When innovating new medicines, drug developers focus on identifying and optimizing an API that achieves a desired biologic effect while also meeting defined efficacy and safety criteria. This process requires substantial investments of time, resources, and funding in early-stage research and discovery focused on refining API activity, pharmacokinetics, and dosing.

While this API-focused approach is essential for developing new molecules targeting novel pathways that can address unmet clinical and patient needs, it often isn’t sufficient to guarantee commercial success without an equal emphasis on formulation. Drug formulation is vital for optimizing and preserving API activity throughout manufacturing, transport, storage, and patient administration. It’s also a key factor in ensuring drug stability, which is essential for maintaining product efficacy. Additionally, formulation significantly impacts cost of goods sold (COGS) and ease of use, both of which are key determinants of drug adoption and profitability.

For example, formulations that require cold chain transport and storage will cost more to deliver to customers, which either drives up end-user costs or reduces profitability. Patients and healthcare providers may avoid drug formulations that have complex administration requirements or reduced tolerability, potentially limiting adoption and overall market potential. Consequently, formulation considerations are as integral to the success (or failure) of a drug as the drug’s target and mechanism of action.  

Optimizing a drug’s formulation presents complex challenges that must be navigated through scientific rigor, often requiring a delicate balance between clinical and commercial priorities and the biochemical and biophysical constraints of the API. Ideally, a well optimized formulation is stable at room temperature without compromising tolerability or complicating administration. Achieving this ideal, however, involves evaluating numerous factors, including buffers, buffer concentration, pH, and surfactants. Despite extensive adjustments, the perfect formulation may remain elusive. In some cases, lyophilization may become necessary, adding a processing step and the potential for human error or contamination during reconstitution, which can compromise efficacy or lead to adverse events. In other instances, the inclusion of excipients may be unavoidable, potentially reducing tolerability by triggering allergic reactions or causing site-specific reactions (rashes, itching, flushing) in injectable or infused drugs.

Even when an ideal formulation is achievable, scalability may be problematic. This highlights the importance of integrating formulation science into pre-clinical development to avoid regulatory setbacks that can arise if the formulation used in early-stage trials is not viable for commercial manufacturing. 

With the growing diversity of therapeutic modalities, the drug formulation landscape is becoming more complex, both scientifically and with respect to resource allocation. Small companies may not have the internal resources or infrastructure to support systematic, rational drug formulation analyses and optimization. Even large, established companies may not have the requisite in-house formulation expertise needed to support the expansion of their portfolios into new therapeutic modalities. In these cases, contract development and manufacturing organizations (CDMOs) are an important resource to drug developers as they can provide formulation expertise gained through years of optimization across a wide array of projects, molecule types, and desired product profiles. The following case studies highlight some of the formulation challenges drug developers may encounter and how Simtra addressed them.

One case study highlights a formulation challenge involving the filling process for a biosimilar drug, specifically the type of pump used to fill vials. A pumping study was conducted using solutions containing the biosimilar. Samples were transferred through a peristaltic pump, which moves liquid through tubing using a rotating wheel, or a piston pump, which displaces liquid using rotating pistons. Samples were collected after 1, 3, and 5 passes and analyzed for aggregate formation. Initially, no aggregates were detected with either pump. However, during a 2-week stability assessment, samples processed with the piston pump showed increased aggregation over time, indicating that the biosimilar formulation was better suited to peristaltic pump filling.

Another case study underscores how seemingly minor changes in sourcing materials can significantly impact a drug’s formulation. The drug in question was a poorly water soluble small molecule formulated with cyclodextrin to enhance solubility. After the client switched API manufacturers, a particle began to appear in solution, suggesting a component interaction. Simtra collaborated with the client to conduct comprehensive studies using API from different manufacturers. Each API was formulated under identical conditions and evaluated for particle formation. Only one API source did not result in particle formation. Further analysis revealed that the API from the new manufacturer interacted with cyclodextrin, producing aluminum phosphate. The studies determined that specific production methods used by some manufacturers left residuals that reacted with cyclodextrin, identifying a single manufacturer capable of supplying suitable API for the formulation.

In an evolving therapeutic landscape, drug developers must carefully evaluate their formulation strategies and determine whether internal teams can effectively execute them or if external support is necessary. The first consideration is accessing the right expertise for each molecule, as formulation challenges differ significantly between small molecules and biologics. Another critical factor is scalable lyophilization expertise. Drug developers should also be mindful that integrating process development, formulation science, and manufacturing as early as possible is essential for preventing knowledge gaps or miscommunication that can cause costly delays late in development. This may be especially challenging for larger organizations in which these functions are siloed. Finally, developers must weigh the cost-benefit of building internal formulation science capacity versus partnering with external experts.

Companies choosing to outsource formulation science should seek a CDMO partner that not only brings expertise beyond what’s available internally but is equally invested in the product’s success. Evaluate the size and focus of a CDMO to ensure your project will receive the attention it deserves, rather than being just another item on a crowded to-do list. Critically, identify a CDMO that is transparent about its limitations and has the scientific network to find the right solutions for complex formulation challenges. In other words, find a CDMO that will see you as a valued partner with shared goals and objectives rather than just another revenue stream. 

Getting formulation science right from the outset is a critical determinant of whether or not a new drug captures the full value of its market potential. Having the right team in place is an essential part of the formula for commercial success.  

This article was contributed by Greg Sacha, the Global Senior Scientist in Development and Pre-Commercial Services at Simtra BioPharma Solutions.