Roundtable Part 3: How are manufacturers of OSD products addressing issues related to bioavailability, patient centricity, testing, QC, and more?

Karry: With regards to bioavailability, we’re developing fit-for-purpose excipients to ensure that not only do we increase solubility, but that we limit the chances of crystallization of these poorly soluble molecules.

We also are working with instrument companies to, for example, assess in vitro in vivo correlations with the latest tools that there are to evaluate permeability.

For example, Well, we’re focused on improving the patient experience, leveraging Excipients to, for example, mask the bitter taste of an API. Others to reduce the tablet size or even improve the swallowing ability of a tablet. What we are seeing with, for example, the big lost weight medications is that also the industry’s becoming a little bit more open with regards to new Excipients specifically permeation enhancers to convert biopharmaceutical to oral solid dosage products. Formulators and engineers are working together even closer than ever to understand the impact of process variables on the stability of drug products. What we see is that many pharma companies are trying to reduce the cost of quality by implementing process analytical technologies, for example, near-infrared Raman in line online to measure quality in real-time. What we’ve also seen is that they’re leveraging more quality by design topics and even design spaces to increase process understanding and flexibility in their filings.

Kane: At Thermo Fisher, we believe in bringing digital tools to help us solve problems early on. So we have developed in-house predictive modeling tools to identify challenges in addressing poor solubility for bioavailability solutions. We have a quadrant 2 model where we predict which technology applies best and which has a higher probability of success. Bringing the right technology and bringing solutions early on, helps speedily address the challenge and bring the right solutions. For the first time in drug discovery and drug development. Thermo Fisher brings other digital tools we require to scale up drug products from early small-scale phase one drug product development through scale-up in different scales of operations to late stage and commercialization. At Thermo Fisher, bringing engineering solutions and scale-up models, we have predictive modeling tools to address challenges, whether it’s for spray drawing, hot melt extrusion, or scalable technologies, bringing the right solutions and scaling up a stable drug product from small-scale to commercial scale at different stages of the program. We also have predictive modeling tools addressing pharmacokinetic models to understand what is the absorption distribution, metabolism, and excretion profile of small molecules or drug substances, and then predict the kind of release so as to bring targeted drug delivery. That brings the best and optimum efficacy of these compounds in humans and to patients. Computational modeling helps reduce the trial and error and time to bring the right solutions at the right time and address the challenges thereby. Based on scientific data, we can address those challenges by bringing the right technology at the right time to bring efficacious medicines into clinical trials, and then later, after approval, bringing them to patients.

Kallelis: This is a big question. It’s been a question that’s been around now for quite a long time. Things were not really moving and progressing much in that particular area, but most recently they have. So there are technologies that are available today, new technologies to do exactly that, improve bioavailability by improving the solubility properties of drugs. One such technology is vapor deposition technology. This has been in the industry now in the electronics industry for many, many years. So it’s not new in that sense, but it has never been applied to pharmaceuticals. Mikart signed an exclusive deal with Nano Farms Solutions in California to apply their technology on nanoparticles to improve the bioavailability of some difficult drugs. So we’re hopeful that these new technologies will do so to do that. the conversion of dialog agents to oral solid dose is something that’s of high interest to the industry because of the convenience of oral solid dose and how it’s administered orally through the mouth. Many large molecules, the biological products. They’re not conducive to that form of administration.

A lot of them are sterile injectable materials and that is a challenge to widely offer them to the population at large. So to the extent you can make them, an oral solid dose would really help with that proliferation of their technology. That being said, they’re very difficult to do in tablet form. In biologics, larger molecules are not the same as small-molecule drugs and are not always conducive to making a tablet a capsule, or a suspension. So until they overcome that technical hurdle, I think biologics, for the most part, are not going to be oral solid dose administered products. However, there is some hope. There are a few peptides in the industry that have been talked about that have successfully become tablets, but that’s really in the infancy right now of going from biologics to oral solid dose medicines. implementing state-of-the-art technologies is a challenge because state-of-the-art technologies are very expensive in this environment where there is pressure to offer less expensive medications. It’s challenging for companies to run a healthy business and have the money to invest in new technologies. we of course do. However outsourcing these technologies to third parties is still the preferred methodology to get access to them. So if you need, for example, elemental analysis using inductive, coupled plasma technology, it doesn’t make much sense for a CDMO to go off and buy one of those tools for a lot of money, millions of dollars in terms of the purchase. And then the technician who’s trained and the maintenance of that equipment, it’s better to simply outsource it. And the same is true for some of the LCMS technology that’s out there. We would love to have those in abundance like we have with HPLC. GC is in dissolution equipment, but it’s probably best right now to outsource those specialties when needed.

Labella: In the solid dosage form market, there are a few niche areas for improving bioavailability, and most of them revolve around solubility enhancement as the primary driver. We see that now products being developed or being discovered typically are PKs class two drugs. So they have good permeability, but they have poor solubility. To get them into the bloodstream they need to be soluble. So different techniques focused on solubility enhancement have been developed over the past few years. Techniques such as spray drying hot, not extrusion, and so forth. We’ve invested in technology with a partner called Nano Pharma Solutions in order to create nano-sized particles to improve the bioavailability of drug products. This product technology of becoming online next year as we bring the equipment into the facility in order to be able to produce clinical trial scale material for this type of technology. So in terms of patient centricity, we see manufacturers are being more focused on the types of platforms, and the types of dosage forms they want to develop, especially when we’re talking about a geriatric product or a pediatric product. So things like chewable or oddities or really disintegrating tablets are things that are very interesting to a lot of the customer base. They’re looking to develop things that taste good. So taste masking technologies are being utilized, different flavor enhancers and so forth, mouthfeel enhancers, and looking at focusing on reducing particle size to reduce grittiness in the mouth is another focus area for these types of platforms. We see a lot of customers developing 505b2s for liquid and suspension products that, are probably the easier route forward versus an oddity or a chewable type platform. So we’ve invested in new technology to manufacture suspensions at my card. This has just come up online in the past year. We’re progressing with several different suspension products currently. So a lot of the products are not stable in solid dosage forms. And if they were taken orally, if you can get it stable in that type of platform, usually get degraded in the stomach or digested by the stomach acids rather than, you know, being effective and being absorbed into the body. So we see that there’s there are only a few products out there that have been converted into a you know, large molecule injectable type product into several dosage forms. So it’s still a big challenge out there to try to produce dosage forms like that.

Bejaoui: Manufacturers of OSD products are addressing issues related to improving bioavailability by utilizing various formulations, and strategies such as enhancing solubility, modifying particle size, and incorporating excipients that enhance absorption. Patient centricity is being addressed through the development of OSD. Products that are easy to swallow, have a pleasant taste, and are available in different strengths and dosage forms to convert biopharmaceuticals to OSD products. Manufacturers are utilizing advanced formulation technologies such as spray drying hot melt extrusion and freeze drying, implementing state-of-the-art testing, quality control, and advanced manufacturing and control technologies is being addressed through the use of automation, advanced analytics and real-time monitoring to enhance efficiency, reduce costs and improve product quality.

Hulvat: Bioavailability remains one of the key challenges for new oral drug products and manufacturers like Thermo Fisher are addressing those challenges in a number of ways. Amorphous drug products and technologies like spray drying and hot melt extrusion, self-emulsifying formulations, and lipid-based capsules are some of the strategies that manufacturers are using to overcome bioavailability challenges and enable oral drug delivery of molecules that were once thought impossible to bring to market in an oral dosage form. At Thermo Fisher Patient centricity is key to everything we do, and it’s a focus of pharmaceutical development. One of the ways we address patient centricity is in the design of our oral drug products, enabling the convenience of once-a-day dosing through delayed release, multi-particulate capsules, and other complex dosage forms that allow drugs to be delivered rather than a handful of pills multiple times a day in a single tablet once a day and meet the needs of the clinician and the patient. A key area of innovation in oral drug product manufacturing? Is the delivery of large molecules of biopharmaceuticals in oral dosage forms once thought impossible certainly early in my career I saw these challenges developing injectable peptide-based drugs, and now we see drugs like that coming to the market in oral dosage forms. You know, this has been tackled through the drug substance itself. Novel strategies to Stabilize biological biomolecules for oral delivery, along with permeation enhancers and other technologies, is to enable the oral delivery of biopharmaceuticals. We also see a lot of innovation in the targeted delivery of biopharmaceuticals to the gut. They’re addressing the gut microbial directly as an alternative to systemic administration for key indications. OCD manufacturers continue to innovate in the implementation of advanced manufacturing capabilities. Digital and analytical tools to improve the efficiency and productivity of our laboratories and enable drugs to be developed with speed and flexibility.

Selling: This is an exciting time to be in the market for addressing bioavailability issues.

There are a number of technologies and capabilities that manufacturers are able to consider. So first is particle sizing and the ability to reduce particle sizes. We have a microencapsulation capability, for example, that allows various techniques, for addressing the bioavailability issues. Another great example would be hot melt extrusion. Certainly, the ability to combine dosage forms in ways that kind of adhere or bring them together again in order to address various viability challenges is really an exciting new, newer capability. So, one of the final ways that manufacturers are looking into solving bioavailability challenges or different dosage forms. Sublingual tablets, for example, are a way to dissolve products to have them enter, the blood system in other ways that are, you know, becoming more and more prevalent in today’s manufacturing. Patient centricity certainly in oral solid products is an exciting area today as we think about the range of capabilities that we’re able to bring forward. One that comes top of mind is pediatric dosage forms.

So, with patient centricity, considerations, having a pediatric dosage form A allows manufacturers to extend their patent, but more importantly, brings products to pediatric marketplaces and pediatric populations that may end up being possible. In the past. two other examples of patient centricity. Capabilities are taste masking. We spend a significant amount of time effort and resources figuring out how to overcome bitter-tasting APIs and being able to make products that are ultimately palatable for our patients. Finally, with various dosing flexibilities, understanding how to bring products in different sizes, different size pills, and different size dosage dose loading enables the product to target various populations. final patient-centricity consideration is the release of the actual product. There are immediate-release and extended-release capabilities. We actually have a long-acting extended-release product, for example, that can be given to patients, and it releases in a profile over 6 to 9 months. So, this is certainly an advantage for patients. As you think about the number of actual pills or products that they have to take on a daily or weekly basis.

So there are some great new resources for more modern technologies and capabilities.

One great example is continuous manufacturing. Another would be quality by design. So these are two techniques and technologies that we’re deploying internally for select clients that are allowing us to produce at high quality, more cost-effective deliverables for our clients and ultimately the patients. So there are exciting times ahead for sure. For oral solid dose products, as I think about the market today and if you look at the types of products that are in early development, one example is oncology products. There’s a wide range of companies that are tackling various forms of cancer. And these products typically are high potency types of products. And so in order to manufacture those, you need certain.

Capabilities and handling within your facilities. As we think about what that means for the industry ultimately is going to mean more targeted products that can treat a wider range of disease states. And this to me is super exciting for the industry. The demand, interestingly, if you think about oral solid products, the demand of the industry that is going to continue to grow is probably peaked in terms of the portion of products that are oral solids today. Just because there is so much emphasis on biologics and selling gene therapy. But the exciting thing is I look at the number of FDA approvals for oral solid and small molecule products over the last several years, and this remains relatively consistent at about 75% of approvals.

Sedlock: Manufacturers of OSD products are focusing on improving bioavailability through novel delivery systems, including lipid-based systems, using different technologies like co-crystallization, salt formation, amorphous, and solid dispersions. These are all services that we’re offering to our customers here in a totally scientific. As far as state-of-the-art testing, like I mentioned earlier, the quality control, raw materials coming in, and the inconsistencies from the pandemic and the totally designed equipment so you can test these materials with a very limited amount of product. So basically before you go ahead and blend 100 kilos of material and find out later that you have a quality problem, these products are designed to test that quality issue before you actually run.