room with tight, stable, and predictable particle counts is demonstrably under control. That indicates the process is under control.
Root cause analysis of excursions can lead to better procedures and controls. An excursion is information. So how your organization handles this information is not just documenting, but it's making sure they understand why, what has changed in the environment that has caused this excursion.
And last but not least, regulators and auditors will look for evidence for continuous improvement. Right? It's not just checking something whether you have passed. That room is meeting a standard.
It's a record showing that there is evidence of investigations. Improvements have been made along the way. The environment is not looking worse over time, but it's starting to improve over time. Problems that you had once found in the past are fixed, and they're fixed with proven data and process control.
With that, I would like to close the presentation. I hope you now have a good overview of how the various regulations and standards are connected. You have heard references to ISO, EU GMP, FDA requirements, and 21 CFR Part 11. Together, these regulations and standards provide a holistic approach to ensuring that sterile manufacturing environments remain clean and consistently produce high-quality products.
Thanks for the great presentation, Nicole. I see we have a couple of questions in the chat. So firstly, when selecting an airborne particle counter, what should users look for to ensure that the instrument and its calibration supports both ISO 14644-1 and ISO 21501-4 requirements?
Good question. So it's important to remember that in the presentation, had mentioned that ISO is a standard and not necessarily a regulation. However, EU GMP Annex 1 and FDA cGMP do point to ISO. And because of that, that expectation is being pulled in.
So when assessing different instrumentation or suppliers, it's important to ask the supplier if their calibrations are to ISO 21501-4 requirements. Are they factory calibrated to that? Is the calibration continuously year to year calibrated to that, which means is someone, you know, an engineer going on-site and calibrating it? There are different aspects of ISO 21501-4 that need to be assessed.
In in this requirement, there are things such as size setting error, size accuracy, resolution, counting efficiency, false counts. All of those are outlined in the regulation or standard, in this case, the ISO standard, and you have criteria for pass or fail. So it's important that all of those are being covered in the calibration annually. Annually.
Perfect. Thank you. So the next question I see is when multiple portable particle counters are used across rooms or sites, what calibration and verification evidence should be maintained under ISO 21501-4 to demonstrate that results remain comparable between instruments?
Good question. So when calibrations are done on an annual basis, it's important to have as-found and as-left data. This is not just a past statement. This is really telling you that as if you're as found, whether the data that you had collected previously or since the last calibration is trustworthy. If anything is out of tolerance, it's important that it's well documented and the instrument which aspect of it is found at out of specification and understanding how that does impact previous data.
From time to time, the user can do interim verification. So doing any zero count testing between instruments in varying different rooms or even side-by-side comparison exercises can be done periodically.
Okay. Thank you.
For facilities that use multiple particle counters, what are the best practices for maintaining consistency and confidence in data across instruments?
I would say there are a few different ways to me be consistent across the fleet. So one is standardizing the hardware. As much as possible, a user that's using one piece of hardware, one type of model or supplier of instruments, across, let's say, several different rooms, different facilities, that ensures that the data that's being produced is data that is consistent in terms of what's being reported out of the instrument.
Also, that it ensures that that particular instrument or supplier that is calibrating that instrument is also the same across the fleet, for example. It's also important to make sure that you have any SOPs that are across sites that are standardized. So fixed sampling times, count times, averaging, whatever that may look like is standardized across method. So first, you have standardized hardware, then you have standardized methods.
And then you have the people in the data portion, which is making sure that the people are trained consistently across all sites or locations with periodic requalification as well as making sure you understand how the data is transmitted from the instrument or from the instrument to any external software or external system, making sure that that data is consistent across sites and fleets.
Great. Thank you. Next question is, if our routine particle count data remains within limits but begins to show a gradual adverse trend, how should we decide when to investigate, adjust internal alert levels, or introduce additional controls before an excursion occurs?
I'm gonna relate this back to EU GMP Annex 1, and EU GMP Annex 1 heavily involves a contamination control strategy as well as looking at various quality risks.
So, really, a user assessing each area process that's happening will have a quality risk assessment and what those alerts should look like. And an alert is typically below the threshold that's being defined within the ISO classification or EU GMP. It's really defining those trend rules in advance. So that way when results are alarming you, they're not actually failing the standard or regulations, but they're providing information that something has changed in the room. And it's important to note and document what has changed. If you're getting close and the trending is continuously going upward, I would say that's definitely a time to pause, escalate appropriately, investigate. If it's something where you're trending upwards and then going maybe back down and you're seeing that consistent over time based on process, I think that shows more about process control and something that maybe can be improved over time.
Awesome. Thank you. Next question. If we're moving from a paper-based environmental monitoring process to electronic records, which controls such as unique user access, version-controlled SOPs, audit trails, and electronic signatures should we prioritize to strengthen 21 CFR Part 11 data integrity without creating additional work for operators?
I would say one of the most important features or improvements would be an automatic audit trail. So instead of having manual records of who is performing which sampling locations with which SOP methods, it's automatically generated within an instrument or computer. It has an automatic timestamp. It's creating a record, any modifications that have been made to the instrument that impacts data, any deletion of samples, any altering of samples. It really does record everything.
I also think it's important to consider having unique user accounts with role-based access. So there are varying levels of roles or users that access the instrument, some that should not be necessarily looking at the network and IT, and those that are looking at the network and IT but not sampling. So allowing to have different access to the instrumentation based on changing settings or even sampling also helps really control that.
There are other options such as record retention and backup. They're also important. Anything where you can get the data retrievable, readable over time, making sure that you have any disaster recovery in place if something were to happen to the instrumentation.
That's great. Thank you. And with that, I'd like to thank you all for joining us today, and thank you for your thoughtful questions.
Any questions that we didn't have time to cover today will be addressed in the chat section. And, of course, to continue to learn more about cleanroom regulations and air particle counting solutions, be sure to visit beckman.com. And until next time, thank you, and goodbye.
She's also a member of the International Organization for Standardization Technical Committee 209. And there, she works to develop and communicate consensus position on ISO 14644.
Nicole has worked with Beckman Coulter Life Sciences for the last six years as a technical specialist and later product manager supporting customers using air particle counters like the MET ONE 3400+.
If you have any questions during Nicole's presentation, please feel free to use the question and answer function to the right of your screen. With that, I'll hand over to Nicole to start the presentation.
Thank you for that introduction. As Kieran noted, my name is Nicole Aguilar. I am a global product manager at Beckman Coulter. And today, we're going to be going through, a presentation webinar on really how do we make sense of cleanroom regulations.
You may have heard many different acronyms, such as ISO, EU GMP, FDA cGMP, and 21 CFR Part 11. Today's goal is for you to leave with a clear understanding of what each standard does and how they all fit together.
As noted, I do work for Beckman Coulter Life Sciences, and we are a proud partner or OpCo of Danaher Corporation since 2011.
So first, just going right into it. This is an outline to show where we're going to be moving throughout the story in this presentation. So first, why do we even care about airborne particles in pharma, biopharma specifically?
Current cleanroom regulations, had mentioned some terms earlier like ISO 21 CFR Part 11. We're gonna go into classification versus routine monitoring as well as data integrity aspects, so FDA 21 CFR Part 11. And then looking more into internal regulations or I should say standards and procedures and guidance documents that you have at your own facilities.
So let's set the stage. What actually keeps this audience up at night? And, really, it's the primary concern in a sterile manufacturing environment is not dust. It's the presence of viable microorganisms that can contaminate drugs.
So a patient receiving an injectable has no barrier between them and that vial. So at the end of the day, what we truly need to measure is a living organism.
And the most frustrating part of this all is that technology is extremely limited today in order to be able to measure, characterize, provide an identification of viable accounts in real time. So I want to emphasize that all of those attributes in real time.
It is important to note that there is technology that is up and coming today and is being discussed in technical committees for implementation that do allow viable particle counting in real time. However, there's still a lot of hardships in implementing this newer technology.
With that being said, because of these challenges, particle counters are used as surrogates in this case. We may not be able to count and characterize microbes in real time just yet, but we can count the total airborne particle instantly and continuously. And in that case, it's an indirect measurement, and we're using particle counting as a proxy.
And you may ask yourself, how does this proxy work? Why does it work? Viable particles are everywhere. They originate from personnel, your clothing, skin, even breathing, for example.
And people really are the dominant source of contamination in a cleanroom. And microorganisms, they don't just float around naked. They actually ride on skin cells or droplets. So when particle counts go up, the probability of viable contamination also goes up with them.
So moving forward, the entire premise of this presentation is that we have guidance documents, regulations for classification, monitoring, even data integrity, and all of these guidance documents were really built on measuring particles as a proxy for microbial risk.
So after just setting the stage of why do we care about air particle counting, the last slide I really ended on the point that people are the source of contamination.
So let's look at this a little bit more. Instead of thinking, hey. We are the main source of contamination. How does that look? We really cannot maybe be a strong source of contamination. Let's look at some of the numbers back in the envelope calculations.
Every hour, up to 3,000 cells are shed from one square centimeter of skin. For reference, one square centimeter is about the size of your pinky fingernail.
Given that, that's about 1,000,000 cells per hour. Now cells alone would just be particles. Right? But we also had mentioned that cells carry microbes or individual particles carry microbes. Your skin has a healthy skin microbiome. It's a complex community, fungi, bacteria, viruses. That is completely normal and healthy.
But it also brings you to the fact that 100,000 skin cells with bacteria are shed per hour. If you look at the two people or the image on this slide, they're having an ordinary day-to-day conversation, talking to one another, breathing, moving in a small space. Although they're doing something completely ordinary, they are also contaminating that space at this point in time.
And all of these statistics that you see right here, these numbers, these are people that are standing still. This is someone who is not moving. So imagine someone in a cleanroom moving, talking, gowning up, making adjustments, really exposing a microbe to or exposure to an open vial or product.
And this is why cleanroom design is so important, and it emphasizes gowning and airflow. It's extremely important the number of people that you have in a critical zone. You are not just trying to stop contamination. You're really trying to manage the source because you are the source, and you can never fully switch it off.
So let's take these statistics, these numbers, and instead of treating it like an academic problem, let's see a real world problem.
In 2012, nearly 800 people across 20 states developed fungal infections linked to contaminated vials produced by a compounding facility.
So the CDC reported that 64 of 753 patients died across nine states.
These steroid injections were given for back pain, simply routine procedures. Patients went in for pain relief, and then they contracted fungal meningitis.
You can see a map here on the slide. This map does show how far the contamination or infections had spread. They were not localized. So one facility contaminated or contamination reached up to 20 states.
It's important to note that the entire problem with microbe contamination couldn't be seen by the naked eye. It was invisible at the point of use, which is exactly why at the point of manufacturing, we need to have a controlled process environment where you are monitoring microbial contamination.
So moving into these regulations and standards that we'll be talking about, it's important to note that all of these grades and limits, these numbers exist to prevent situations like we see here.
So next, we're just gonna go into the current cleanroom regulations. I've hoped at this point, I've convinced you why airborne particle counters and particles are important to monitor and classify clean rooms in pharma, biopharma specifically, or just sterile manufacturing. With that being said, it's important to remember that you are the main source of contamination. At the end of the day, you are someone that not only provides that contamination, but should be someone that's enforcing procedures to help control that contamination.
So before going into any regulations or standards, I want to go into the umbrella or the framework. So the framework being Good Manufacturing Practices, so GMP.
This framework covers personnel, premises, equipment, containers, and documentation. The underlying concept is to produce a high-quality product consistently.
And what this image on the right is really getting at is that GMP is not just a single requirement. It's an entire vocabulary. It's a framework. So you're gonna see words such as compliance, quality control, audit, documentation. If you work in a space similar to this, these words are in your daily life.
And here's the connection that I want to make moving forward. So if we look at the second bullet, it's notes that both EU GMP and FDA cGMP reference ISO 14644 for the methodology of cleanroom classification.
That is a lot of acronyms, so I want to take a step back for a second.
We mentioned good manufacturing practices. It has this framework. And under this framework, we have regulations and we have standards.
So the in this case, ISO 14644, this is a published set of standards that is done by voluntary consensus. So this is done by the International Organization for Standardization. It is a nongovernmental body. Basically, the output of this documentation is a consensus among technical experts and industry participants.
You will also hear terms such as EU GMP and FDA cGMP. These are regulations issued by government authorities.
And as you can see that these regulators didn't write their own method for referencing or cleanroom classification. What they did is they referenced or pointed to ISO specifically. So one thing I want you to take from this slide is that ISO is a method. It tells you how to count particles, locations, sample volumes. It's technical. Whereas the regulation is more, gives you obligation. What is your expected outcome?
And the last bullet point is that the success of GMP compliance relies heavily on the people implementing it. When you think back to earlier in the presentation shedding numbers, it's especially true that both people are the ones enforcing it, and they're the primary source of contamination.
So let's go into a little more specifically into the introduction of ISO 14644. So ISO 14644 is a multipart standard. It is a family of separately published documents that share a common desire in mind. So in this case, ISO 14644 is very specific to cleanroom and associated control environments. The dash one or part one is one of those separately published documents where the focus of part one is to ensure that clean rooms are meeting specific requirements regarding size, counting, and testing locations and frequencies. This allows you to classify clean rooms. Please pay attention or make note of that word classification because we're going to come back to that.
So it specifies cleanroom or air cleanliness within a specific environment. I want to note that classification is a snapshot in time. It is not looking at the process as a whole. It is looking at the room in a snapshot state.
The particle populations that you'll be seeing, and we will show ISO tables, a little bit further in the presentation, are really distributions based on threshold particle sizes ranging from 0.1 microns to 5 microns.
So going into a little more about the details and what it looks like to classify a cleanroom, you probably have often seen, tables that reference ISO class numbers. So right here, there is a reference to a table that is actually in ISO 14644. This slide, once again, is gonna give you scope of that statement. This is what it looks like in practice. So you have rows on this table, which are classes one through nine, class one being the cleanest class. You have columns which show particle thresholds. So you see it through, 0.1 micron in size all the way up to 5 micron in size.
And each cell is your maximum allowable concentration in particles per cubic meter that are allowed in that specific space.
Now I want you to notice a couple things. You may see some blanks, for example. So there are some empty cells that are on the smaller particle end for cleaner classes, and then you might see some on the higher end, empty cells as well, closer to the 5 micron end. Those blanks are intentional, and that's because at very low concentrations, sampling and statistical limitations make classification very unreliable. And at 5 micron and above, particles are heavy enough that they physically just drop out of the sample tubing.
So collection efficiency in this case also drops at those higher sizes. So rather than ISO publish limits for instrumentations for numbers that they can't defend, it is to remove those and have statistically or risk assessments to really show the contamination control in those areas.
So it's important to note that when you are classifying a room, you are not just specifying a room's classification based on any particle size for any class, this table constrains you to which combinations you can actually be classified at.
It is also important to note that your results are only as trustworthy as the instrument you use. The technology should be properly calibrated, robust, and consistent with the relevant standards. We will discuss this later in the presentation.
So I had pointed out earlier to really hold on to that word classification, and the words classification and the term routine monitoring are often used interchangeably. And they are genuinely different activities.
They have different purposes, different sampling locations, different governing documents. So classification, as I noted before, is a snapshot in time. It's about certifying a cleanroom's state. It's the assessment of the room itself.
It tells you that that room met its limit the day you tested it under the state of how many personnel and equipment that you tested it in. It says nothing about that room and what will happen in its state two days from now or three months later.
So classification is very important, and it demonstrates that the cleanroom as a whole complies with its intended air particle concentration class. The key phrase once again, as a whole, you're proving the entire room's performance, not one favorable location.
Now I think what we I really want you to draw from this slide is the last statement at the bottom, that both EU GMP Annex 1 and the FDA cGMP state that classification is done to method defined in the ISO 14644-1.
This is a bridge and showing you that both of these regulatory bodies are pointing documentation. Once again, ISO, very method oriented and technical where these regulatory bodies are relying on that method development.
So let's look take a little bit or let's look into a little bit the EU GMP Annex 1. So the table on the right we looked at is the ISO 14644 classification table. And I had mentioned that the EU GMP Annex 1 is a regulation. It's governed by a regulatory body. It's I also noted that this EU GMP Annex 1 or just reference Annex 1 here on out, does reference ISO 14644.
However, these two tables have one job. They look similar in a way and also have some major differences that I want to point out. So ISO 14644 references class numbers. Whereas Annex 1 uses an entirely different vocabulary, it uses grades. So Grades A, B, C, and D.
Same underlying principles, different naming systems, basically.
So walking through the Annex 1 table on the right side, you will see grade a and grade b. Those are outlined. It's important to note that grade a and grade b must comply with ISO Class 5 requirements in an at rest state.
So I'm trying to show you similarities between the Annex 1 as well as the ISO 14644 guidelines.
Grade C must comply with the ISO Class 7 at rest, and grade d must comply with ISO Class 8 at rest.
I also want you to notice the phrase that I keep using, which is at rest. So if you look at the Annex table on the right, you'll see at rest and in operation. There are different states of what the cleanroom is in, and that's because Annex One is very specific to sterile manufacturing or pharmaceutical biopharmaceutical sterile manufacturing of drugs.
At rest, your room is certified.
The in-operation state is completely different. Personnel are in the room, and instruments and equipment are being used. Annex 1 requires risk to the patient and product to be assessed not only in the at-rest state, but also during operation, when personnel movement and interaction can increase the risk of microbial contamination.
It is important to note that ISO 14644 is intended for a broad audience. It applies not only to FDA-regulated facilities, but also to environments such as hospitals, semiconductor facilities, and aerospace facilities. Annex 1, by contrast, is specific to sterile manufacturing activities, such as gowning, filling vials, and masking.
So looking at cleanroom classification, that's a definition that we held on to before. Now looking at routine monitoring. Routine monitoring means that you're taking daily life or daily processes consideration while you're looking and monitoring air particle cleanliness. So compared to that classification, classification might happen once or twice a year. There is a different rhythm of sampling that happens with classification versus routine monitoring.
Routine monitoring is continuous. It really depends on the processes and personnel that are on in a day-to-day basis that are at play.
Data from routine monitoring can be used to trend overall cleanroom contamination level.
So monitoring does something very different than classification does. Classification is a snapshot in time. You can't use those data points to really trend and look at changes in background or air particle concentrations over time.
Whereas for routine monitoring where you have more frequent sampling at various different locations, the individual can start seeing trends, and these could be early mornings for example, catching a degrading HEPA filter or maybe gowning practices are drifting a little bit and you start to see particle concentrations rising.
A third difference is really to underline is that monitoring sampling locations are focused on contamination risks. So this is what's really happening at play.
Contrast to classification, classification has fixed locations. It's distributed out the methodology is distributed throughout the room, basically, where classification deliberately samples everywhere more often.
So a simple way to kind of remember this is classification is something alright. You can ask yourself, is the room capable? Whereas monitoring generally asks the question, is my product at risk right now at this point in time?
So we showed the relationship between, FDA cGMP, EU GMP, and ISO 14644. This is EU GMP Annex 1 snapshot just going into a little more detail. So it's important to note that Annex 1 really does provide guidance on designing and controlling facilities, equipment systems, and procedures for manufacturing sterile products.
What also makes Annex 1 different than ISO 14644 is that it does expect ongoing routine monitoring, so not just periodical classification or certification. So this is something that we had talked about previously between classification versus routine monitoring.
Annex 1 also does assign grades to different activities. So we had mentioned at rest versus in operation.
Annex 1, once again, was written for a manufacturing sterile product environment, where ISO 14644 is more of a general guidance.
Another difference is that Annex 1 does require viable monitoring, and it also does use quality risk management principles to ensuring that the final product is free of contamination. So quality risk assessment looks at different processes, personnel that's happening within the room, where instrumentation is placed, different practices. Whereas ISO 14644 is very technical, and it's a more of a method development to be referenced.
Next, I want to look into ISO 21501-4. So once again, this is an international standard, by the ISO committee. Once again, it's a consensus or, method that's really developed by a group of subject matter experts or industry and or industry participants. So the purpose of ISO 14644 is to provide a calibration procedure and verification method for particle counters. So your particle counters are used for your classification and routine monitoring methods, for example.
It's important to note that ISO 14644 does actually reference ISO 21501-4, and it specifically states that the particle counter should have a valid calibration certificate.
Frequency and method of the calibration should be based upon accepted practice in ISO 21501. Therefore, ISO 14644 does hand off the calibration procedure verification method to ISO 21501-4.
So what does that mean in the sake of all of these regulations and ISO standards that I haven't mentioned today?
Let's trace the entire chain. Annex 1 and FDA cGMP point to ISO 14644. ISO 14644 then points to ISO 21501-4, which means ISO 21501-4 isn't a nice to have. It's really pulled into regulatory expectation by reference.
Therefore, any user manufacturer that is buying or qualifying instrumentation, if their instrument is not calibrated per ISO 21501-4, there is a gap in your classification and routine monitoring data.
So we went over cleanroom regulations. We heard terms and phrases such as EU GMP Annex 1, ISO 21501-4, ISO 14644, as well as the FDA cGMP.
Next, we're going to go into the FDA 21 CFR Part 11. It's important to note that this is a completely different requirement. It has nothing specifically to do with air particle counting, but everything to do with your data and how to make sure that it's accurate and reliable over time.
So let's take a look at a typical process and what you would see in a routine environmental monitoring program. So this is just an intro to two one 21 CFR Part 11.
Consider a factory-floor diagram with five touchpoints representing manual steps. In a routine monitoring program at a large biopharmaceutical facility, multiple technicians may use several airborne particle counters to collect more than 3,000 samples per month through a highly manual, labor-intensive process that is susceptible to human error.
So looking at our five touch points of data, touch point one, you have someone that's ensuring your technician, someone that's taking the sampling, ensuring that you have the correct SOPs in hand. You're reading. You're understanding those SOPs. Touch point two is that you are manually typing each and every sample and location name into your sampler.
It could be a sampler. It could be something more of like a LIMS system, some sort of facility monitoring system. Nonetheless, someone is manually entering. I want to point out that you could have up to 10 different technicians at multiple different factories using multiple different air particle counters.
That's multiple touch points per day on various units by various users.
Sample or touch point number three is manually configuring the counter. So entering things such as sample time, number of samples, results averaging, making sure that you have multipliers and factors for the volume or units that you're using.
Touch point four is that the user is really taking that printout, that data printout, and they're making photocopies. And the reason for that is that printers and a lot of the counters that are used out there are thermal, so the printouts fade over time. So your raw data literally disappears. So it's important to make photocopies of those.
Last but not least, touch point five, which is manually transcribing the results, typically in an electronic format one by one.
I want to highlight that this is five opportunities for error multiplied by 3,000 samples per month.
One mistyped location, incorrect multiplier, or incorrect sample time or volume can undermine the reliability of your documentation. Is the record reliable? Is it accurate? An auditor may look at the process and ask, 'How can you demonstrate that this sample was truly taken at this time and location?'
And that's where 21 CFR Part 11 comes in. 21 CFR Part 11 is a section within the code of federal regulations established by the US FDA.
It does outline a process for creating, managing, and maintaining electronic records. So it's not just about storage. It's really that full life cycle. It's how a record is created, who can change it, whether the changes are traceable, from what value to which value, and how a signature is bound to those changes or records.
It helps ensure that organizations follow good business practices and that electronic records and signatures are accurate, authentic, reliable, and confidential. These four concepts are worth emphasizing. Accuracy: does the record reflect what actually happened?
Authenticity, can you prove who created it? Reliability, is it complete? Is it consistent? And confidentiality, is it protected from an unauthorized user?
So this is a gap that we typically see today in a monitoring, program. Right? We saw the five touch points before. The five touch points are very manual and labor-intensive.
Today, increasingly, manufacturers, users, those that are looking or doing classification, routine monitoring are looking at more streamlined automated processes. And because that's becoming more and more important, so is 21 CFR Part 11.
Next, I just wanna go into internal regulations. So, really, this is just focusing on a specific company's internal standards, regulations, guidance, and practices. Right? Every company has slightly different take on data integrity and and security.
So larger corporations, for example, take data integrity and security very seriously. They have very different IT infrastructure than than a smaller facility might. Put it in perspective, a data breach one data breach can cost up to $4,880,000.
Every piece of digital equipment must be evaluated for cyber risk and security. So your digital exposure really needs to be assessed much earlier in the process and not later in the process once the process has already been implemented.
So for example, that network particle counter that you have deployed, is is that something that an unauthorized user can have access to? Can they have access to the data? Can they have access to the instrumentation and start actually manipulating not only the data but the settings on the instrument?
What I want to know is that digital equipment does make your process easier, but it does expose you to risk or your company to risk at the same time. So with that being said, just a point of caution or suggestion is really to make sure that your IT and security teams are involved with every new project that you have to know the risks and mitigations early. Any new instrument technology or instrumentation or technology that you are evaluating for your routine monitoring or classification program should be discussed with IT and security systems to ensure that everyone has a clear idea of how 21 CFR Part 11 is applied, whether it's making sure authorized users, networking, what happens to the data after it has been produced, is it going to a shared network, so on and so forth.
And lastly, just looking at internal regulations risk assessment. So one thing I did point out, which was a main difference between EU GMP Annex 1 and ISO 14644 is that EU GMP Annex 1 does rely heavily on quality risk assessments.
The standard of your cleanroom usage is driven by your risk assessment. Your risk assessment determines how you actually operate within your process, product, or facility.
The bottom line is that risk assessment combined with trending information, let's say routine monitoring, may lead for a user or facility setting up criteria or standards that are tighter than the ISO 14644 or EU GMP criteria.
And when I say below those regulatory limits, I mean, they're tighter, stricter because as you're trending data and that data, which typically is trending normally, all of a sudden starts to trend higher, now you have an alert or you're being proactive rather than reactive getting trending that is basically at what the threshold would be for ISO or e l EU GMP Annex 1 guidelines.
Quality is achieved through consistent performance, not simply by meeting pass-or-fail criteria. A room that barely meets the thresholds may technically pass, but a room with tight, stable, and predictable particle counts is demonstrably under control. That indicates the process is under control.
Root cause analysis of excursions can lead to better procedures and controls. An excursion is information. So how your organization handles this information is not just documenting, but it's making sure they understand why, what has changed in the environment that has caused this excursion.
And last but not least, regulators and auditors will look for evidence for continuous improvement. Right? It's not just checking something whether you have passed. That room is meeting a standard.
It's a record showing that there is evidence of investigations. Improvements have been made along the way. The environment is not looking worse over time, but it's starting to improve over time. Problems that you had once found in the past are fixed, and they're fixed with proven data and process control.
With that, I would like to close the presentation. I hope you now have a good overview of how the various regulations and standards are connected. You have heard references to ISO, EU GMP, FDA requirements, and 21 CFR Part 11. Together, these regulations and standards provide a holistic approach to ensuring that sterile manufacturing environments remain clean and consistently produce high-quality products.
Thanks for the great presentation, Nicole. I see we have a couple of questions in the chat. So firstly, when selecting an airborne particle counter, what should users look for to ensure that the instrument and its calibration supports both ISO 14644-1 and ISO 21501-4 requirements?
Good question. So it's important to remember that in the presentation, had mentioned that ISO is a standard and not necessarily a regulation. However, EU GMP Annex 1 and FDA cGMP do point to ISO. And because of that, that expectation is being pulled in.
So when assessing different instrumentation or suppliers, it's important to ask the supplier if their calibrations are to ISO 21501-4 requirements. Are they factory calibrated to that? Is the calibration continuously year to year calibrated to that, which means is someone, you know, an engineer going on-site and calibrating it? There are different aspects of ISO 21501-4 that need to be assessed.
In in this requirement, there are things such as size setting error, size accuracy, resolution, counting efficiency, false counts. All of those are outlined in the regulation or standard, in this case, the ISO standard, and you have criteria for pass or fail. So it's important that all of those are being covered in the calibration annually. Annually.
Perfect. Thank you. So the next question I see is when multiple portable particle counters are used across rooms or sites, what calibration and verification evidence should be maintained under ISO 21501-4 to demonstrate that results remain comparable between instruments?
Good question. So when calibrations are done on an annual basis, it's important to have as-found and as-left data. This is not just a past statement. This is really telling you that as if you're as found, whether the data that you had collected previously or since the last calibration is trustworthy. If anything is out of tolerance, it's important that it's well documented and the instrument which aspect of it is found at out of specification and understanding how that does impact previous data.
From time to time, the user can do interim verification. So doing any zero count testing between instruments in varying different rooms or even side-by-side comparison exercises can be done periodically.
Okay. Thank you.
For facilities that use multiple particle counters, what are the best practices for maintaining consistency and confidence in data across instruments?
I would say there are a few different ways to me be consistent across the fleet. So one is standardizing the hardware. As much as possible, a user that's using one piece of hardware, one type of model or supplier of instruments, across, let's say, several different rooms, different facilities, that ensures that the data that's being produced is data that is consistent in terms of what's being reported out of the instrument.
Also, that it ensures that that particular instrument or supplier that is calibrating that instrument is also the same across the fleet, for example. It's also important to make sure that you have any SOPs that are across sites that are standardized. So fixed sampling times, count times, averaging, whatever that may look like is standardized across method. So first, you have standardized hardware, then you have standardized methods.
And then you have the people in the data portion, which is making sure that the people are trained consistently across all sites or locations with periodic requalification as well as making sure you understand how the data is transmitted from the instrument or from the instrument to any external software or external system, making sure that that data is consistent across sites and fleets.
Great. Thank you. Next question is, if our routine particle count data remains within limits but begins to show a gradual adverse trend, how should we decide when to investigate, adjust internal alert levels, or introduce additional controls before an excursion occurs?
I'm gonna relate this back to EU GMP Annex 1, and EU GMP Annex 1 heavily involves a contamination control strategy as well as looking at various quality risks.
So, really, a user assessing each area process that's happening will have a quality risk assessment and what those alerts should look like. And an alert is typically below the threshold that's being defined within the ISO classification or EU GMP. It's really defining those trend rules in advance. So that way when results are alarming you, they're not actually failing the standard or regulations, but they're providing information that something has changed in the room. And it's important to note and document what has changed. If you're getting close and the trending is continuously going upward, I would say that's definitely a time to pause, escalate appropriately, investigate. If it's something where you're trending upwards and then going maybe back down and you're seeing that consistent over time based on process, I think that shows more about process control and something that maybe can be improved over time.
Awesome. Thank you. Next question. If we're moving from a paper-based environmental monitoring process to electronic records, which controls such as unique user access, version-controlled SOPs, audit trails, and electronic signatures should we prioritize to strengthen 21 CFR Part 11 data integrity without creating additional work for operators?
I would say one of the most important features or improvements would be an automatic audit trail. So instead of having manual records of who is performing which sampling locations with which SOP methods, it's automatically generated within an instrument or computer. It has an automatic timestamp. It's creating a record, any modifications that have been made to the instrument that impacts data, any deletion of samples, any altering of samples. It really does record everything.
I also think it's important to consider having unique user accounts with role-based access. So there are varying levels of roles or users that access the instrument, some that should not be necessarily looking at the network and IT, and those that are looking at the network and IT but not sampling. So allowing to have different access to the instrumentation based on changing settings or even sampling also helps really control that.
There are other options such as record retention and backup. They're also important. Anything where you can get the data retrievable, readable over time, making sure that you have any disaster recovery in place if something were to happen to the instrumentation.
That's great. Thank you. And with that, I'd like to thank you all for joining us today, and thank you for your thoughtful questions.
Any questions that we didn't have time to cover today will be addressed in the chat section. And, of course, to continue to learn more about cleanroom regulations and air particle counting solutions, be sure to visit beckman.com. And until next time, thank you, and goodbye.
