[Solutions Spotlight] Overcoming drug formulation challenges

Jan. 19, 2023
An Off Script podcast with Daniel Price, director and head of excipients, solid applications at MilliporeSigma

In this latest episode of Off Script: A Pharma Manufacturing Podcast, Andrea Corona is joined by Daniel Price, director and head of excipients, solid applications at MilliporeSigma, to discuss his work driving innovation in the fields of 3d printing of oral solid dosage forms, next generation pharmaceutical manufacturing, oral delivery of novel modalities and predictive formulation, and how these innovations can help overcome today's drug formulation challenges.


Andrea Corona: Hi, I'm Andrea Corona, senior editor for Pharma Manufacturing magazine, and you're listening to a special Solution Spotlight edition of Off Script: A Pharma Manufacturing Podcast about what's happening behind the scenes in our magazine, and what's trending in the drug industry. Joining me today to talk more about what's going on is Daniel Price, Director and Head of excipients, solid applications at MilliporeSigma. Dan currently leads the solid formulation business for the company and has dedicated his career to help drive innovation in the fields of 3d printing of oral solid dosage forms, next generation pharmaceutical manufacturing, oral delivery of novel modalities and predictive formulation.

Welcome, Dan.

Dan Price: Thanks, Andrea. Great to be here today. Thank you for the introduction.

Corona: Of course, we're very happy to have you. So we have a lot to cover today. So I'll go ahead and get started with the first question here. So I'm wondering, what do you see today's most pressing challenges in formulation?

Price:  I think perhaps a lot of people don't realize that formulation is one of the most crucial parts of the drug development process. We have to be able to deliver the drug to the body in whatever dosage form will provide the best effect for that medication. So without formulation, we don't have an additional product. And as with other parts of the pharmaceutical development pipeline, the formulation is under increasing pressure. So that's both time and cost for pharmaceutical scientists. The people who develop formulations are wanting to develop quickly formulations for clinical trials. At the same time, they have reduced resources or resource challenges. So it's all about developing the most cost-effective formulation as quickly as possible because the quicker that we can get a formulation into a human, the quicker we can know if it has a therapeutic effect, and ultimately the quicker that that medication can make its way to patients and have a real impact in the world.

So what's affecting these two parameters time and cost? One of the biggest challenges in formulation development, especially of small molecules, which are orally delivered is the pharmaceutical or biopharmaceutical performance. So that means how well that formulation releases the molecule and how well that molecule passes from the gastrointestinal tract into the systemic circulation. And this process is less efficient when drug solubility is reduced. And what we've seen over the past decades is that the solubility of drug molecules has been decreasing year on year on year. It's reported today, that up to 90% of the drugs in the drug development pipeline are poorly soluble. So if you have poly soluble drugs in your development pipeline, you're going to have to spend more time and more money in order to bring that drug to the clinic. The reason why solubility is an issue is that when you take the molecule when you take the medicine, if you imagine, for example, an ibuprofen tablet that ibuprofen tablet reaches your stomach from the stomach, it passes to the gastrointestinal tract.

At that point, the drug needs to be released from the tablet into the gastrointestinal fluids. And then from here, it passes through the intestinal membrane and into the systemic circulation. Now, for this process to occur, the drug has to be soluble within the gastrointestinal tract. So if the drug isn't soluble, we have a big problem on our hands and we have to invest time and money to develop formulations that overcome these issues. Another potential challenge in the formulation is more downstream. So when we actually want to manufacture our drug drugs are becoming less soluble, but they're also becoming more challenging to work with. That means that they're not flowing very well, that they don't compress into a tablet very easily. Maybe they have some unreliable structures, different crystal structures, for example, and this can really add a lot of time and cost in the development of a manufacturing process. So I would say those are the two biggest challenges that we currently face in formulation, small molecules, and solubility. And then on the other side, processability

Corona: Can you tell me more about how these challenges are typically addressed? Do you see any specific trends or common approaches to overcoming these challenges?

Price: Absolutely. So let me start with solubility. This has been an active, an extremely active area of the scientific literature for the past decade scientists across the world in academic institutions and pharma companies and life science companies like ours have been working to develop approaches that can enhance solubility and broadly speaking, these two approaches can be grouped into two different categories. On the one hand, we have a chemical modification of the API. This means we take the drug that has low solubility, and we actually change the chemical structure of the API. So we might add a polar group to make the molecule more polar. We might synthesize a salt version of the drug to increase solubility that way. Or we might use something like a prodrug and a product is basically where you tag on an additional part of the molecule that is ultimately improving the solubility.

But then when the drug is absorbed, that product is cleaved. And then you reveal the original drug. So sometimes called Trojan horse drug delivery, because that pro-drug component is not actually part of the molecule, but it's just there to enhance the solubility. So those are broadly speaking, the chemical approaches to solubility. Now the problem is more often than not. When a medicinal chemist has developed a molecule, it's been fine-tuned over various iterations to have the most effective interaction with its sites of action. So, you know, the whole dogma of pharmaceuticals is that you develop a molecule that molecule interacts with a biological site of action. And in that interaction, you get some sort of positive biological effect that hopefully can alleviate the symptom or the disease or the condition that you were trying to treat. So you've developed a molecule to perform misfunction, to interact with a biological target.

If you now, all of a sudden say, okay, we need to add on a group here. We need to turn this into a salt. We need to make this a product. Then you run the risk of basically losing out on all of that very strong interaction that you've built into that molecule. And so simply put chemical modification sometimes is simply not an option. And that's where we tend to formulation approaches. Now, there are a wide array of different formulation approaches. You can change the solid-state structure of the molecule. So you can formulate what we call an amorphous form of a molecule in the amorphous form, you have no crystal structure. And because you have no crystal structure, you have a much higher solubility, or you can use things such as dissolution enhancement aids. So these are things such as hings such as surfactants, so Polaxomer here is a great example of dissolution aids.

These molecules basically make the dissolution more favorable, and if you make the dissolution more favorable, you have a quicker dissolution, and therefore you address your low solubility. Then there are approaches such as lipid formulations. This is where you use hydrophobic lipids to solubilize hydrophobic molecules. And then also we see same advances in porous carrier specifically mesoporous silica has been used as a really powerful technology. And essentially how mesoporous silica functions is it absorbs exactly like a sponge, those very crystalline and poorly soluble molecules into its structure, and inside the structure of the silica, you get a stabilization of the amorphous form and this amorphous form of substantially more soluble. So for the solubility challenge, I'd say chemical and formulation approaches are more common than not or we use formulation approaches, and of those mesoporous silica is a great option for that purpose.

And that is in processability. Where mesoporous silica can also be used to address the second challenge that I discussed in formulation development, and that is processability. And so specifically here, we're talking about crystal structure. So one of the big challenges in the development of small molecules is that you change the chemistry. You change the synthesis at every single stage. So you start with one synthetic route, preclinical trials, and med chem. Then you have different synthetic routes when you do your pilot batch for your clinical trials. And then finally, when you get to commercial manufacturing, you need to totally change the chemical synthesis again, to make it economical, et cetera. And so at all of these different changes, you can introduce changes into your molecule. And one of the changes that we see is in the crystal structure. So depending on your synthesis, you might get a different crystal structure. And if your crystal structure is different, you might get totally different performance. This is called polymorph variation, and polymorph variation is something that is really challenging to deal with in drug development.

Now, what we have demonstrated in our organization is that mesoporous silica can be used to de-risk this entire process. So you don't have to worry about what crystal structure you're going to get outside of your structure match out of your production batch out of your clinical batch, because you take that molecule and you load that molecule again, in, in the exact same way, like a molecular sponge, the Melo of silica takes up that molecule and it homogenizes the structure. It means you have the same structure every single time. And that allows you the possibility of developing a platform whereby you don't have to worry about polymorphism-related changes.

Corona:  In general, how important are functional excipients? What value do platform solutions bring?

Price: Functional excipients allow us to solve problems that basic excipients do not allow us to solve, you know, with mesoporous silica, that is a functional excipient, it has a function that it brings to your formulation. You can use it to enhance all your ability to stabilize your amorphous , or you can use it to de-risk drug development by homogenizing a particle property. And of course, we have several functional excipients available on the market and in our organization. And each one of those functional excipients that sounds silly to say performs a function. And that can range from solubility enhancements that can be dissolution enhancements. That could be as a sweetener, for example. It could be to aid in the manufacturing of tablets as a tableting aid. They make the formulation development process easier, and more cost-effective, and ultimately, they allow more cost-effective medications to be delivered to patients quicker.

Corona: Can you tell us about a platform solution or technology that you see as beneficial and effective? How does it help to improve efficiency and formulation development and bring products to market?

Price: If you have a different crystal structure, you have big problems because your molecule will behave differently. And we demonstrated that mesoporous silica and in particular,  our product Parteck® SLC can be used to can be used to homogenize particle properties and therefore reduce the risk of these polymorphism-related changes. So this has a lot of power potentially because if you know that you're going to get the same chemical, and physical structure, every single time for your molecule, you don't have to worry about changes in polymorphism, but we believe it goes beyond even this. Because if you take a molecule and you load Parteck®  SLC, you absorb that molecule within the mesoporous silica. You take the molecule, you dissolve it, and you add this solution to Parteck®  SLC. It absorbs the solution and your drug is essentially trapped inside that porous carrier.

Now what's really powerful about this is it doesn't matter what your molecule looks like. The end product looks the same because you take your molecule, absorb it onto silica, and the end result is the drug-loaded silica. We’ve demonstrated that you can take molecules with substantially differing properties, different molecular weights, different hydro Felicity, and different PKA, and you can load that molecule onto Parteck®  SLC, and you will get the same solid-state every single time. So not only does this provide the opportunity to reduce the risk of polymorphism, but it also actually provides the opportunity to have a platform-based formulation approach. It doesn't matter what your drug looks like. You will be able to load it onto Parteck® SLC, and you'll be able to develop the same formulation every single time. And here I'd like to loop back to the first question, what are the two biggest pressures in formulation development, time and money. If you can develop a platform formulation, you save time, you save money, and you get to the clinic much more quickly.

Corona: How can this technology be used from preclinical to commercial?

Price: I think that's one of the great things about this approach because it allows you to implement the technology as early as preclinical development. So as soon as you're doing pre-formulation development, for example, animal trials, you can use this technology and you know that this technology will go with you from preclinical to phase one, to phase two, to phase three, because you get the same drug product every time. And as said, with a platform approach, you don't have to go and change the formulation in every single stage. So it really can go with you from preclinical all the way to market. So another important consideration here is how do we actually do this process, you know, from a, from a production perspective. And what we can say is the loading of these drugs onto Parteck®  SLC is fully scalable from the smaller scale in the lab, all the way to large scale productions in 150 kilo batches ready for commercial manufacturing.

Corona: In general, what are the expectations of an excipient supplier? And how would you define the role from your perspective?

Price: Yeah, so our role as a partner you know, we don't like the customer-supplier dynamic. We are a partner. We exist to support the drug development process as much as it's the mission of our customers to bring their products to the market, to provide benefit to patients. That is exactly what we want to support as well. We want to provide the technologies, products, and quality needed to bring drug products to the market. And so there are lots of different considerations when you consider that dynamic, we need to provide excipients that are the highest possible quality. And here we have our flagship Emprove®  branding. And this is where we provide all of the necessary quality and regulatory documentation our customers could possibly need. So quality is a very important part of our offer. Also, reliability when our products are being used in lifesaving medications, we need to deliver on time and with sufficient reliability. And that's something we take very seriously. And then the final part I'd say here is really innovation. So pharmaceutical manufacturing companies, are busy figuring out what molecules can be used to treat diseases, and they don't necessarily have the resources to develop new excipients, to develop new formulation technologies. And so that's our role in this dynamic. We want to develop new technologies that can provide value in the formulation development process. So it's quality, it's reliability, and it's really a partner in innovation.

Corona: So how can excipient suppliers and pharma manufacturers work together to support a more efficient and successful drug development process?

Price: I think the key here is openness. Again, when we view each other as partners, we're more willing to work together, and there are lots of different ways that pharma manufacturers and excipient suppliers can work together. For example, in our organization, we offer an application service lab network. So we have expert labs in in Darmstadt, Germany, in Mumbai, India and in Shanghai, China. And these labs work hand in hand with pharmaceutical manufacturers to develop formulations, troubleshoot problems with existing formulations, and exchange on a high technical level. In addition, and I take Parteck® SLC as an example,  when you get to commercial scale manufacturing, you need to be certain that this formulation technology will be scalable and manufacturable. And here is where we can also provide solutions with partners in CDMOs that actually can manufacture the commercial product. So it goes all the way from early-stage research, all the way to commercial-scale production.

Corona: So regulatory requirements and risk management are an additional challenge that drug developers are facing. Do you have any advice that you could share with us on how to navigate these?

Price: Absolutely. And it's a crucial part of our relationship with our partners. We need to provide reliability and quality. Those are the two points that I mentioned earlier. And within our portfolio, the Emprove® program, as I mentioned, is a really robust and credible program that provides regulatory and quality documentation. So if you are a formulation scientist, if you are a colleague in QC or QA or regulatory sciences, you need to provide a vast amount of data to the regulatory authorities to satisfy them that the molecule is safe and effective and should be launched to market. Now, wouldn't it be nice if you could pull on these documents at a click of a button that's exactly the whole ethos of the Emprove® program, you can go on our websites, and you can access the Emprove® suites. You can download all of the necessary documentation that you need to do your job. And your job is to bring lifesaving medications to the market. In addition, we've seen huge shifts in digitalization and data, and what's also important is that we evolve alongside these shifts and here E data becomes really important. So how can we share data seamlessly between one organization and another, and here E data is crucial. And so we're really working intensively to improve how we share data, how we can tap directly into our partners systems and share the most important and relevant information seamlessly and quickly.

Corona: So what is the future of pharmaceutical formulation and manufacturing? What would you see as major issues and opportunities over the next few years?

Price: It's a great question. And from my perspective, there are two major paradigm shifts on the horizon in the pharmaceutical industry. So I'll tackle one and then the next, so the first is all about how we manufacture. So historically the way we manufacture small molecule drug products is in batch processing. So we exactly is the name implies. You have a big vessel, you put everything in one vessel, you mix it. Then you take it from one vessel to the next etcetera, et cetera. And it's, it's a process that works, but is inefficient. And what we've seen is the rise of continuous manufacturing. And as the name implies, continuous manufacturing is not in batch, but rather is a continuous process. So you go from one unit operations to the next, in a seamless transition without any downtime, without any kind of transfer required. And this improves efficiency, it reduces the footprint.

So you need less of a manufacturing facility and it's ultimately more cost-effective. And again, a link back to the main challenges we face in formulation, development, time, money, and continuous manufacturing reduces the need for both. And so we are developing technologies, excipients. We are really creating thought leadership in how excipients will play a role in continuous manufacturing. Also for manufacturing, 3d printing has the potential to be a huge game changer. You may have read online, you know, this idea that one day we'll go into the pharmacy and we will have our medication printed for us on demand. And that may sound like science fiction, but within our lifetimes, that will be a reality. And we want to make sure that we provide the technical know-how, the technology, and the excipient that will be used in that process, but 3d printing is already being used today. There are 3d printed drugs on the market.

3D printing has huge benefits in clinical trial development and supply and can make things quicker and cheaper. So that was the first kind of paradigm shift that I think's on, the horizon changes in our manufacturing. The second paradigm shift that's coming our way is the oral delivery of biologics of novel modalities. The COVID pandemic basically thrust mRNA onto the scene. And mRNA is just one of the novel modalities or biologics that are really growing double digits. You know, we're seeing more and more therapeutics on the market. The problem with these therapeutics is you have to be at the doctor's facility. You need to get an injection. You need to go out, you need to wait 20 minutes to make sure everything's okay.

We would all prefer it if we could take a pill at home safely, and securely and have the same effect as that injection. Now, this is not a reality, but again, within our lifetimes, we will be able to take these types of medicines by mouth, with tablets. And we want to play a crucial role in developing the technologies that will enable this process. So we are actively involved in understanding how these novel modalities and biologics will make the transition from parental application needles to solid application tablets. And again, this is where the whole partnership ethos really comes into play. Working with academic organizations, working with pharmaceutical companies. We want to develop the technologies that will change pharmaceuticals.

Corona: Well, it sounds like you're definitely busy doing that, and you have some very exciting things going on. I'm looking forward to hearing more about them. So thank you so much for joining me today and sharing your insights with our audience.

Price: Thanks a lot, Andrea. It was a pleasure to join you today.

Corona: Of course. And for our audience. This is Andrea Corona and you've been listening to a special edition of Off Script: A Pharma Manufacturing Podcast. Stay healthy and stay informed.

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