Questions have started coming in since people have started doing their build outs and are having issues passing their cleanroom certifications. First, I have to say that not all cleanroom design companies are created equal. There are two that if I had known about them in 2015 I would’ve went with rather than the one I did. They both are very well aware of the issues I had (see this post – click here) and how we fixed. Both Bryan Prince (cleanroom designer – click here) and Cleanroom Design, LLC (click here) know the potential dangers of a USP <800> build if not mitigated properly. Let me explain.
The issues and solutions
The first thing you have to realize is that negative pressure sucks; literally. Even if you have a positive pressure anteroom that then leads into a negative pressure buffer room there’s a high likeliness that anything in the anteroom will inevitably be in your negative pressure buffer room. This is why I backed out my layer of cleanliness one more room. Outside my ANTEROOM I ALSO have HEPA filtered air. Was that absolutely necessary? There’s always more than one way to dice this up, that’s the way we did it. The take home here is that you need to think about what you’re bringing into your anteroom is potentially going to contaminate your negative pressure buffer. I have very minimal amounts of “stuff” in my anteroom; only what I need.
You may also want to think ahead for the revisions that are possibly going to be in the new 797; they recommend against a sink in there (UPDATE: to clarify, per USP revision it is OPTIONAL to NOT have a sink in your anteroom, not mandatory) . I would be VERY surprised if this was changed as it’s the right thing to do. A sink is a vector and reservoir for microorganisms and really has no place directly adjacent to a negative pressure area. (UPDATE: I still contend it’s the right thing to NOT have a sink in the anteroom, if you’re able to remove).
If you’re using an anteroom the way it should be, as a gowning/staging area, you of course are going to have people that do not have any PPE on at one point and of course shedding millions of particles. These particles carry microorganisms which ALSO may be traveling into your negative pressure buffer (because of the suction from the room). This begs the question, should there be another room in between your anteroom and the negative pressure buffer area? Again, that’s one way to do it but not the only way. This would look more like a design that a manufacturer might have. I would really say it depends on the risk level of what you’re compounding. Every precaution should be put in place if you’re doing the riskiest of compounding; non-sterile to sterile.
When you have a failing room due to microbial contamination you should look VERY carefully at the results. Many people have come to me with just the report and asked, “can you figure out why this is failing?” Honestly, the report is only half the story. You need to look at what bacteria are growing, where they’re growing (what specific place in the room), what the typical origin of that bacteria is (e.g. staphylococcus are from humans typically, bacillus are from soil, materials, cardboard potentially) and then what in the room is possibly shedding those. You need to do a root cause analysis. Below is a fishbone (or Ishikawa) diagram of what could be causing contamination. A simple google search will tell you the origin of the bacteria once you’ve identified the genus.
After you’ve identified the genus of the microorganisms you can then try to figure out what or WHO the offender is. It requires a little detective work but honestly this becomes more like a game! I find it fun. Don’t go changing EVERYTHING all at once though. It really helps to have your own equipment rather than having your certifier come back each time. Honestly, if you have a 2 certifications, that’s more than you’ll pay for the two pieces of equipment you need to see whether or not your solutions are working. All you need is a particle counter (which just gives you the total particle count of the room – what is typically called NON-VIABLE) and an active air sampler (which takes in air to impact on an agar plate – this is your VIABLE air sampler). There’s many of these on the market; these are the ones I have:
Honestly though, I wouldn’t have gone with the particle counter I have knowing what I know now. I would’ve rather have gotten something like this:
I don’t get anything for endorsing this but I just wish I took in a cubic meter of air per minute. These can get really fancy with a ton of bells and whistles; climet even makes one with internet connectivity that will output to a computer outside the cleanroom with no one having to push a button from the inside. Again, there are a bunch of these on the market.
Words to the wise
These are EASY to operate and will give you the ability to assess the state of your cleanroom yourself on a daily, weekly or monthly basis; use as often as you’d like. One other thing I should mention is that your certification company may also be taking WAY TOO MANY VIABLE samples. Particle counts are dictated by the square footage of your room (that’s a set number per ISO 14644), HOWEVER, many companies will take the VIABLE samples in all of those same locations and that’s not necessary. You should be taking viable samples based on risk. You must get viable samples inside your ISO 5 area (your hood) and depending on the size of the room 1 or two other locations that you frequently move between; but not in six locations.
After you have each of these use them wisely. Think of the total particle counter as a barometer for when to use the active air sampler. This requires you to take particle counts frequently though. First you’d get a baseline particle count in each location of all of your rooms (this will be notated on your certification report) in triplicate. This means that you’d take 3 samples in each location with NO ONE in the room. When you get the numbers from the counter, this is raw data and you must do the math to put it in terms like the cleanroom certifier would give you. Purchase ISO 14644 to see all of the math that needs to be done. However, if you have a particle counter that is pulling in a cubic meter/minute it makes the math slightly easier. 14644 can be purchased here.
Once you have the baseline measurements you can then play around with dynamic conditions. Go in the room, set up the particle counter in each location and walk around, open the door, shuffle your feet, drop objects, etc. Create conditions that might occur when people are in the room. If you normally have two people in the room, then have two people do all of the aforementioned movements. Over time (doing this daily or weekly routinely) you’re able to see what your room “normally” looks like. As you continue to take these measurements you’re able to see if there are spikes in particle counts. IF you see an excursion from the norm you can then use the active air sampler to see what VIABLES are growing in the room which you can then pinpoint where the excursions is coming from. Is this above and beyond what 797 is currently asking you to do? Yes, absolutely…but changes are coming and you need to be ahead of these in my opinion.
A paradigm shift has occurred and we’re expected to have a better idea of the state of our cleanroom at all times. Relying on your certification company no longer cuts it. Above I’ve really given an oversimplified way to tackle this. The approach that needs to be taken is one that tracks and trends this data on a routine basis over time. Two data points per year (certifications) does not show any kind of trends. I really think with the number of type A personalities in pharmacy, once you start doing this sampling on your own it becomes slightly addictive. 🙂
I’ll be doing a webinar on the details of this in the months to come but in the meantime if you have any questions feel free to ask: email@example.com
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About the Author:
Seth DePasquale is a pharmacist and co-owner of BET Pharm, LLC in Lexington, KY; a compounding pharmacy specializing in long-acting injectable hormone formulations for equine reproduction. Seth is a 2002 graduate of Albany College of Pharmacy in Albany, NY and is a Registered Pharmacist in New York, Kentucky, Michigan, Oklahoma, Texas, West Virginia, Virginia, Alabama, Tennessee, Mississippi, Arkansas, Nebraska, Louisiana and Oregon.