Thanks for tuning in to the Pharmacy Inspection Podcast! Today we have Pharmacist Greg Stanley on the show and we're going to be talking about implementation of an IV workflow system!

Greg Stanley received his Bachelor of Science in Pharmacy degree in 1998, having also completed undergraduate research fellowships in Biological/Environmental Sciences and Polymer Sciences.  He has over twenty-five years of experience with compounded sterile products; both in hospital and home infusion settings.  Greg has extensive experience with policy development, staff training, pharmacy management and regulatory compliance. 

Currently, Greg is an Associate Director at SUNY Upstate Medical University.  He is involved with several projects related to USP <797> and USP <800>.  His oversight includes sterile compounding, hazardous compounding, and robotic/automated technologies. 

In this weeks episode we welcome Bryan Prince back to the show to talk about cleanrooms. We discuss common issues that we see with cleanrooms, talk about particle counts and certification reports as well as some cool technology being used to simulate a cleanroom before it's even built (computational fluid dynamics - CFD).

Today on the podcast we welcome Lilit Smith. Lilit is a board certified sterile compounding pharmacist and is currently the Manager of Compounding and Compliance at Baptist Health South Florida. In her role she supports across the pharmacy enterprise with cleanroom design and construction, regulatory compliance and process and policy standardization. We're going to be talking about her experience with building a compliance team to oversee compounding operations at a large health system.

In this episode of the pharmacy inspection podcast I go over some of the changes to USP <797> in the latest revision to the chapter.

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.

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.

1. Discuss the importance of low levels of endotoxins in parenteral preparations
2. Discuss the limits for endotoxins for various routes of administration
3. Discuss ways to control the levels of endotoxins in final preparations

In this weeks' 483 we're going to be talking about Bacterial Endotoxins and the testing related to endotoxins. Let's first take a look at the observation then we'll discuss what endotoxins are and why it's important to keep them out of your preparations.

First thing that should be talked about specific to this 483 is that we're dealing with preparations that are intrathecals or will be injected into the spinal fluid. One thing to know about intrathecal injections in particular is that they have a lower limit for endotoxins than other injections.

When performing final testing for preparations one of the tests is a bacterial endotoxin test. This test is performed according to USP Chapter <85> Bacterial Endotoxins Test. For parenterals that are not intended for intrathecal administration the limit is 5 EU/kg (Endotoxin Units). For intrathecal injections the limit is 0.2 EU/kg. The per kilogram is the weight of the patient.

The fact that there is a much lower limit of endotoxin specifically for intrathecal injections should give an indication as to the importance of having very low levels of endotoxin in the final preparation.

This particular pharmacy is probably compounding the intrathecal in either very low batch sizes (less than 5) or one at a time as they're ordered by a physician. By not batch compounding the intrathecals there's not enough of the final preparation to send off for testing. My guess is that these are being made one at a time per order and are delivered to be administered within 24 hours.

What are Bacterial Endotoxins and where do they come from?

Most common, endotoxins are by-products of the gram negative bacterial cell lysis. They are lipopolysaccharides that make up part of the cell wall. Gram negative bacteria are commonly found in water sources. So if at any point you are using water either in the preparation itself or using materials that have been washed (i.e. glassware), there is a very high risk of having bacterial endotoxins in the preparation if there aren't any controls in place to limit the level of bacterial endotoxins.

If glassware is being washed and re-used for processing the preparation, the glassware should go through a depyrogenation cycle meaning they would be held at a temperature of 250 degrees celsius for a minimum of 30 minutes. The time may vary depending on the glassware and oven that's being used for the depyrogenation process. Depyrogenation cycles of glassware should be validated to show that the process of depyrogenation is producing a 3-log reduction in bacterial endotoxins.

Even if the process for limiting endotoxins in glassware in place you still need to consider any of the raw materials you're using (i.e. the active pharmaceutical ingredient or API). Water is used quite frequently in the manufacturing of pharmaceutical ingredients and the certificates of analysis for your API should include the limit for endotoxin and the results of testing for endotoxins. It's pointed out in this 483, that the certificates of analysis (COAs) do not include results of endotoxin limits for the APIs.

Why are Endotoxin limits so critical?

When a sufficient amount of endotoxins are injected this could result in a fever or can be as severe as death; particularly if injected into the spinal fluid where there is no immune system. Since this pharmacy doesn't have COAs that show the endotoxin results and are not testing for endotoxin in their final preparation, they really have no way of showing that their intrathecal injections are meeting the required limits for endotoxins.

There are several ways that this pharmacy could increase the level of assurance that their process is limiting the endotoxin in the final preparation. According to USP Chapter <1228> there are 3 ways of controlling endotoxin in parenteral products:

• Indirect Control, "which is comprised of a series of preventive measures that control bioburden, the potential endotoxin contribution by formulation components (e.g., raw materials, APIs, excipients), water, primary packaging components, equipment, and the manufacturing environment, including personnel."
• Process Control, "in which endotoxin is monitored at Critical Control points (CCP) during processing to ensure that there is no increase in endotoxin. These process control elements are subject to validation or qualification."
• Direct Control, "or the direct destruction or removal of endotoxins from product streams, equipment, and primary packaging materials. As with controls on processing, direct measures of endotoxin destruction or removal must be validated."

First, you'd need to evaluate the process for compounding the preparation. At any point is water being used in the process (i.e. glassware and other materials for compounding)? If so, are you using the proper process to control endotoxins? Are there ways to possibly eliminate the need for glassware and materials that may have endotoxins; could single use depyrogenated and sterilized materials and equipment be used?

Lastly, is there a way to compound the intrathecals in batches so that a percentage of the batch is sent off for testing to increase the level of assurance that endotoxins are at low enough limits for the injectable being compounded.

1. FDA Inspection Technical Guide: Bacterial Endotoxins/Pyrogens
2. USP Chapter <85> Bacterial Endotoxins Test
3. Associates of Cape Cod BET White Paper: ENDOTOXIN LIMITS For Parenteral Drug Products
4. USP Chapter <1228> Depyrogenation
5. USP Chapter <1228.1> Dry Heat Depyrogenation
6. USP Chapter <1228.3> Depyrogenation by Filtration
7. USP Chapter <1228.4> Depyrogenation by Rinsing

Learning Objectives

1. Discuss the use of USP graded ingredients in pharmaceutical preparations and the importance
2. Explain what prompted the FD&C act of 1938 to be enacted

In this weeks 483 Friday we're going to be talking about the use of ungraded ingredients in pharmaceutical preparations. First, I'd like to show you a 483 where this was done, then we'll look at a case where non-USP ingredients led to real issues in patients where the drug product contained non-USP graded ingredients.

Let's take a look at the first 483:

In this 483 it looks like the use of grain alcohol was used to make several products. Of course, using everclear 95% is NOT a USP graded alcohol and is actually meant to be for consumption, but not as a pharmaceutical ingredient.

So what's the difference of whether something is USP-graded and a substance that doesn't carry that same grade? First, USP graded ingredients are tested for a number of things including the stability of the ingredient itself. This is the major difference between those ingredients that carry the USP grading and those that do not.

First, is there such a product that exists for this pharmacy? Are there USP graded ethanols that could've been used in this product? The answer is yes. There is in fact a USP monograph for ethanol which typically means that alcohol USP can be found in the market that's been tested for impurities and degradation products. So the easiest way to solve the issue for this pharmacy is to simply use USP graded 200 proof alcohol.

I would like to note that in this particular 483 it's noted that this pharmacy is a "Producer of Non-Sterile Drug Products". So one thing I can say is that all of their products were being used for topical use and not to be consumed. Nonetheless, the alcohol used was not USP-graded so the point that the final preparation wasn't consumed orally or by given by injection still doesn't necessarily matter.

The next question in my mind, if there is no substitute for something that is intended to be laboratory grade, is there a way to qualify this ingredient for use in your drug product. I would say yes, however much research and testing would need to be done prior to its use. How to go about doing that goes beyond what this episode will cover but the possibility is there.

Next, let's look at a scenario where using non-USP graded ingredients were used in an injection and actually caused harm to the patient.

In 2017, there were two infusions of curcumin compounded with non-USP graded polyethylene glycol (PEG) 40 castor oil. As a result when these injections were administered patients had hypersensitivity reactions to the IV product. Note that in this preparation it actually was administered intravenously, so this was a sterile product.

So what happened to these patients and why? The FDA reports:

On March 10, 2017, the U.S. Food and Drug Administration received an adverse event report concerning a 30-year-old female patient who experienced cardiac arrest after IV administration of a curcumin emulsion product...The patient reportedly had a history of allergies and was being treated for eczema by a naturopathic doctor. Within minutes of starting the infusion, the patient became pulseless and required CPR. The patient suffered anoxic (depleted oxygen) brain injury and subsequently died. An adverse reaction to infused curcumin solution was identified as a cause of death by the local authorities.

FDA investigates two serious adverse events associated with...compounded curcumin emulsion product for injection

In a second case where this drug was administered the FDA reports:

On May 1, 2017, FDA received an adverse event report concerning a 71-year-old male patient who developed a hypersensitivity reaction after IV administration of (name of facility removed) compounded curcumin emulsion product. The patient had a history of allergies and was being treated for thrombocytopenia (a low platelet count) at a holistic health center. According to information FDA received from the center, within minutes of starting the infusion, the patient developed a cough and erythema (skin reddening). Diphenhydramine (an antihistamine) was administered; however, symptoms escalated to include shortness of breath, itching, and hypotension (low blood pressure). The patient was treated with IV epinephrine and transferred to a nearby emergency room where he was treated and then released.

FDA investigates two serious adverse events associated with...compounded curcumin emulsion product for injection

What's particularly interesting about this injection is that the ungraded PEG 40 Castor oil sort of has a history with the FDA. In 1937, a sulfinilamide was compounded using diethylene glycol. The Diethylene Glycole (DEG) was used as a solvent to dissolve the sulfinilamide (an antibiotic). Diethylene glycol is now known to cause kidney failure in patients. As a result over 100 people in 15 states died as Far East as Virginia and as far west as California.

Diethylene glycol, while it is a great solvent, it's normally used as antifreeze, a deadly poison. Unfortunately, prior to making this oral preparation of sulfinilamide, there were no studies conducted for toxicity and at the time the food and drugs law did not exist. The FDA responded to this disaster with the Food, drug and cosmetic act of 1938 which established quality standards for food, drugs, medical devices and cosmetics manufactured and sold in the United States.

Back to our original 483. What you may or may NOT know about polyethelene glycol is that one of its degradation products is diethylene glycol. Perhaps if the PEG castor oil was USP graded or if studies were done prior to dispensing the curcumin injection, the fatality and injury as a result of the injection would never have occurred. Diethylene glycol is a known manufacturing impurity in polyethylene glycol. What's more is that it was found that the polyethylene glycol that was used to make this curcumin preparation had the labeling of "CAUTION: for manufacturing or laboratory use only." Unfortunately, there is currently no USP monograph for PEG 40 castor oil.

I cannot stress this enough, using USP graded ingredients is absolutely paramount to compounding a safe and effective product for your patients. If you have the resources to do studies on the individual ingredients that may not have a USP grade then it's possible that you're able to show that the use of such an ingredient is safe to be used in your preparation. It's also important to know the history of the FDA and why some of the laws that have been enacted over the past 100 or so years have been enacted.

The last thing I'll say is that just because something CAN be compounded doesn't always mean it SHOULD be compounded. Be sure to do your research on any of the ingredients you're using in the compounding of your preparations.