Compounding: reducing the risk

And our aim is to highlight areas where practitioners can improve safety and reduce unwanted outcomes through greater focus on good compounding practices. Our pharmacy board of Australia's guidelines on compounding of medicines comes into effect from October 1st this year. The board's guidelines provide updated, explanatory information about the regulatory environment in which compounding of medicines should be applied by pharmacists.

It is important to understand that compounding is regulated under a number of different legislative requirements, including the Therapeutic Goods Act and the therapeutic goods regulations, state and territory legislation and the poison standard, which is often known as the S-U-S-M-P. We know that pharmacists must comply with all legislation and that failure to practice in accordance with the requirements can lead to action by the pharmacy board or a jurisdictional regulatory body.

There are three main themes in our podcast and we invite you to follow along as we begin by discussing some important foundations of operating a compounding service. Followed then by the topic of governance and compliance in our work practices. And in our final theme, we will speak about real life compounding scenarios and strategies for risk minimization. Let's begin by discussing some foundation topics around the work environment and training requirements for simple and complex compounding.

I'll start by asking Patricia to discuss the importance of what a well-maintained compounding lab is.

So that might be the room specifications, depending again the nature of the chemicals that we are handling, whether they're hazardous cytotoxic or non-hazardous. We need to look at the equipment, the devices, and the packaging we need to ensure we have a formulary and over time we'll need to develop that formulary to include evidence of safety, efficacy and stability that will relate to the particular therapeutic intent and is safe for the specific patient for whom we are compounding.

We need to look at the quality of the active pharmaceutical ingredients, which I'll refer to as APIs. And really importantly, we need to have the appropriate training Yes, staff, depending on what it is that they're undertaking.

scientific evidence? And just as the theory may change, the manual dexterity skills which are perishable would be subject to review as well. So just because I learned how to compound a particular dosage form at the beginning 10 years ago, five years ago, it's a matter of use it or lose it unless I have recurrent training and my training is actually assessed, competency assessed, I don't know. And so we can't rely on hope as a plan to succeed. We must actually be doing continuous learning.

Learning that is competency assist and then is maintained. And apart from that foundational course, we also need to look at compounding as an area where there are niche markets. So other than that foundation, you may be practicing in pediatric, in hormone therapy, in analgesic, in veterinary medicine, in dermatology. So you need to actually add these electives if you like, to your suite of learning skills and be able to apply them.

So it's really important that we provide counseling, written and or verbal, particularly about hazardous materials, which can be genic cytotoxic for example. So we'd need to inform patient what is compounded, why is it compounded in the first place, how do they store it and dispose of it? They need to have an idea about the adverse event profile and really

importantly, what to do if it actually occurs. But we also need to as usual, explain the instructions about how to use it or how to administer it. And that includes meter dose packaging. So sometimes the prescriptions come through and they're written in international units or they're written to be delivered as a weight in milligrams, but we are delivering them in a meter dose package that will deliver a volume.

So we need to actually be aware ourselves and explain to the patient how to convert that into milliliters and get the right dose.

supervised. So of course the nature of compounding pharmacies and who's owning compounding pharmacies is rapidly changing. We're seeing a big change. Compoundings been going in this country complex compounding the way we see it now, it's been going for more than 25 years.

And of course we're seeing a lot of original owners of compounding pharmacies retiring, stepping back, and of course the nature of the pharmacy business generally is that we're seeing often more than one owner coming into a new business when they're buying. So there may be two or three co proprietors in that business as well.

We're also seeing a young early career pharmacist wanting to open their own business, but I think it's really, really important that we realize that if we are a proprietor or a co proprietor, there's no such thing as a silent partner. So you might not be the person in the business who is really all that interested in compounding. You might have a different scope of practice.

There might be someone who's driving the idea of doing the compounding or you might be buying into a business that already has compounding going. It's still really, really important that all proprietors understand that they need to have a working knowledge of what's going on in that part of the business, even if it's not their thing. So what does that really mean? You need to have some sort of a way to think about how are you going to audit

that business if you're not there. So it might be developing an audit checklist that each proprietor goes through individually, maybe on a rotational basis, and you need to do your due diligence. You need to know what the rules are, the regulations. That means that you need to do some training yourself.

So it may be that all of you get together, talk about what are the requirements, who's going to be on a day-to-Day responsible, or are you going to have a responsible pharmacist at the store managing that business, and how are you going to have those conversations with the manager of the store and the other staff when you're not there?

procedures are. So a set of procedures, what we call standard operating procedures or SOPs, the proprietors need to understand what the roles are of any compounding technicians. And the pharmacist must understand also that the person who's on on the day, the responsible pharmacist is going to be responsible for covering off on any jobs that those technicians are doing.

The pharmacist is responsible for critical calculations, for example, looking at any critical steps when you're making the product. And they can do that while supervising the technician,

but ultimately it is the pharmacist signing off. And then the proprietor needs to have some way to make sure that all of this is being managed appropriately, that raw materials are being sourced appropriately, that risk assessments are being done and that documentation is happening because we know that poor documentation is the bane of the pharmacist's life, but without that documentation, no one can see what's going on.

So even just introducing a new idea or a new part of the concept, just the owner needs to know whether we're suddenly making a whole lot of new dosage forms. You can't just introduce doing cytotoxics into the lab, for example, if you don't have an appropriate facility. So everyone needs to know what that's about and needs to make sure that they're on board with the responsibilities related to those services.

What are some of the key principles around safety and risk awareness when staff are handling compounding medicines that contain cytotoxic or hazardous materials? So we really need to.

There is the NIOSH N-I-O-S-H, which is a North American list. It has a website that allows free access for Australian pharmacists as well, and that is a list that will help you identify hazardous materials. We do have the EVQ. There is also the APF, and really importantly, the safety data sheets provide a lot of information that will also guide us about how to handle an API before it

even arrives. So within the safety data sheet, the SDS will have information about first aid, so what to do should there be an emergency situation. And in that case it's really important to have our procedures ready and our staff trained, for example, the spill kit, we don't just buy the spill kit and hope that we never have to use it, but not had any training about how to use it, should something go wrong.

The safety data sheet also provides information about the appropriate personal protective equipment, so the PPE and the primary and secondary engineering controls that we need to have in place in order to handle these cytotoxic or hazardous materials. So for example, it might be a hazardous material. Do we use a surgical mask or do we use a P 2 and N95, which gloves should we be using nitrile or surgical? What should our primary engineering and secondary engineering controls be like?

Can we take the risk that air recirculates because airborne particles are going to recirculate in the room and that exposes the operator, it exposes the environment. We don't want to share those airborne particles of hazardous drugs with our neighbors, and it also has the risk to the patient of cross-contamination from one medicine to the other.

So once we've actually identified in our mind what might be hazardous material, we need a way to communicate that we've implemented some of the risk mitigation and how do we communicate that? So one easy way is to actually label the bottles, and you might choose something as practical as having a red sticker on something that's hazardous or in a red texter you write HD.

But just as importantly, you need to identify the non-hazardous materials, and that might be with a green sticker or a green tick, whichever way you are identifying it, make sure it's communicated and staff are trained to identify it as a visual clue. You would also separate hazardous from non-hazardous materials that might be in a different room suddenly at least in on a different shelf categorize and label your shelves accordingly.

We also need to have this hazardous training and communication program before staff are exposed to these risks because we want to prevent those risks from occurring. We'll have a medical surveillance program for staff that are handling hazardous drugs, and that really means that we're following up their medical results on a regular basis or that the appropriate physicians are doing that on our behalf to ensure that nothing untoward is happening there.

But apart from that, we also need to have a medical exclusion policy. So that means things like knowing when specific tasks should not occur if a particular staff member has a particular medical condition or has a particular illness or is pregnant or is breastfeeding. So to assist us in that, the A PF actually has two categories, listing medicines requiring special handling. So one of those categories is for all persons actually handling hazardous drugs.

And the second category is for persons who are pregnant or are breastfeeding. And although these categories were originally developed for commercial medicines, they took the pie for compounded medicines as well, and we can take advantage of that. There is an additional list in APF, which is a recommendation to use cautionary label 21. So that's what people other than patients are handling the medicines, and that's for carers and family members.

So there's certainly a lot of resource and lots of practical things we can do to identify and mitigate risk.

we like to call them standard operating procedures. So SOPs, they're sort of a boring type of document, but they outline so that everyone can understand what needs to be done, how that process needs to happen within the lab. So that's really, really important to have a cleaning SOP so that you do minimize any chance of cross-contamination because that's going to protect the product and

therefore keep your patients safe. It's also really, really important that when you're doing counseling, that you're counseling the patient appropriately, how to handle their product, how to store it appropriately if it needs to be kept out of reach of children, make sure you're talking about those sorts of things. There's a lot of things that we prepare that we often assume that the patient will know how to use.

We've heard over the years stories about pessaries that are being wrapped in brightly colored foils to children that just looks like lollies to them or chocolates if they're kept in the fridge. So it's really, really important to make sure that we counsel our patients, how they handling it, how they storing these things to make sure that they and their families are safe. Same thing, even with veterinary medicines, a lot of those veterinary medicines are very potent.

Even cleaning up the dog poo can be a real problem if you're pregnant and using a drug like your dog is getting a drug that may have the potential to cause harm to the baby. So that's really,

really important. I think also as pharmacists, we know about disposing of unwanted medicines, and I think it's always appropriate to make sure that patients understand that if their medication is not suitable or it's out of date, they can return their compounded medicines and we can dispose of those in the rum bin as well. And we can also use the RUM bin to dispose of any expired stock that we have in our labs.

There are.

And those records, which will be supported by the standard operating procedures that tell us how to do things, will include qualitative and quantitative information. So they'll include things like the specific patient, the batch number of the API that it came from, that the actives came from, which we'll need to retrieve in case of a recall or an adverse event, how much was weighed. And all this information provides an opportunity for a third person to review.

So we're not just doing this documentation for the purpose of recording it, but we want an opportunity to review to approval. And these standard operating procedures will lead to these consistent, reliable, accurate reproducible quality medicines. There's so many of them, we can't just rely on buying them and forgetting about them. We need to have this organized system that you're talking about, Kylie.

And what I found in practice is once we've customized them for our facility, we've added anything specific to our jurisdiction, maybe a professional practice standards updated, maybe something specific in our state or territory, we then need to categorize 'em into files. And I like to categorize according to frequency of when they need to be executed.

So compiling a set of SOPs that need to be done daily, a set of SOPs that need to be done weekly, and as part of the training, it may be the first Monday of the week, for example, the ones that are executed quarterly, and it might be the second Tuesday of the quarter or monthly or yearly. And so we need these folders and we need to be able to train our staff to refer to a calendar to the set of folders so that they know

what their responsibilities are. And really importantly, when we're training our staff and we need to train them on how to use them, how to use the SOPs prior to the time we're asking them to execute it for a real patient, we need to include all staff, and that means locums and casuals. So we train, we retrain, we assess, and we need to also review these SOPs or these folders of SOPs when an incident occurs and at least yearly.

And that's actually in the new guidelines that we need to be reviewing the SOPs.

How can pharmacists avoid the silo effect and what are the benefits of sharing information with other pharmacists colleagues so it can really open up more areas of your professional practice?

things like that. I think when pharmacists can, they should try and get to some face-to-face training, whether it's retraining, even if you haven't had training for a while, just the going back to a lab and doing the hands-on training. Again, there'll be skills that you've forgotten, but the networking and the opportunity to be able to talk to people

is key. Really, we forget sometimes and we get into a situation where we're just plodding along and it's all good because you don't know that there's anything else out there you might not be aware of. Changes in regulation and legislation change in the focus of what is going on in the industry, change in the types of practice, the trends actually in medication. There's lots of new products available. A lot has changed certainly in the 20 years that I've been in compounding.

And we still have people coming in going, oh, I'm still doing it the way we did it. They'll talk about an old formula number that has really almost been retired now because there are many, many better things. We're talking about having longer expiry dates on products. We are talking about products that have many less allergens, for example. And if you don't know and if you haven't spoken to anyone, and that's where it's really, really important to read what's available.

So we have lots of articles in places like the AJP and the Australian Pharmacist listening to podcasts such as this where it can just prompt you again to take a look. There are lots of journals that come from the US as well, but I think it is also important, such as the International Journal of Compounding Pharmacy, the IJPC. These are excellent journals that are peer reviewed and written by pharmacists.

But I think it's also important to note that we do have different rules in Australia compared with in the us. So just because something is trending in the US it doesn't necessarily mean it's appropriate here. And I think we're going to talk a little bit about semaglutide later, but that's definitely one of those that's very, very high in the media at the moment. But in the US the rules are a little bit different.

So I think it's important to be able to talk to other colleagues as well, meeting people at conferences, reaching out if you do know someone else who is compounding, but to also be careful not to just rely on what your mates are saying, whether it's right or not. Get a few opinions, make sure that it's backed up by legal and regulatory soundness and think about whether it's appropriate in your facility as well.

And what are some of the ways that pharmacists can demonstrate ongoing competence in complex compounding Marina?

in the way that you normally make it. So for example, I'm making a hundred capsules of something and then you send a small sample away to check whether what you've actually made comes back in the same, exactly the same strength as you expected it to come. There is a little bit of a plus or minus 10% potential for error, but those of us who work in the compounding space know that we usually try and weigh out with a much lower error. So usually something like plus or minus 3%.

So you're really trying to get as close to the mark as you can. If you're getting further away, that might demonstrate that it's time to do some extra practice or retraining may be required. That's a very physical hands-on way of doing that. And of course completing CPD as well is still very relevant.

So we're going to move into our final theme for our podcast and we're really going to focus on some real life case studies that have been reported to PD L. So as a professional officer, I see sometimes we come across compounding incidents that have occurred and the compounding of medicines is complicated, there's no doubt. And these cases can highlight the areas of risk and also an aware and awareness of knowing your professional practice limits.

A very common incident that we see at PDL are dilution areas. So the example of, I'll take the example of a compounded clonidine suspension that provides a case study for us, and it's also the basis of one of our PDL practice alerts, which can be found on our PDL website. So a pediatric formulation for clonidine isn't commercially available and the therapeutic dose is often prescribed in micrograms rather than milligrams and below.

Therapeutic index of clonidine in children introduces levels of high risk as overdose could result in hospitalization. A mix up between units of measure during the preparation of a clon and suspension can sometimes lead to a child receiving 10 to even a thousand times more than the intended dose errors such as this are preventable. And there are many points in the compounding process when an oversight can be detected and mitigated against. So if it's okay, we'll start with Marina.

I'll ask you a couple for your thoughts on these questions. If a pharmacist is unsure of a formulation and feels like they're out of their depth when it comes to understanding a formula, who can help that pharmacist?

enough to have that. If not, you might consider using one of the clinical support services that are available, and both Patricia and I work for companies that do supply those or do you have another mentor, for example, who you can reach out to who can independently check that? And when I say independently, it's really important that that pharmacist does those calculations separately to you. Otherwise we have this predictive text sort of an idea where we

all see the same numbers and that might not be correct. And it is really, really important that if you're not strong on calculations and not everyone is, and let's be honest, milligrams, micrograms in a hurry, it's very, very easy to make those errors. And if you've been out of pharmacy for just even a little while when it comes to things like millimoles, most of us can't even remember what they're about.

So I guess the thing is, if you are looking at something and you're not sure and you have a new formulation, the most important advice that I can give you, stop and think as part of that risk assessment. Don't go ahead if something seems more complicated than you've ever seen before because that stopping is not going to make a difference to the patient, except that it might save their life and save your professional situation from going out of control.

Because taking an extra moment to double check things is really, really important and really critical. Absolutely. I'll just add there.

So as a result of mislabeling of the outside of the bag by the supplier, the compounding pharmacist released vials to approximately a hundred patients believing that the medicine was actually tirzepatide, but it was however semaglutide. Now this is a great example. The pharmacy's documentation was of a very high standard and all the affected patients were notified with no harmful incidents recorded. So I'll maybe ask Patricia to weigh in on this one.

This case highlights just how critical good record keeping is and the documentation in a compounding environment. Can you expand on the essential role of traceability in respect to lab procedures and protocols? Thank you, Kylie.

Do we have a quarantine area so that when the medicine comes in, it can be inspected, it needs to be reviewed against what was ordered according to the label, inside the label, outside the certificate of analysis, it's is compared to what is received because the C of A does have some indication of what the medicine should look, what the ingredient should look like, and then we do all of that quarantining, if you like, prior to releasing it for the storage. So later use or for use now.

So part of our own process to actually have this preventative system, and now of course we have the right as pharmacists to reject or question ingredients. We can go back to our suppliers and ask for explanations. If something doesn't look the way it should, according to the C of A, it doesn't smell right, the texture is wrong, or even the assay results don't seem right. But apart from that quality verification process internally, we should also be having vendor qualifications.

So that means who are we purchasing from? Are they TGA registered or do they have a simple wholesaler license? Because the TGA registered facility has to have an audited and auditable quality management system that is audited by the TGA on a regular basis. The wholesaling is a simple license you buy from the state or territory jurisdiction. Is the manufacturer of the A-P-I-G-M-P qualified, are they practicing under the code of good manufacturing practice?

When you look at the active itself, are you buying sar capel grade? Does it comply to a monograph? Because if not, the guidelines actually are very clear that if you don't have a C of A or the C of A is questionable, you, the pharmacist are required to test it independently by a NTA accredited lab. So while this incident had to do with the process of the supplier, there were things internally that we could have done preventatively.