Exploring Drug Storage, Drug Dosage, and the Supply Chain with Ulrike Lemke (DCAT Week)

Dr. Ulrike Lemke, Head of Sterile Fill Finish at Recipharm, sat down with Grant Playter, associate editor, to discuss drug delivery forms. Topics of discussion include drug storage, drug dosage, and the greater supply chain.

A full transcript of the conversation can be found below.

What are some of the benefits of prefilled syringes?

Ulrike Lemke: Prefilled syringes are a subset of the dosage forms that currently enjoys a lot of growth, and there are multiple reasons for that, and for an increasing preference, particularly in the high value markets, to go to prefilled syringes. One of the facts is, of course, the lower risk at the point of care to misdose.

The second very important advantage of prefilled syringes is, when it comes to filling a high-value API, you don't need to overfill. So in vials, you have single-dose, multi-dose vials, and then you need to extract, at the point of care, the volumes that you want to deliver to the patient. In the prefilled syringe everything is preset, so the risk of doing any mistakes is lower, and you can fill the exact volume that you need. In that regard, you preserve valuable API as well.

Now, what is a disadvantage of prefilled syringes versus other fill forms? Of course you need to have the storage space available for that, and that's why every technology has its pros and cons and you really need to understand, in the end, markets how your patient will need to be treated. There's no need of specific preparation of material or so, the prefilled syringes ready to go, that makes it a preferred option today,

Can you illuminate the process behind lyophilization a bit for our readers? What are some of the factors that we might not be considering?

Lemke: First of all, lyophilization is really freeze drying of formulations to make them more stable. The main advantage of this is you can keep sensitive compounds and materials stable for a longer period of time. So lyophilized products can often be maintained at ambient temperature, so you're avoiding cold chain requirements, and also the degradation in the dry form for sensitive product is much slower if at all present. And with that, you increase the shelf life of products. It is not suitable for every product as well, but often chosen for a really long term stability and storage reasons.

Lemke: You have seen this during the COVID crisis, so there are certain products, particularly in the vaccine space that right now need ultra cold storage, and when you want to hit less developed markets such as the African markets, it really puts constraints on how you can deliver these dosage forms. There are routes around this, and we have seen improvements also with ultra cold storage.

For example, the elongate shelf life of these products after freezing for a couple of days, in two to eight, but generally for markets that don't have these elaborate cold chains very well developed, I think a lyophilized product would be advantageous. At Recipharm we have done this in the mRNA space, for example in lyophilization, and that would circumvent some of the disadvantages of ultra cold storage. It's also costlier and you have to establish the -70, -80 degree storage, and then the question is the access to energy at point of care, so this makes lyophilization easier.

Now, here we come to a counter argument when you look to prefilled syringes versus fill form in vial, for example. In markets where you where you want to deliver to patients also cost effectively, storage space is a limitation. And then, of course, also the way that you want to deliver to the patient. So often you see multiple dosage forms -- or multiple doses in a vial, not multiple dosage forms, to just make that clear -- and it's advantageous to do that. Because it is simpler at the point of care or at the delivery to the patient you reduce the space that is needed. So prefilled syringes, for example in Africa would put a constraint on storage spaces in different countries.

I do think there's opportunity in the lyophilization space, especially given the supply chain disruptions we got from COVID. I know there was so much talk about vaccines expiring in storage, it was just very unfortunate.

Lemke: That's unfortunate. It's a waste of a high value API. But again, I would also like to stress the point that there are different ways of tackling it, lyophilization is one. But I think the other thing is to make the formulation more stable after thawing which were routes that we have seen customers taking, and we can support both. In the end there's always a good solution to it. I think we have alluded to lyophilization, but ultracold storage is something that we should not unnecessarily exclude, but it has constraints.

I'll refrain myself for getting further in the weeds, this is all very interesting. In the parenterals market, can you talk about some technologies whose impact might be overlooked? Because I know there's these heavy hitters of things that dominate the headlines, but I'm curious about the lesser known things.

Lemke: When you think of the market today, first of all, the market has moved a bit from terminal sterilization and to aseptic filling, and we're all talking about the standard dosage forms, which is liquid vial, lyophilized vial, and BFS.

One thing that we take a particular interest in, and that can offer new opportunities, is blow fill seal. We see some first applications in the vaccine space coming up. It's a cost efficient technology, but it is, as the name says, you blow the device, you fill it with the medicine, and then you seal it. There's certain energy or heat involved, so it doesn't lend itself to all kinds of applications. But we think that there is a potential, particularly in the vaccine space, but possibly also other applications in biologics that would be suitable. We're very interested in how this market is going to develop.

We're looking also into the early stages and are very happy to test formulations for customers that want to have a cost-efficient delivery form. One specialty in this is not necessarily a sterile delivery, but when you think about how you need to administer, particularly to children, is an oral route of a liquid into children, and that is another element where BFS could play a role.

Can you tell me about some of the key factors that you would take into consideration when deciding on a form of drug delivery specifically?

Lemke: Well, I think for every medicine, the first element that is really important is how do you want to deliver to your patient, and what is the dosage scheme? So how often does he get it, and what is the point at which the customer will receive the medicine? It's the self-administered, for example, or is this given at a point of care in a hospital or so. Then based on this, of course, you need to design your ideal dosage forms.

Other elements, and we alluded to this earlier in this conversation, is really also which markets are you targeting? How mature are they? What is the training status of the caregiver? How do you avoid any mistakes in the formulation? For example, when you look into a lyophilized product, you need to bring it back into the liquid phase at some point in time. So that requires a caregiver or the patient itself to mix the final medicine again. These types of considerations are what you want to look through before you're defining what your delivery form is going to be. So it's really patient centric, and also understanding what is the health system that you go into. There's a lot of constraints – I mean, we’re talking supply chain, we're talking training centers of the caregiver, we're talking the convenience for the patient itself — you want to avoid pain, so that's one important thing.

And this is physical chemical parameters really, is what kind of a drug substance do you have? Is this stable under certain conditions or not? How can you stabilize it? How can you elongate the shelf life of it? How can you improve the bioavailability of it due to your formulation? So, these are the technical considerations.

Last but not least, and this is also where we were focusing on a lot, is you want to think about the efficacy of the manufacturing process itself. So though we want to do this, we don't want to lose a lot of API in our manufacturing process. We want to make sure that when the dosage forms are being delivered, that this works from a distribution perspective. We have touched upon this when we looked into COVID and when we looked into what cold chain, for example, requires, what kind of space do you have available to store? What kind of customs borders do you have to do? So all these things matter because, for example, when you're very sensitive drug substance or drug product in the end, and you cannot break the cold chain, how do you make sure that this is happening?

All these considerations go in, that's not necessarily only considerations that we do for ourselves, but our customers, the pharmaceutical companies, the biotechs, the innovators, come with this thought process already, and we aid them in it. It's not a one fits all approach, that's why we see them mixing the different dosage forms, and there is always a question of how to serve the market that is a mix of multiple factors.

How would you evaluate the current state of the market in terms of drug delivery, specifically? I'm so curious, because I was talking with Gregor and I feel he does a lot of market instability in the greater biopharma space. But do you think that is being mirrored here?

Lemke: I would not call it, "This is an unstable market." If anything, what I would say is, first of all, due to COVID there was an increasing demand. I think there was an over focus on liquid vial manufacturing and speed of lines. I see that there is still a need for serving the mid-size market segments, so companies that don't have large volume expectations, but have smaller products for global demand and in smaller indications, and I think they need to be served really well and have maybe gotten a little less attention during the COVID years but now we're coming back.

I think there are market segments in which we see that there is a bit of an imbalance between supply and demand, and that is really in the high volume, large throughput liquid vial segment, where we have seen lots of investments coming in. And of course, we see a couple of new players appearing on the market that have yet to prove that they can work under aseptic conditions and can bring the sterile products to market at the required quality.

Last but not least — and I mean this keeps our industry on our toes, and rightly so — the continued expectations from regulatory authorities to push for more patient safety led to the annex one compliance framework that comes into place in August 2023, this year, and this is really to make the market rethink about what does it mean to handle a aseptic products? So what does it mean from a patient safety perspective, and that requires of course investments. I think this is all good, as long as the cost for the patients do not explode while we're managing continuous increase in safety for these types of medicines.

Without going into who these new players are, how would you say they’re affecting the industry?

Lemke: They have a large capacity they have filled during the COVID crisis, and there's a certain mindset also with these companies. I think it's good that new competitors are coming in, it puts pressure on the industry to also rethink. There's a lot of new lines that are coming in, but I think that the point is not about lines alone, it's about the service model that you have to your customers, and it is about resilience in these situations.

I think one of the things, for example, that in this industry for us was very important was to learn how our supply chain really worked, because our suppliers were constraining us to some degree as well. So how do you manage packing material that is relatively consolidate in the industry? How do you make sure that you get access to filters? That was a significant problem during the COVID crisis. And again, there's a consolidated industry on the supplier base, and to manage your supply chain effectively, is a capability that will also affect your customers and the delivery ultimately to patients. So these are the nuances that you need to think through in addition to having manufacturing capacity.

This might be a bit of a blasé question, I guess. But would you say there's a surplus of lines existing from the COVID pandemic, or is it just a matter we haven't thought of how to best use the existing ones?

Lemke: Not everywhere, I think it depends really on the dosage form that you look at. We have not done the full analysis of this, but my impression at this point in time is when you're really looking to large scale high throughput liquid vial aseptic, there seems to be a certain surplus. In other areas, absolutely not, lyophilization I don't see that at all, prefilled syringes, I don't see it at all. And I see in smaller lines, liquid aseptic vial filling also no surplus. So it's really an a specific segment that actually targeted vaccines and large volume biologics, if you will.

Now, conversely, can you say there are any segments you think of a shortage like that need to be start ramping it up?

Lemke: I said that lyophilization -- I don't see it, I see prefilled syringes and market that continues to increase. I believe there's more capabilities and also capacity coming on stream in the years to come and rightly so. Because what drives it is a very vivid pipeline in biologics with new needs.

I think the one unknown for me is going to be what's happening with single use technologies and different ways of handling liquids that are not the classical sterile fill forms that we discussed here, but when it comes in bags. So there are elements in gene therapy that I observed with interest and we'll see how this goes. But I think there's more to be done because the underlying innovative growth for new molecules coming just sustains the trend of growth and sterile fill finish.

Is there anything you would want to point out to advances that might be on the horizon, in addition to what you've already stated in this segment?

Lemke: As I said, one thing for me that that I watch with interest is liquid handling technologies in ATMPs that may not be glassware based. I think we touched upon the BFS technology, we touched upon single use bags for point of care applications -- we need to see to which volumes this will come down.I think then some minor elements will be how much will be glass versus plastic, and let's see how this goes.

And there's one element that of course we also look into, and this is the combination of cartridge, and then devices where a point of care could shift from a hospital-based model to an auto-injector, for example, where the patient treats himself. So lots of things to observe, I think we're in a very dynamic industry and I really enjoy being here.

I can clearly tell your enthusiasm for what you're saying. Do you have any final thoughts you want to share?

Lemke: I think for me, it's really a good point to be in this industry. I think the underlying growth in biologics and innovation will continue to fuel it. I think competition is good for the business, and I like it. I think what I would like to take a focus on in the coming years is not only the dosage angle and the modality angle that we looked for, but the angle of how will we serve markets that are underserved today? So Africa comes to mind in this, and how can we make sure that some of the learnings that we had in the pandemic will be applied so that we can avoid future shortages, particularly of medicines that prevent pandemics or stop them?

Absolutely. Thank you so much for taking the time to speak with us.

Lemke: Thanks.

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