FDA 483 #10 – Non-Viable Particle Counting

Learning Objectives

  1. Discuss the importance of particulate in relation to microorganisms
  2. Explain why 0.5 micron and larger sized particles are of great importance
  3. Discuss 3 ways that we can minimize the number of particles in our cleanroom

In todays 483 we’re going to be looking at non-viable particle counts otherwise and more accurately known as total particle counts and why they’re so important. So let’s take a look at the 483 observation first then we’ll dive into it a little deeper.

In this 483 it’s noted that there was an out of specification result for environmental monitoring samples. I’ve talked in a previous podcast and posts about viable particles, but this week let’s focus on non-viables.

In observation 2 under section “d” it talks about not further investigating sterility failures for two particular compounds.

The investigation documentation did not include and evaluation of production batch record reviews, EM for hoods and rooms (non-viable or viable particulates, personnel monitoring, press plates), cleaning logs for the room, qualification of the hoods, retain samples or previous OOS.

FDA 483 Observation 2

So why does it mention specifically looking at non-viable samples, aside from all of the others? Let’s take a quick look at a table that’s from USP <797>, which is actually from an international document, ISO 14644.

I’m sure you’ve seen this before but if you haven’t here it is. But what exactly do all of these numbers mean and why are they so important? In the left column you have ISO classes which are the classes of different areas of the clean room. Your primary engineering controls or your hoods are typically ISO class 5 and your secondary engineering controls or your room are typically ISO class 7 or you may have an anteroom that’s ISO class 8.

In the right hand column you have the limits of the particle counts per cubic meter, meaning if you have particle counts higher than the numbers in this column corresponding to the particular ISO class that area fails and cannot be classified as such.

One thing to note here, at the bottom of the table in small writing it specifically mentions the numbers pertain to particles of a particular size 0.5 micron or larger. Why are 0.5 micron sized particles of importance? Well, there’s one thing you should know about microorganisms. Rarely are microorganisms free floating by themselves. They actually travel on particles, and if you haven’t already guessed they’re usually attached to particles that are 0.5 micron or larger.

One other interesting point worth mentioning and this may seem like common sense but the larger the particle, the more dense it is and the heavier it is. These larger sized particles are the ones that tend to settle on surfaces. Smaller, lighter particles can stay free floating in the air but it’s the job of our engineering controls to push them away from our critical areas and hopefully push them down toward the ground where they’re not a threat to our preparations.

Now, if you have high particle counts in your cleanroom or primary engineering control does that mean that every one of those particles has a microorganism attached to it? No, not necessarily. However, taking particle counts is a great, general way of looking at the state of cleanliness of your cleanroom.

Another question is, do we know the percentage of particles that have microorganisms attached to them? To be completely honest, I’m not sure if there’s been a study done to make that correlation but one thing that’s for certain is that the higher the particle counts in your classified areas, the higher the chance for contamination.

One point I really want to drive home is that when we get our cleanroom certified and we’re looking at the numbers of particle counts, you can glean a lot of information from that report. If you have high particle counts in a particular area, you can look inside your room and see what might be causing those high particle counts.

How do particles get inside our cleanroom? GREAT question, they travel on materials that are brought into the cleanroom, equipment, and of course people that are going in and out of the cleanroom.

Ok, great…we know what particle sizes we’re looking for, why those particular particle sizes are important (because they carry microorganisms) and we know how they get in the cleanroom. The next question is how do we keep them OUT of the cleanroom?

This comes down to a few simple and easy practices that you can do on a daily basis to minimize the number of particles you’re bringing into the cleanroom. First, people. It’s inevitable that people are going to be in the cleanroom since they’re the ones performing the compounding. It comes down to how these people are gowned, how much skin is visible, and their general behavior while inside the cleanroom.

As I said before if our engineering controls are doing their job properly they’re hopefully pushing particles out of our primary engineering controls and the secondary engineering controls are pushing them down to the ground. This is where good daily practices come into play. As a cleanroom operator, we should have an awareness at all times all of the things I’ve just gone over.

Just being in the cleanroom, we’re disrupting the flow of air, so we want to do our best to disrupt this airflow as little as possible and we do that by moving slowly, methodically and purposefully. You don’t want your operators rushing around, using fast hand movements or shuffling their feet which only puts the particles that may be on the ground back into the air.

Another way of minimizing particle counts is ALWAYS wiping off materials with disinfectants prior to bringing them into the cleanroom and also prior to putting them into our primary engineering controls. This is absolutely critical. Using a wipe saturated in disinfectant and using unidirectional strokes to wipe off the materials prior to bringing them into the cleanroom drastically reduces the amount of particulate you’re putting into your controlled environment.

Lastly, having cleaning protocols that remove particulate from the cleanroom is also of utmost importance. According to USP <797>, at minimum we should be cleaning our floors on a daily basis. Again, the floor, if our engineering controls are doing their job properly, is where a lot of these particles will reside. So cleaning the floors on a daily basis removes particles as well.

We should also be wiping off and disinfecting our critical surfaces frequently. In particular your primary engineering control should be cleaned prior to every use and according to USP <797> they should be cleaned and disinfected every 30 minutes during continuous use.

I’m actually going to reference the 2019 revision of USP <797> which is currently in an appeal process because of the BUD sections of the standard. However, this table should not be disregarded as it is a great guide for what surfaces should be cleaned and how often it should be performed.

USP <797> 2019 Revision Table 8

Keeping particulate down to a minimum is of utmost importance. WHY? Just to review, particles are what microorganisms travel on. So if you’re able to control the number of particles, you’re able to control the level of microorganisms. Review this with your operators on a regular basis, it should absolutely be a part of your regular training.

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