483 #3 – Smoke Studies and Media Fills

Learning Objectives

  1. Explain the purpose of smoke studies
  2. Define the two types of smoke studies that need to be performed
  3. Explain the two conditions under which smoke studies need to be performed.
  4. List 5 conditions that make a compounding procedure more challenging
  5. Discuss the purpose of having control vials or preparations for media fills

In todays 483, we’re going to look at comments to observations made by the FDA for a firm’s smoke studies and media fills. Both of these processes seem to have confusion surrounding them and are worth reviewing to see what the standards have to say about each.

We’re only going to look at two observations from this particular 483. The first is an observation of their recent smoke studies.

Observation 1 – Smoke Study

Unfortunately, USP <797> doesn’t give much information as to how to properly perform a smoke study but I have a couple great videos that explore this really well; both of which are a part of the ACPE Accredited video-based sterile compounding course. I’ll put the videos at the bottom of this post.

<797> does tell us that we need to perform smoke studies as a part of our re-certification process for our cleanroom and primary engineering control. This 483 gives us clues as to at least what the FDA is looking for in a smoke study. Notice one key phrase being used repeatedly in this observation: “dynamic,” meaning the smoke study should be done while operators are inside the engineering control simulating actual compounding conditions. Specifically, the FDA inspector noted that the smoke study didn’t include a simulation of filling activities while it was being performed.

It’s also good practice to show a smoke study being performed at-rest or without any operators or any disturbances of any kind to show that your engineering controls are working properly.

The main purpose of a smoke study is to show that both the engineering control and the operators are working properly. The operators at any time shouldn’t be blocking the airflow of the primary engineering control from washing over the preparation. In order to see this you really need to perform a smoke study under dynamic conditions.

The FDA also notes that there wasn’t enough smoke being generated to adequately see the visualization of the airflow. There should be enough smoke in the primary engineering control for the camera to see that the hood at all times is demonstrating laminar airflow or airflow that is in a straight line. If the air is turbulent, this could cause particulate and/or microorganisms to fall into the products being made.

The FDA also points out that the “static” smoke study didn’t have adequate smoke to determine unidirectional airflow. So, there’s actually two different smoke studies the FDA expects to see, both static or without any operators or movement and dynamic or a simulation of filling activities.

Airflow Visualization Part 1
Airflow Visualization Part 2

In the next observation, the FDA comments briefly on media fills. The reason why I chose to put both smoke studies and media fills together is because having to do a smoke study every six months during the re-certification of the room is the perfect time to also perform media fills. The media fills can be the part of the smoke studies that are performed under dynamic conditions.

Observation 5

Also, just like smoke studies, you should be performing media fills in all of your primary engineering controls; that’s a point that is often missed by pharmacies but just makes sense. If you have a biological safety cabinet and only perform a media fill in it, that doesn’t mean the same operator is proficient in using your other primary engineering controls; especially if the control is completely different like a laminar airflow workstation. So remember both smoke studies and media fills should be performed in all engineering controls. In fact, this is also the perfect time to do gloved fingertip and thumb sampling as well; which should be completed upon finishing the media fill.

A couple things to know about media fills is that these should:

…simulate the most difficult and challenging compounding procedures and processing conditions encountered by the person replacing all the components used in the CSPs with soybean-casein digest media.

USP <797> 2.3 Competency Testing in Aseptic Manipulation

In the above video it explains what “the most difficult and challenging” conditions means. Your media fill should be done with the maximum number of operators in the room, at a time of day that might be more challenging, like right after lunch, and also be the most complex procedure you perform in your facility.

You need to have control vials (or whatever type of preparation you’re simulating). Control vials are unprocessed, non-sterile growth media that show your media is able to sustain microorganism growth. When these are incubated they should be visibly turbid or cloudy, while your other media you prepared under aseptic conditions should be clear. Remember, a media fill is simply simulating your most challenging compounding procedure but just replacing your active ingredient with growth media.

According to USP <797>, you need to then incubate the media at 20-25 degrees C for 7 days then at 30-35 degrees C for an additional 7 days to detect a broad spectrum of microorganisms.

How do we know what our most challenging procedure is? There are a number of factors to help you know which you should be simulating:

  • Number of manipulations
  • Number of operators
  • Quantity of preparation
  • Length of procedure
  • Sterile vs Non-sterile starting ingredients (non-sterile being more challenging)

Again, I just want to mention you should also perform the media fill in conjunction with your gloved fingertip and thumb sampling at the end of the procedure.

Again, media fills are simply a simulation of your most difficult, challenging procedure; the only difference is that you’re substituting growth media instead of compounding with actual drug.

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  1. Seth,
    Great job on this topic as well as the stability vs potency discussion.
    You are a great teacher!