Issue:June 2024

EXECUTIVE INTERVIEW - Lonza: Navigating Today’s Challenges in Drug Solubility & Bioavailability

Today, compounds with low solubility or low bioavailability are becoming the rule rather than the norm, as around 90% of preclinical compounds are now estimated to have bioavailability challenges. Low solubility in the earliest stages of drug development presents many challenges for small and emerging biopharma companies. These companies often require the expertise and resources of a strategic partner, like a contract drug manufacturing organization (CDMO), that has the experience, expertise, and advanced technologies to improve dissolution rate, solubility, and overall bioavailability. To help navigate these challenges, CDMOs can leverage approaches like amorphous solid dispersions (ASDs) to enhance drug solubility and bioavailability by converting crystalline drugs to the amorphous form most commonly using spray drying or hot-melt extrusion.

Drug Development & Delivery recently interviewed Adi Kaushal, Director and Technology Head, Bioavailability Enhancement at Lonza, to discuss solubility and bioavailability challenges and Lonza’s approach.

Q: Why is there an increasing number of compounds with low solubility or low bioavailability entering today’s drug development pipeline? What is the impact on the industry and time it takes to develop these products?

A: For years, poor solubility and low bioavailability have presented drug companies with many challenges in drug development, impacting timelines and ability to scale-up. This is the result of more new chemical entities with complex needs entering drug development pipelines.

Poor solubility often stems from the disconnect between drug discovery and drug delivery. The former often exclusively focuses on receptor binding and activity sometimes at the expense of whether the drug can be delivered to the site of action.

As drug companies face challenges in drug solubility, they are also simultaneously faced with the rising demand for orally administered drugs. Today, patients prefer the convenience, non-invasiveness, and lower cost of oral tablets or capsules. This is because orally administered drugs are much easier to adhere to compared to other approaches for drug administration. Further, these drugs maximize patient compliance and minimize expenses. This is critical, as patient compliance is a paramount priority in drug development. The challenge, however, is the low intrinsic solubility of the API in the gastrointestinal (GI) tract, which results in poor bioavailability.

Q: What techniques do drug manufacturers implement to solve these challenges? What are the benefits?

A: The continued preference for orally administered drugs will present challenges for drug manufacturers to enhance medications with low solubility, which constitute a substantial portion of newly developed chemical entities. To tackle this issue, one effective formulation strategy involves the use of ASDs. These formulations work by increasing drug solubility, thereby facilitating dissolution in GI fluids, and optimizing the quantity of drug that enters the bloodstream. This boost in oral bioavailability holds the potential to enhance patient outcomes by reducing variations in plasma exposure, lowering required dosages, and mitigating potential drug interactions with other medications or food.

While there are several platform technologies and manufacturing techniques to produce ASDs, hot-melt extrusion (HME) is a leading approach based on mature process understanding, small process footprint, continuous operation, and readily scalable. These attributes allow for more flexibility of the unit operation, resulting in relatively lower manufacturing costs and making it a more appealing commercial process train.

HME is also a solvent free unit operation as opposed to spray drying that can not only reduce cost but avoid concerns with solvent impurities and enable sustainability.

Q: Developing a stable ASD formulation can be complex. How do CDMOs approach optimizing the hot-melt extrusion (HME) process for different drug candidates?

A: CDMOs should take a multifaceted approach to optimizing the HME formulation and process for different drug candidates. For example, at Lonza, we conduct thorough pre-formulation studies to gain a deep understanding of a drug’s physicochemical properties, including its solubility, melting point, and chemical stability. This helps us identify the most appropriate polymers to achieve bioperformance and physical and chemical stability in the amorphous state.

Next, we optimize the HME process itself. This involves studying various processing parameters such as temperature, screw speed, and feed rate. Our goal is to achieve a uniform dispersion of the drug throughout the polymer matrix while minimizing potential degradation of the drug or polymer.

Finally, we carefully characterize the ASD formulation using advanced analytical techniques. This helps us ensure the drug remains in its amorphous state, is uniformly distributed, and possesses the desired dissolution properties. By following this comprehensive approach, CDMOs can develop stable ASD formulations for a broad range of drug candidates using HME.

Q: What are some current challenges CDMOs face with these techniques?

A: One of the primary bottlenecks is the lack of material-sparing approaches for HME evaluation. This often leads to scenarios where the HME is either not evaluated at all or studied too late when the change of the process can be costly and risky.

Design of a HME formulation and process requires not only a thorough understanding of the API and polymer properties but also requires balancing of bioperformance, API loading, or pill burden concerns as well as chemical and physical stability considerations.

Another area that is often overlooked is the formulation and optimization of the dosage form for HME. While the HME intermediate may demonstrate higher bioavailability, a tablet or capsule (and not the HME by itself) will be the final presentation to a patient. Thus, it is important to formulate a dosage from that not only retains the bioperformance achieved through the HME formulation and process but also minimizes pill burden for a given dose.

Q: When looking for a strategic partner, what criteria should small and emerging biopharma companies look for to help develop their products?

A: It is essential for small and emerging biopharma companies to partner with a CDMO that has an integrated offering to develop their products from clinical stages of development to commercial.

As companies navigate their drug product through development, it is important to focus on the ability to scale that formulation to the next phase. Early clinical trials can require significant quantities of drug product that may be challenging to provide under accelerated timelines without a well-planned scale-up strategy.

ASDs, including those produced by HME, are often more complicated/involved than crystalline API-based products. It is important to work with a CDMO partner that has experience in the ASD products formulating in material sparing way for early stage that can be scaled up when the product enters later phases of development and commercialization.

Further, companies should try to avoid working with multiple outsourcing partners. This can result in duplicated efforts, longer timelines, and increased costs. This can be addressed with a single outsourcing model, where the right partner can perform API synthesis, solid form/salt screening, optimize your formulation, progress your compound through clinical trials, and rapidly scale the drug product to launch.

Q: Looking ahead, what exciting developments do you see in the field of HME and its application in ASD production?

A: One of the key aspects of HME that Lonza has been focused on is making material sparing such that evaluation is possible in early stages when API availability is limited. This enables a parallel evaluation of spray drying and HME, thereby ensuring the most appropriate approach is selected for progression. While the process to achieve ASD is different between solid dispersions (SD) and HME, the material science involved is very similar. Therefore, being able to screen both HME and SD in parallel allows for a direct comparison and selection of the most appropriate path to advance ASD formulation.

Another aspect of further progression in HME across the industry is the expansion of API and polymer space. Currently, the application is limited to APIs below a certain melting point, and the polymer choices are often more constrained than SD.

Finally, the HME process being a continuous unit-op lends itself for integration into a complete process train starting from the API to finished drug product such as a tablet or a capsule.