 Learning Objectives Discuss the importance of particulate in relation to microorganisms Explain why 0.5 micron and larger sized particles are of great importance 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 , 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 , 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 they should be cleaned and disinfected every 30 minutes during continuous use. I'm actually going to reference the 2019 revision of USP 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. USP 2019 Revision Table 8 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. 

Pharmacy Inspection Podcast

FDA 483 #10 – Non-Viable Particle Counting

 Learning Objectives Discuss the importance of low levels of endotoxins in parenteral preparations Discuss the limits for endotoxins for various routes of administration 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 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 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. References FDA Inspection Technical Guide: Bacterial Endotoxins/Pyrogens USP Chapter Bacterial Endotoxins Test Associates of Cape Cod BET White Paper: ENDOTOXIN LIMITS For Parenteral Drug Products USP Chapter Depyrogenation USP Chapter Dry Heat Depyrogenation USP Chapter Depyrogenation by Filtration USP Chapter Depyrogenation by Rinsing 

FDA 483 #9 – Bacterial Endotoxin Testing

I am going to be talking today about something that is maybe a little bit controversial, but has been brought up at the last public forum that USP had in regards to the appeals to  797,  795. And that’s talking about shared stability studies Or a shared database of stability studies that multiple pharmacies could share amongst themselves. 

Pharmacy Inspection Podcast – Episode 48 – Can we share stability studies?

 Learning Objectives Discuss the use of USP graded ingredients in pharmaceutical preparations and the importance 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. 

FDA 483 #8 - Using ungraded ingredients

This week Bryan discusses the use of a HEPA filter prior to exhausting out of a building with a non-sterile USP compliant room - Is it necessary?

Pharmacy Inspection Podcast – Episode 46 – HEPA Filtered Exhaust

 Learning Objectives Explain the purpose of viable air sampling 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 USP Action levels for viable air sampling There's actually a chart within USP 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 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 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. 

483 Friday #7 - Viable Air Sampling

Bryan will be talking about some of the unintended consequences of implementing USP 800 and this particular story he is going to tell you was incredibly expensive...

Pharmacy Inspection Podcast – Episode 44 – Is my building right for my compounding pharmacy?

 The learning objectives for this week’s 483: Discuss the engineering control requirements for handling and compounding with hazardous drugs List two agents that can be used to deactivate hazardous drugs 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 . 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 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 Non-sterile Compounding USP Chapter Engineering Control Requirements for Non-sterile Compounding This table, taken directly from USP , 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 13. Compounding Above this paragraph in it also mentions: Clean equipment should be dedicated for use with HDs and should be decontaminated after every use. USP Chapter 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 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. USP Chapter Cleaning Steps 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 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: https://vimeo.com/424310980 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: seth@lyceumce.com 

483 #6 - Cross-Contamination

 The learning objectives for this week's 483: Explain the typical out of specification range of potency for many compounded formulations Discuss a type of testing that is both economical and scientifically sound 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 , there's still a need for testing this critical attribute of our preparations. In fact, doesn't give us any requirements for testing for potency or the interval at which we should test our preparations. USP Chapter , 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 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 , Stability Considerations in Dispensing Practice Throughout the rest of USP , it talks about what can cause chemical instability and the signs you should look for in particular dosage forms. However, even gives no direction on how frequently potency should be tested on sterile preparations Observation 8 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. Zolner W, IJPC, Quality-Control Analytical Methods: A Guide to Quality Control Testing for the Compounding Pharmacist, Volume 10 No. 4 July August 2006 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 USP Chapter , Stability Considerations in Dispensing Practice Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances 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 

483 Friday #5 - Potency Testing

 Learning Objectives Explain how action levels are used to maintain a controlled environment Define the 5 steps to DMAIC Explain the 5 why's technique for finding a root cause Discuss the proper documentation for documenting a deviation In this week's 483 we're going to talk about investigating microbial contaminations inside the cleanroom to find out possible sources and remediate the issue. We're also going to talk about writing up that investigation and the resulting corrective action/preventive action or CAPA as a result. In this 483 the firm failed to adequately evaluate and test for possible causes to the contaminations. The first observation In this first observation, the FDA notes that the PIC identified one possible cause of the contamination, but failed to test that theory; they didn't re-test the air in that area of the buffer room to see whether or not it was in fact the cause. It's a little difficult for us to perform a full investigation with the limited information we have from the 483 alone but we do know that there were 15 CFU found in a particular location; which exceeds the action level for their ISO 7 class buffer room. Here are the action levels we should refer to found in USP : USP doesn't give too much direction on how to go about doing an investigation either. If levels measured during viable air sampling exceed the levels in Table 5, an attempt must be made to identify any microorganisms recovered to the genus level with the assistance of a microbiologist. USP Data evaluation and action levels only gives us possible corrective actions for us to take once we've figured out the source of the contamination: If levels measured during the viable air monitoring program exceed the levels in Table 5 for the ISO classification levels of the area sampled, the cause must be investigated and corrective action must be taken. 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. USP Data evaluation and action levels There's a system I like to use to investigate issues like this and it's borrowed from Six Sigma called DMAIC (pronounced Duh-May-Ick). DMAIC is an acronym for: Define Measure Analyze Improve Control Define In the define step you're going to do just that, define the problem. You'll want to document how the problem was identified and create a problem statement that describes the issue in detail and what needs to occur for the problem to be considered remediated. In this 483 we would define the problem as being a contamination of 15 CFUs (colony forming units) were found to be in the ISO 7 buffer room in one particular location. Measure You're then going to set up a way to collect data that will help you identify the root cause of the problem. In this case, the data measurement collection tool we would be using would be continued air monitoring. The key with viable air sampling is that you identify the colony to the genus level at least. This will give you the origin of the microorganisms to help you narrow down where they may be coming from. But there also could be other measurements you may want to take once you've properly analyzed the problem. Analyze To analyze the problem there's a few tools that you can use. One is called the "5 Why's." This is simply asking the question WHY 5 times to get to the ultimate root cause of the issue. Why did this contamination occur? - There was equipment in the room that was running that didn't need to be turned on. Why was this the cause of the contamination? - The equipment has a fan that unnecessarily disturbs the airflow Why does it disturb airflow during compounding operations - It doesn't need to be turned on Why doesn't it need to be turned on - it's not necessary for compounding Why is the equipment running then? This piece of equipment will be turned off during compounding operations But I wouldn't just stop here. This gets down to one possible root cause but when it comes to contamination there are up to 6 possible causes. For this I would fill out what's called a Fishbone (or Ishikawa) diagram. https://en.wikipedia.org/wiki/Ishikawa_diagram#/media/File:Ishikawa_Fishbone_Diagram.svg This is where the firm didn't go far enough to investigate the issue. As you can see there's quite a number of factors that can contribute to a contamination and finding out the root cause is really important. Unfortunately, the 483 didn't detail whether or not the 15 CFU were identified so this makes the investigation nearly impossible. Remember without knowing at least the genus of the microorganisms found, there's no way to tell where they came from (people, materials, equipment, etc.) Improve In the improve step you'll want to test your possible causes of contamination. If you've determined it's equipment, maybe the HEPA filters in your SEC need to be checked/changed. If it's people, perhaps the gowning procedures aren't sufficient for lowering the shedding of particles from your operators. Are materials being wiped off and disinfected before they're being brought into the cleanroom? Again, all of these possible causes would be identified by the fishbone diagram. Control You've now narrowed down that it was a number of factors that contributed to the contamination; let's just say for this case we found that materials and equipment weren't being wiped off and disinfected prior to entry into the cleanroom. Also, let's say that the operators needed to change their procedure for gowning, using more protective covering so that no skin is exposed while in the cleanroom. You then need to measure each of these solutions in some way to show that the root causes identified were in fact the issue and that the cleanroom is now under a state of control. First and foremost, you'll use viable air sampling, at the very least testing in that one location that had 15 CFU. If any CFUs are detected, then identify them to see what might still be causing the contamination. Next you could ensure everyone is properly wiping off materials prior to entry into the cleanroom using a checklist for cleanroom entry. Also, maybe you'd want to sample the operators fingertips and thumb as well as parts of their gown, post-compounding (prior to them disinfecting their gloves but at the end of the procedure), to ensure the operator is using proper aseptic technique, not contaminating their gowns and using the proper behavior when inside the cleanroom. The results The results are in and each of the new policies and procedures you've implemented worked. There have been zero CFUs detected in that location for several weeks in a row now. However, you're only halfway done. You need to document all of this information in the form of a corrective action/preventive action documentation form. Corrective Action & Preventive Action Depending on where you look you may see that there are either 8 or 10 phases to a corrective/preventive action process. https://asqasktheexperts.com/tag/corrective-action-and-preventative-action-capa/ https://www.pharmaceuticalonline.com/doc/the-phases-of-an-effective-capa-0001 In the CAPA, you're going to use all of the data you collected from DMAIC to document how you remediated the deviation and how you're going to check the effectiveness of the solution(s). Free Templates for Download I've made a simple DMAIC worksheet for people to fill out to follow along with and implement solutions to test for possible causes to a contamination event. But DMAIC can be used for any number of problems, when you have a deviation of any kind I suggest going through the DMAIC process to identify the root cause of the problem, test possible solutions, implement the ultimate solution and continued monitoring to ensure control over the issue. I've also included a Corrective Action Preventive Action form for download which will allow you to officially document the deviation, how it was remediated and what policies, procedures and training resulted from the investigation and analysis. Resources THE DEFINE, MEASURE, ANALYZE, IMPROVE, CONTROL (DMAIC) PROCESS Establishing and Maintaining a CAPA System The 10 Phases Of An Effective CAPA 

483 #4 - Investigations & CAPAs

Bryan lays out two mistakes that he recently came across in a very well designed 3D model of a cleanroom...the only problem, there were two fairly critical mistakes. Don't make these mistakes...

Pharmacy Inspection Podcast - Episode 40 - Cleanroom design mistakes you shouldn't make

Are you paying too much for viable sampling when you certify your cleanroom? This week we discuss how the lack of guidance for viable sampling is potentially costing you!

Pharmacy Inspection Podcast - Episode 39 - PAYING TOO MUCH FOR VIABLE SAMPLING!?

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Pharmacy Inspection Podcast - Episode 38 - Environmental Sampling Plan

PIP - Episode 37 - Materials of Construction

 Having issues controlling temperature in your cleanroom? Here's what NOT to do and what you should do... Do you have a question or comment for the show? Leave us a VOICEMAIL, right on our site!   SUBSCRIBE: You Tube   Stitcher   Anchor FM   iHeart   Spotify   Radio Public   Pocket Casts   over cast   Cast box   Podcast App   Breaker   Google Podcasts   iTunes   Podbean

Pharmacy Inspection Podcast - Episode 36 - Controlling Temperature by putting holes in my cleanroom?

The Pharmacy Inspection podcast is a show dedicated to discussing issues and topics related to sterile and non-sterile pharmacy compounding and compliance with industry standards.

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Pharmacy Inspection Podcast

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