The pharmaceutical industry’s current focus on accelerating all aspects of drug discovery and development has become something of a crusade, with companies rushing to compress the timeline from initial idea to first-in-human safety and efficacy data. As biotech and pharma companies engage in the dash to proof of concept, they are often tripped up by compounds with low solubility and poor bioavailability. The emergence of solubility problems in the early stages of drug development can be especially troubling, creating a domino effect that can delay or possibly derail later stages. Partnering with a CDMO early in the development process can help drug developers avoid many of the pitfalls of low solubility. With their expertise in solubility-enhancing formulation strategies and technologies, CDMOs can ensure that development programs remain on track.

 Drug Development & Delivery recently interviewed Adi Kaushal, Director and Technology Head, Bioavailability Enhancement at Lonza, to discuss solubility issues and Lonza’s approach to addressing these challenges in the early stages of drug development.

Q: Solubility challenges are a common hurdle in drug development. How can integrating solubility-enhancing strategies earlier in the pipeline help streamline development and improve outcomes?

A: Solubility and bioavailability hurdles are often a challenge in advancing new molecules, as they require enabling technologies even for phase I studies, which makes it critical to choose a development and manufacturing partner as early in the drug development process as possible. Aligning with a single service partner can reduce the complexities, risks, and costs associated with low-solubility compounds, thereby shortening the timeline to reaching clinical milestones.

Q: How can a CDMO partner help accelerate drug development through solubility enhancement and phase-appropriate processing?

 A: A CDMO partner helps accelerate drug development by tackling a critical challenge: poor compound solubility. Many promising drug candidates are poorly soluble, which hinders their absorption and effectiveness in the body. A specialized CDMO can employ a variety of advanced techniques to enhance the solubility and bioavailability of the active pharmaceutical ingredient (API). This expertise ensures the development of an effective and stable formulation early on, preventing costly delays and reformulation efforts later in the clinical pipeline.

Furthermore, a CDMO’s ability to implement phase-appropriate processing streamlines the entire development timeline. This involves tailoring the manufacturing process to the specific needs of each clinical phase. For early-stage trials, they focus on rapid, flexible, and scalable processes to produce small batches for “first-in-human” studies. As the drug progresses to larger, late-stage trials, the CDMO scales up manufacturing and optimizes the process for efficiency and reproducibility, preparing for commercial production. This strategic, phased approach avoids overinvesting in complex manufacturing too early, while ensuring a smooth, seamless transition from clinical development to commercialization.

Q: What are some of the latest innovations aimed at overcoming solubility and bioavailability challenges?

A: One effective formulation strategy involves the use of amorphous solid dispersions (ASDs). These formulations work by increasing drug solubility, thereby facilitating dissolution in gastrointestinal (GI) fluids and optimizing the quantity of drug that enters the bloodstream. This boost in oral bioavailability holds the potential to improve patient outcomes by reducing variations in plasma exposure, lowering required dosages, and mitigating potential drug interactions with other medications or food.

ASDs can be produced through several platform technologies and manufacturing techniques. One of the leading approaches is hot-melt extrusion (HME), which offers the advantages of mature process understanding, a small process footprint, continuous operation, and ready scalability. These attributes can enhance the flexibility of the unit operation, resulting in relatively lower manufacturing costs and a more appealing commercial process train. HME is also a solvent-free unit operation that can eliminate concerns about solvent impurities while enabling sustainability.

Q: As more complex molecules enter the pipeline, what trends are you seeing in customer demand or formulation needs when it comes to enhancing solubility?

A: We continue to see an increase in demand from biotech and pharma companies for highly complex solubility enhancement solutions due to the rising number of poorly soluble new chemical entities entering clinical pipelines. This growing demand is shifting formulation needs toward advanced technologies and strategies that can mitigate risks early in development, such as quality and reproducibility challenges.

One approach is establishing bioavailability techniques like spray-drying or HME as a core component in early-phase development. Deciding between these two depends on which technique is more suitable for the molecule, provides optimal solubility and physical and chemical stability. This decision also can be challenging when a company’s needs change as a drug moves through the pipeline. For example, early in development, companies are focused on performance and rapidly getting their drugs into the clinic rather than cost. However, as the drug progresses through clinical trials towards commercialization, cost, throughput and sustainability become increasingly important.

Both spray-drying and HME have their own unique advantages. As we continue to see molecules become increasingly more challenging, CDMOs like Lonza must continue to have more tools to advance them in the clinical pipeline. Through new and more versatile applications we can solve these early phase challenges in a more sustainable way.