Recently, Pharma Manufacturing spoke with Daniel Price, director and head of Excipients Solid Application at MilliporeSigma, about how functional excipients can help pharma address formulation challenges.
Q: What are today’s most pressing challenges in formulation?
A: One of the biggest challenges in formulation development, especially of orally delivered small molecules, is performance — how well that formulation releases the molecule and how well that molecule passes from the gastrointestinal tract into the systemic circulation. This process is less efficient when drug solubility is reduced.
It’s reported today that up to 90% of drugs in development are poorly soluble. If you have poorly soluble drugs in your pipeline, you’ll have to spend more time and money to bring those drugs to the clinic.
Another potential obstacle in formulation occurs downstream. As we attempt to deal with solubility issues, manufactured drugs are becoming more challenging to work with — they’re not flowing very well and they don’t compress into a tablet very easily. Maybe they have different crystal structures, for example — and this can add a lot of time and cost in the development of a manufacturing process.
Q: What approaches can be used to overcome these challenges?
A: Scientists across the world have been working to develop approaches that can enhance solubility and broadly speaking, these 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 change the chemical structure of the API. We might add a polar group to make the molecule more polar, for example. Or, we might synthesize a salt version of the drug to increase solubility.
In terms of processabilty, one of the obstacles is that, depending on your synthesis, you might get a different crystal structure. And if your crystal structure is different, you might get a totally different performance. This is called polymorphic variation, and it’s something that is really challenging to deal with in drug development. But we have demonstrated that using a silica drug carrier can help de-risk this entire process. The mesopores of the silica material take up that molecule, homogenizing the structure. Having the same structure every single time allows you to develop a platform approach without worrying about polymorphism-related changes.
Q: How important are functional excipients?
A: Functional excipients allow us to solve problems that basic excipients don’t allow us to solve because of the function that they bring formulations. You can use a functional excipient to stabilize your amorphous form, or you can use it to de-risk drug development by homogenizing a particle property.
We have developed several functional excipients which are available on the market. Each one comes with a specific function, ranging from solubility enhancement to dissolution enhancement, sweetener to tableting aid. They make the formulation development process easier and more cost-effective, and ultimately, allow more affordable medications to be delivered to patients quicker.
Q: How can technology help improve efficiency and formulation development?
A: We have found that mesoporous silica and in particular, our product, can be used to homogenize particle properties and therefore reduce the risk of these polymorphism-related changes. This is powerful because if you know that you’re going to get the same chemical and physical structure, you don’t have to worry about changes in polymorphism, but we believe it goes beyond even this.
We’ve demonstrated that you can take molecules with substantially differing properties, molecular weights, hydrophilicity and pKa, and you can load that molecule onto part of a silica drug carrier and you will get the same solid state every single time. Not only does this reduce the risk of polymorphism, but it also provides the opportunity to have a platform-based formulation approach. You will be able to load it onto Parteck® SLC and develop the same formulation every single time.
Q: How can this technology be used from preclinical to commercial?
A: One of the great things about this approach is that it allows you to implement the technology as early as preclinical development. As soon as you’re doing preformulation development — for example, in animal trials — you can use this technology and you know that it will go with you from preclinical to commercial because you get the same drug product every time. With a platform approach, you don’t have to change the formulation in every single stage. This is why it is important to note that the loading of these drugs onto Parteck® SLC silica is fully scalable from the small lab scale to large scale productions in 150 kg batches ready for commercial manufacturing.
Q: How would you define the role of excipient suppliers?
A: We see our role as a partner, which goes beyond the customer-supplier dynamic. We exist to support the drug development process as much as it’s the mission of our customers to bring products to market that benefit to patients.
This is why we provide excipients that are the highest possible quality, and why we have our flagship Emprove® Program which provides all of the necessary quality and regulatory documentation our customers could possibly need.
Also, reliability is crucial when our products are being used in lifesaving medications. We understand the need to deliver on time and with sufficient reliability.
Innovation is also important. Pharma companies are busy figuring out what excipients and molecules can be used to treat diseases, and they don’t necessarily have the resources to develop new excipients or new formulation technologies. We want to develop new technologies that can provide value in the formulation development process.
Q: How can excipient suppliers and pharma manufacturers work together towards a more successful drug development process?
A: The key here is openness. When we view each other as partners, we’re more willing to work together in various ways. For example, at MilliporeSigma, we offer an application service lab network. We have expert labs in Darmstadt, Germany; Mumbai, India; and Shanghai, China. Our labs work hand-in-hand with pharma manufacturers to develop new formulations, troubleshoot problems with existing formulations, and exchange on a technical level.
When you get to commercial scale manufacturing, you need to be certain that your formulation technology will be scalable. Here we can also provide solutions to CDMO partners that manufacture the commercial product.
Q: How can drug developers better navigate regulatory requirements and risk management?
A: This is a crucial part of our relationship with our partners. We need to provide reliability and quality. The Emprove® Program is a really robust and credible program that provides regulatory and quality documentation. You can access our Emprove® suite 24/7 on our website and download all of the necessary documentation. In addition, there are huge shifts in digitalization and data, and we evolve alongside these shifts.
We’re working intensively to improve how we share the most important and relevant information seamlessly and quickly.
Q: How do you see the future of pharmaceutical formulation?
A: From my perspective, there are two major paradigm shifts on the horizon in the pharma industry.
The first shift has to do with how we approach manufacturing. Historically, we manufactured small molecule drug products in batches, but lately we’re seeing a rise in continuous manufacturing. Continuous manufacturing allows you to go from one unit operation to the next, in a seamless transition without any downtime or tech transfer. This improves efficiency and reduces the footprint. 3D printing also has the potential to be a huge game-changer.
The second paradigm shift that’s coming is the oral delivery of biologics or novel modalities. Within our lifetimes, we will be able to take biologics by mouth as tablets. We see these as important areas where we can and should contribute. In continuous manufacturing, we are developing a deep level of process understanding, and will be launching the next generation of excipients to enable this process. In 3D printing, we are actively partnering with companies who are bringing this technology to customers and patients. Finally, in oral delivery of novel modalities, we are forging relationships and creating research projects with pioneering academic institutions.