In the first post of this series Bryan highlighted an interesting issue that I don’t think too many people are aware of: the understanding of where powder containment enclosures need to be set for optimal control over the powder that is currently being used in many compounding pharmacies. There seems to be a difference in manufacturer’s recommendations for their hood’s face velocity versus what is necessary for adequate containment of the powder (the lower the better in this case – between 60-75 LFPM).  This week I’d like to highlight another difference that I’ve noticed in getting my Primary and Secondary Engineering Controls certified.

You would think that when a company comes in to certify your room it should be relatively standardized across the board independent of what company is performing the certification. Well, I’d like to say that’s true but it’s not. In fact, in some cases your certification company may be doing more than they need to. Before you get upset about that last statement let me say that it’s not necessarily the certifier’s fault for doing excessive testing; but without direction from the customer (you) they’re going to do so their certification doesn’t get called into question. More on that later.

Inconsistent Reporting

If you have a cleanroom you’re required to have it certified semi-annually (every 6 months) and at the end of it you will get a so many paged report with numbers, graphs, charts and maybe a page that says, “passed” in nice, bold colored lettering. Raise your hand if you take that report and file it the second you get it without cracking a page. Alright put your hand down, people are going to start to wonder about you.

Well, I used to be in the same category so you’re not alone. Problem was that by not knowing what all of those pages actually said I had no way of defending myself if I was ever scrutinized by an inspector or some regulatory body. On top of that, as I eluded to above, I was also being charged for extra testing I didn’t actually need. However, the problem is a little more complex than that I found. It’s more than just learning what the report says and means, what I figured out is that there’s some inconsistencies between the companies that perform our testing. To add one other layer of complexity it’s not their fault either.

A VERY brief, incomplete history

I don’t know every detail and it’s not the sort of thing that can be googled but to answer the question as to why some certification companies may be testing more than others is not too difficult to piece together. First, the major organization that set standards for the air quality of cleanrooms is the International Organization for Standardization (ISO) but they don’t set the standards specifically to the healthcare industry; these standards are for air quality in general. For example, the part of the electronics industry that makes processors for computers have even more stringent standards than the pharmaceutical industry; meaning the air has even fewer particles per cubic meter by multiple orders of magnitude. The downside is that these standards (ISO 14644) talk about particle counts only and don’t set any microbial limits at all.

Here’s where the USP comes in as they set standards for the pharmaceutical industry. With Chapter <797> the USP laid out the standards for the conditions under which sterile compounds should be made and even went as far to adopt another organization’s mode for certifying engineering controls. The organization they referenced is called the Controlled Environment Testing Association (CETA). CETA has various “Certification Application Guides” or CAGs that give certifiers a checklist of what should be performed and how to go about doing a certification. Cool right? Well, only problem is that not every certification company is a member of CETA and may not be following those guidances.

What about the FDA and big pharma? Glad you asked. I won’t say that there are NO standards but they’re not as specific as one might want or hope. The FDA doesn’t micromanage pharmaceutical companies. They have the GMPs and guidances and beyond that they place the burden on the manufacturer to prove they have their environment under a state of control. How that is being done is up to the manufacturer to some degree. This FDA guidance (click here) talks about some of the testing they expect to be performed on HEPA filters. Needless to say, big pharma NOR the FDA reference any CETA documents whatsoever. So there’s possibly a slight double standard between how cleanrooms are certified in compounding pharmacies versus large manufacturers; and honestly this is one area where there really shouldn’t be any difference.

What’s in the report? Show me the PharmFax…?

There’s quite a few tests that need to be performed not just to ensure that the room is meeting particle counts and bacterial/bioburden levels, you also must ascertain whether the controls are damaged in any way or working to their specs (HEPA filters should be filtering out 99.97% of particles 0.3 micron or greater in size).

List of Tests for Certifying SECs

Airflow testing: What’s being measured here is the number of times your room’s air is being changed over a specific period of time. For instance <797> states that the total volume of room air should be replaced a minimum 30 times in an hour (for an ISO 7 room); and no more than 15 of these air changes can be contributed by the Primary Engineering Control (PEC aka hood). For an ISO 8 Hazardous environment there should be a minimum of 12 air changes per hour.

Also, with airflow they will test to see if the flow is unidirectional as opposed to turbulent. Typically in cleanroom environments you don’t want turbulence so that air is always going in one direction AWAY from your aseptic processing.

Airflow smoke pattern testing: This is simply referred to as “smoke testing (study)” but is better known as an air visualization study. This is meant to visually demonstrate the air flow patterns to make sure there’s no turbulence in the critical areas where compounding is being performed. It can also be used to show the pattern of air for the entire room; typically you’ll want this done in all of your PECs, pass-throughs, doorways and equipment like refrigerators and lyophilizers (equipment that will disturb air flow).

Room Pressurization and Segregation: This defines a minimum pressure differential between two rooms; for positive pressure it should be greater than 0.02 inches water column (Hazardous – negative pressure between -0.01 and -0.03). The whole point of this is to have air going from the “cleaner” space INTO the “dirtier” in order to keep contaminants from coming in.  The segregation part comes into play because the areas are separated by the pressure gradient (but also by a door typically).

Airflow displacement: This is a “concept” that in my opinion doesn’t have much place in compounding, it’s an open space concept using ONLY air to separate two spaces using a minimum velocity of 40 feet per minute across the “threshold.” In fact, this concept is limited to only being used in low and medium risk compounding.

HEPA filter installation leak test: This is performed to test the integrity of the filter; to see if there are any leaks. An olefin aerosol is sprayed upstream of the filter and the concentration of the aerosol is measured using a photometer. Downstream of the filter a second measurement is taken to see how much if any came through the filter. If the concentration of the olefin is greater than 0.01% after the air exits the filter the filter is considered leaky and should be replaced.

Airborne Non-Viable particle Counting: Arguably, this is one of the most important sections as it can tell you a quick snapshot in time of how effective your engineering controls, cleaning procedures, gowning procedure and just general care of your cleanroom. A particle counter is a machine that draws in a set volume of air over a period of time and as particles pass through the vision of a laser various size particles are counted. The ones that are important for the sake of aseptic operations are 0.5 micron. If you’d like to read more about the testing is performed and the calculations used it’s all in ISO 14644 in a fairly easy to read format. So 0.5 micron is an important size because this is the typical size particle that bacteria tend to attach themselves to. Ideally the number would be zero at all times. However, given there are objects coming in and out of the room and of course humans being the biggest particle generator of all, it’s just impossible to have a zero particle count in your room at all times. Below is the table that can be found in 14644 and again for our purposed just focus on the 0.5 micron column.

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The ISO classes 1-9 are in the first column and in the 3rd from the right you have 0.5 micron. Typically, our hoods or primary engineering controls are tested to be ISO 5 so therefore can’t have any more than 3,520 particles per cubic meter to qualify for that rating. Our rooms or secondary engineering controls are usually either an ISO 7 or 8. If our rooms come even CLOSE to these numbers you’re in bad shape and need to do some remediation for sure. In reality, you should have nearly zero particles detected in your ISO 5 area. Your room is a different story, I can’t really narrow down a range because it really depends on size of the room, number of operators etc. The reality of this though is that you should be doing particle counts in your room far more often than every 6 months; this is how you would know definitively what is “good” or “bad” for your facility.

Honestly, particle counting is a separate topic all on its own but I think the main point here is that you NEED to pay attention to those numbers in particular. Ask your certifiers to explain how they go those numbers. You’re paying them thousands of dollars to come and certify your room you should ask them as many questions as you can! Here are some questions to ask:

  1. How many particle counts are taken at EACH location? Is it an average for each location?
  2. How do you do the calculation for the entire room’s particle count to qualify it for ISO “x,” is this an average of each location?
  3. How are you creating “dynamic” conditions? (NOTE: this is something that DEFINITELY needs to be done – it shouldn’t just be one or two people in the room standing still, literally simulate or perform actual compounding while particle counts are being done – open doors, shuffle feet, drop an object on the floor – see what each of these activities does to the particle count and most importantly HOW QUICKLY THE ROOM RECOVERS from that activity)
  4. What are you using to visualize the air (for the hood and the room – specifically at doorways and pass-throughs)? Did you record that? Can I have the file? (you NEED this documented and saved for audits)

I think it’s worth noting here that EVERY one of these tests are mentioned in the FDA guidance Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice. I’m not sure why there are two separate documents that say more or less the same thing but one is for compounding and the other for manufacturers. In fact, the CETA guidance actually references the FDA guidance. Moving along.

Viable Sampling

So here’s where there’s a bit of controversy: Viable sampling. Viable sampling is when certifiers are using agar plates to isolate growth of bacteria either in the air or on surfaces in your cleanroom. I’m seeing a trend that certifiers will take viable air sampling at every location where they do non-viable particle counting. This is probably one of the more expensive things on your certification report because many times the certifier is sending those samples off to another third party to have them incubated and interpreted. NO WHERE does it say that this is what needs to be done but if you don’t give your certifier a sampling plan typically this is what they’ll do; and it MAY be excessive. Honestly, I don’t really fault the certifiers in this case as they’re caught between a rock and a hard place because they need to be able to stand behind their certification and more sampling (in their eyes) is better. If they have no sampling plan to go by (which should be provided by the facility) then they default to using all of the locations where non-viable sampling is performed. However, the places that really need to be sampled are those that are most critical to your operation (typically the ISO 5 area most importantly and maybe a couple other areas that are frequently used during compounding). Getting a better handle on this alone can save you possibly a $1,000 or more. I’m not advocating for doing your certification on the cheap because it’s extremely important but you should also be educated enough to know when you may be getting overcharged or billed for potentially unnecessary testing.

That’s all folks…

Well, not really. I could write a whole bunch more on this topic and plan to follow this post up with a short video going through one of my own reports. Have a question? Ask away!

And remember; don’t fall asleep at the wheel.


FDA Guidance – Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice

CETA CAG 003-2006 Certification Guide for Sterile Compounding Facilities

ISO 14644-1 Cleanrooms and associated controlled environments Part 1: Classification of air cleanliness by particle concentration

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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.

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