SterileAF Podcast

1. Explain the purpose of viable air sampling
2. Discuss how conclusions can be made from the results of viable air sampling

Happy Friday!

This weeks 483 we're going to focus on viable air sampling, which is one part of an environmental sampling plan. The information gained from viable air sampling can be very telling of the cleanliness and control you have over your cleanroom.

In this particular 483 viable air sampling was performed by a third party testing company for the purposes of re-certifying the cleanroom. Here's what the observation said:

So if you're unfamiliar with viable air sampling, it's the type of sampling where you use a piece of equipment to draw in a known volume of air and impact the air on a plate of growth media to see if there are microorganisms in the air.

This 483 states that a third party contractor had done the viable air sampling inside their ISO 5 engineering control or hood and in their ISO 7 buffer room. What's interesting here is that the 483 shows the results from not one certification of their cleanroom but the inspector reported a second certification six months later as well. What's most concerning is the April 2019 results where a total of 19 CFU or colony forming units were found. However, six months later, while there was still microorganisms found in the air in the same location, it was much less with only one found. Let's continue to just focus on the ISO 5 location as this is the most critical part of the cleanroom as this is where the compounding is performed.

In either case, April and October, an investigation should have been done in the cleanroom to figure out what the underlying issue is. I encourage you to go back and listen to the podcast episode on Investigations and CAPAs for learning how to properly investigate and document microbial excursions.

In this 483, because it was a third party contractor, they also reported the type of organisms present. This can be extremely helpful in finding out the root cause of the contamination. In April, 19 CFU were found and they were:

• Bacillus
• Coagulase negative Staphylococcus
• Micrococcus

There's actually a chart within USP <797> that tells us when we should take action if there's greater than 1 CFU found to be in our ISO class 5 area. So the fact that in April there were 19 found, an investigation absolutely should have been performed.

Looking up where these particular microorganisms come from would be the first step in an investigation. Bacillus are gram positive bacteria that are usually able to form spores, which are highly resistant when they're in their spore form. Bacillus can be found in soil or can be of animal origin.

Coagulase negative staphylococcus and micrococcus are typically normal flora found on humans. This information gives us two possible places to look for ingress routes for these organisms: materials and people or operators inside the cleanroom.

Remember, these were found in their ISO class 5 engineering control which is supposed to be extremely clean and free of microorganisms at any given time. So this could also suggest that maybe there's something wrong with their engineering control as well as it should be actively pushing microorganisms out of the hood.

In an investigation, we would possibly look at:

• Gowning procedures for operators
• Cleaning procedures: what agents are being used, the frequency of cleaning
• Operator technique while inside the cleanroom
• Our process for bringing materials into the cleanroom
• The engineering control itself: is it working properly, is there enough airflow, is there anything wrong with the HEPA filters

Six months later when the recertification was done again, there was only 1 CFU of bacillus found in the ISO 5 hood. This suggests that the firm did possibly investigate the cause of the contamination and made some improvements. However, there was no documentation found to definitively say that was done. I will say it might've been helpful if there was also results from surface sampling in the hood as this might give us further indication of what was causing the contamination.

Without sharing the entire 483, there are other key issues found that suggest other possibilities. For instance observation 2 notes that cleaning is performed in the ISO 5 area with non-sterile cleaning agents and wipes. Observation 6 discusses how there's a loose light fixture inside the ISO 5 laminar airflow hood. Observation 8 points out that prior to entering the cleanroom some materials were not disinfected. In observation 9 it's discovered that there's signs of rust and chipped paint inside the ISO 5 laminar airflow hood.

Needless to say, there's a lot of issues that we can look at and remediate to fix the underlying contamination. USP <797> says:

Data collected in response to corrective actions must be reviewed to confirm that the actions taken have been effective. The corrective action plan must be dependent on the cfu count and the microorganism recovered. Some examples of corrective action include process or facility improvements, personnel training, cleaning and disinfecting, or HEPA filter replacement and/or repair. The extent of the investigation should be consistent with the deviation and should include an evaluation of trends. The corrective action plan must be documented.

USP <797> Data evaluation and action levels

The point I'm trying to make here is that there's an abundance of information given for us to find and remediate the root cause of this particular contamination. The abundance of CFU found in the April 2019 recertification should have prompted the pharmacy to fix at minimum:

• Cleaning, materials agents and frequencies should be examined, possibly no longer using non-sterile wipes to clean and disinfect the hood
• Operator's gowning should be examined to see if people are gowning properly and if the gowning itself is sufficient (is there skin exposed while inside the laminar airflow hood)
• The visible rust and other issues with the ISO 5 area should have been remediated

Another point to be made is that viable air sampling is only performed every six months during recertification of the cleanroom. Perhaps after the first results, where there was 19 CFU found in the ISO 5 area, that should've also prompted more frequent viable air sampling. No follow up was performed until six months later. It's hard to make the case of any trend taking place when the data points are six months apart from each other. Follow up viable air sampling most definitely should've been performed to see if any of the improvements actually did remediate the issue. Also, sterile operations didn't cease when there was 19 CFU found, which calls into question any of the batches that were made in that hood between April of 2019 and October.

Lastly, I'd encourage pharmacies to perform their own viable air sampling. These sampling devices range in price usually from $5-10K but can absolutely give you more data to defend your operation from batches being called into question for sterility concerns. The point here is that perhaps the pharmacy should've made the purchase of a viable air sampler, made improvements, then performed viable air sampling while compounding operations took place. Had this been done, you could've seen a real trend line and further analysis could've been done while certain "fixes" (e.g. more cleaning, training operators, different garbing, engineering control examination) were taken place one at a time.

In compounding pharmacy the one thing that is not taken as seriously as it should is an environmental sampling plan. It's evident that had the pharmacy more closely examined the findings from the first certification in April 2019, there may have not been an issue also found in the October certification.

If you'd like to fully explore how to implement an environmental sampling plan that makes sense for your operation I'd suggest looking at the Environmental monitoring course available on learn.lyceumce.com. It's available here for free or if you'd like continuing education credit along with the lesson you can take that here.

The learning objectives for this week’s 483:

1. Discuss the engineering control requirements for handling and compounding with hazardous drugs
2. List two agents that can be used to deactivate hazardous drugs
3. Discuss the 4 steps required to properly remove hazardous drugs from surfaces and equipment

In this week's 483 we're going to look at the importance of cleaning work and non-work surfaces to prevent cross-contamination. What's interesting about this particular 483 is that the FDA doesn't note this on sterile products, but an operation's non-sterile compounding areas. Also, the 483 specifically mentions "hazardous drugs," so there should be no question in your mind whether the FDA is looking for some compliance with USP Chapter <800>.

Let's take a look at the observation:

There's quite a bit of information packed into this short paragraph. First, the 483 mentions that drugs are produced without providing adequate containment. This suggests that perhaps the firm wasn't using containment ventilated enclosures or powder hoods while compounding. They are also cited for having non-dedicated utensils and equipment for compounding with hazardous drugs. The hazardous drug in this case being tretinoin.

USP <800> specifically talks about non-sterile compounding and the requirements that must be followed:

The C-PECs used for manipulation of nonsterile HDs must be either externally vented (preferred) or have redundant–HEPA filters in series.

USP Chapter <800> Non-sterile Compounding

This table, taken directly from USP <800>, gives the required engineering controls for when you're compounding with hazardous drugs. First, HDs should be inside an externally vented room or secondary engineering control that has at least 12 air changes per hour and a negative pressure between -0.01 and -0.03 inches water column. Also, the compounding must be performed inside an externally vented primary engineering control or it must have redundant-HEPA filters in series.

Next, let's talk about the use of dedicated equipment and utensils. If you're compounding with hazardous drugs, all of the materials and equipment you use should be dedicated specifically for HDs and not be used for non-HD compounding. USP mentions this specifically here:

Disposable or clean equipment for compounding (such as mortars and pestles, and spatulas) must be dedicated for use with HDs.

USP Chapter <800> 13. Compounding

Above this paragraph in <800> it also mentions:

Clean equipment should be dedicated for use with HDs and should be decontaminated after every use.

USP Chapter <800> 12. Dispensing Final Dosage Forms

Even the 483 talks about cleaning utensils, specifically citing that,

...you do not use deactivating agents for the removal of hazardous ingredients on shared utensils.

FDA 483

What agents specifically is the agency talking about when they mention the term "deactivating agent"? A deactivating agent is one that renders the hazardous drug or residue inert. The specific agents that deactivate HDs are oxidizing agents, such as peroxide formulations or sodium hypochlorite.

Here's another table from USP <800> that talks about all of the steps that need to take place to properly deactivate, decontaminate, clean and disinfect items or surfaces that may have come in contact with hazardous drugs.

So this applies not just to your surfaces that you've potentially contaminated with hazardous drugs, but any of the equipment and utensils used as well. While the FDA may not specifically cite you for something where they quote directly out of USP <800> they're still concerned with cross-contamination between products. Even trace amounts of hazardous drugs in other formulations is just not acceptable.

If you'd like a more in-depth post on the procedure specifically for cleaning up a hazardous drug spill I'd recommend check this post out.

I also made a video that visually details the steps:

About the author:

Seth DePasquale is a Board Certified Sterile Compounding pharmacist and former 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.

Contact Seth: [email protected]

The learning objectives for this week's 483:

1. Explain the typical out of specification range of potency for many compounded formulations
2. Discuss a type of testing that is both economical and scientifically sound
3. Discuss the 5 elements of an SOP on potency testing should include

This week we'll be looking at one observation the FDA made at a facility concerning the potency testing of their drug products. While there's not much direction given to pharmacies through USP Chapter <797>, there's still a need for testing this critical attribute of our preparations. In fact, <797> doesn't give us any requirements for testing for potency or the interval at which we should test our preparations.

USP Chapter <1191>, Stability considerations in dispensing practice, only helps us look for signs of chemical instability (i.e. potency) but still gives us no interval to guide the frequency of potency testing that should be performed.

USP Chapter <1191> says:

Pharmacists should avoid ingredients and conditions that could result in excessive physical deterioration or chemical decomposition of drug preparations, especially when compounding...Pharmacists should establish and maintain compounding conditions that include the ensuring of drug stability to help prevent therapeutic failure and adverse responses.

USP Chapter <1191>, Stability Considerations in Dispensing Practice

Throughout the rest of USP <1191>, it talks about what can cause chemical instability and the signs you should look for in particular dosage forms. However, even <1191> gives no direction on how frequently potency should be tested on sterile preparations

Going by this 483 observation, the FDA would like to see:

• A plan in place for how frequently you're testing your preparations for potency
• The acceptable criteria for potency (less or greater than 10% loss/gain of potency)
• Written SOPs for the frequency and criteria of your potency testing program
• Written SOPs for what to do when a preparation falls out of specification for potency

So how do compounders come up with a frequency for testing their batches for potency? In manufacturing there's a concept known as "skip lot" testing for critical attributes of products for processes that are under a state of control. However, the manufacturer must justify this decision to perform skip lot testing.

In an FDA Guidance, "Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances" the FDA gives details on what attributes could be chosen for skip lot or periodic testing:

Data generated during product development may be sufficient to justify skip lot testing or elimination of some or all attributes from the specification.

Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances

There's no debate on whether potency testing will give extra assurance that your product/preparation is of the purported and expected potency which in turn ensures the safety of the preparation for the patient. However, cost does become a factor as extra testing increases the cost of a batch and will be passed on to the patient.

I'd like to suggest a scientifically and statistically sound procedure for determining how often compounders test for potency. Let's talk about what you would want to have in an SOP that dictates potency testing for your compounded preparations (sterile or non-sterile).

The SOP should consist of:3

• Verifying that the compounded preparation is correct at the start of the program by appropriate potency testing in an independent quality control lab.
• Choosing a sampling interval, which will define the maximum out of specification (OOS) limits that will be detected (Surprisingly, these intervals can be relatively long. For example a failure rate greater than 5.5% should be detected if every 25th lot (or batch) of a preparation is tested, which is a 4% sampling plan)
• Setting up a scheduled or random sampling plan for the preparation to be sent out for potency testing
• Collecting and recording the testing data
• Reverifying the preparation if it fails a test or if changes are made to the formula, procedures or people making the preparation

The key to a skip lot testing program is the initial testing and results. The initial verification test(s) should illustrate that the product's potency attribute is under a state of control through the processes and procedures used for compounding that particular preparation.

At first, perhaps sending 3 consecutive verification batches off for potency testing to verify all are within the specified potency range (e.g. +/- 10% the preparation's potency is greater than 90% and less than 110% of the labeled concentration) would suffice for maintaining that your process and preparation are under a state of control.

That being said, if all verification batches are within specification you can now justify an interval based on statistical data. The table below provides guidance on the frequency for potency testing batches and the percentage of the time it should detect an out of specification result.

Just to explain the table a little further:,

• 2% sampling rate means you'll be sampling 1 lot out of every 50 and this will detect an OOS failure greater than 10% of the time.
• 3% sampling rate is testing 3 lots out of 100 or 1 out of every 33 batches
• 4% would be testing 1 out of every 25 lots
• 5% would be testing 1 out of every 20 lots
• 50% would be testing every other lot

For regulators you should be able to show that your process is under a state of control for your compounds, you've established a procedure for potency testing and that you have a procedure in the case of a potency failure.

When you have a potency failure you'll need to figure out the root cause, correct the problem and re-validate the compound for potency. If you'd like a guide on how to go about finding the root cause check out this post on investigations and CAPAs.

References

1. USP Chapter <1191>, Stability Considerations in Dispensing Practice
2. Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances
3. Zolner, W; International Journal of Pharm Compounding, Quality-Control Analytical Methods: A Guide to Quality Control Testing for the Compounding Pharmacist; Volume 10 No. 4 July August 2006

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Do you have a question or comment for the show? Leave us a VOICEMAIL, right on our site!

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Do you have a question or comment for the show? Leave us a VOICEMAIL, right on our site!