As the pharmaceutical industry continues to trend toward more customized, higher leverage formulations, the development and manufacture of drug products containing highly potent active pharmaceutical ingredients (HPAPIs) is experiencing a particularly promising growth curve.
For example, now through 2029, the drug discovery market for small molecule formulations — nearly half (45.5%) of which are considered highly potent1 — is expected to achieve a compound annual growth rate of almost 9%.2
Among the categories at the forefront of this expanding market is oncology. At present, about 60% of HPAPIs are being developed for oncological indications.3 It’s easy to understand why: The development of increasingly tailored therapies and precision medicines has revolutionized cancer treatment, resulting in more effective and potentially less toxic therapeutic options. To further encourage breakthroughs, regulatory agencies including the FDA have implemented accelerated approval pathways, fostering innovation and promoting faster commercialization of novel oncology drugs.
In this robust and dynamic landscape, the intricate processes of formulation development and tech transfer become even more critical, as they ensure the successful translation of each progressive new discovery into safe, effective and accessible drug products, while ensuring a greater speed to market for sponsor organizations. It’s a win-win scenario, but those victories must be hard-fought through detail-oriented due diligence. Steering a new formulation from early phase clinical development through final commercialization requires interconnected expertise across a variety of disciplines, including analytical, manufacturing, quality control and, of course, formulation development.
As the drugs become ever more sophisticated and potent, so must their developers and manufacturers. In this elevated environment, collaboration is key and information transparency paramount.
Early Riser: Design of Experiment
Practices Gain Momentum Gradually, the complexity and high-leverage nature of these next-generation drugs is instilling a ‘first time’s a charm’ mindset. A noticeable trend in the formulation development space is the utilization of Design of Experiment (DoE) approaches at the earliest stages of product life cycles.
DoE is a systematic, statistical approach with the aim of optimizing the product and the process by understanding the relationship between various factors (known as input variables) and responses (known as output variables). This method helps identify the most influential factors, determine their optimal levels and design space, and establish efficient and enduring processes while minimizing the number of experimental runs.
Several choices made during formulation development can influence the quality, safety and efficacy of final drug products; these include excipient selection, API concentration, processing conditions and manufacturing equipment. Traditional trial-and-error methods can be time-consuming and resource-intensive and — even after considerable effort and cost — ultimately may not identify the precise combination of factors ideal for a best-possible drug product.
By contrast, DoE provides a deeper understanding of the interactions between various factors and their corresponding impact on the final product, enabling a more streamlined identification of critical process parameters (CPPs) and critical quality attributes (CQAs). By using a structured approach to experiment design, DoE allows for the simultaneous assessment of multiple factors and their interactions, reducing the total number of experiments required. The smarter the process, the more time and resources saved.
By identifying optimal factor settings and establishing a versatile design space, DoE helps create holistic yet efficient processes, a marriage of comprehensiveness and speed that can lead to improved product quality, reduced variability and an expedited product journey. It also helps pinpoint potential risks and sources of variability in the formulation and process, allowing for proactive mitigation strategies to counteract adverse issues.
Such metrics-informed principles in pharmaceutical development are encouraged by regulatory agencies like the FDA, which considers DoE a key component in a larger Quality by Design (QbD) approach. There is good reason for this: Without a thorough and transferrable DoE process that helps move subsequent steps seamlessly forward, any number of things can suddenly go sideways. Unsurprisingly, this includes development- or scaleup-stage tech transfer, especially to external players like contract development and manufacturing organizations.
Case Study: Splitting Headache
As a dynamic and inherently experimental process, high potent formulation development is a niche where the smallest of details can be a big deal — or, should those details be omitted, a dealbreaker. To truly reap the benefits of DoE, sponsor pharma companies must transfer not just APIs and excipients but specs, spreadsheets and knowledge. The more data is withheld, the more is left to chance.
Far too frequently, incomplete or insufficiently transferred information leaves CDMO partners flying partially blind through gaping data holes. The resulting enforced errors can comprise anything from temporary delays to onerously long, expensive reworks. Let’s explore a real-world example, one in which a specific challenge was encountered during the development of a film-coated tablet with a highly potent API.
The sponsor had previously experienced issues related to powder static and poor flowability of the blend during the development phase. However, this critical information was not shared with the sponsor’s CDMO upon initial tech transfer. The issue only came to light when the sponsor requested the CDMO incorporate debossed tooling on the tablets. During scale-up using the new tooling, tablet splitting issues were observed halfway through the production run. Only then did it come to light that the sponsor had experienced similar issues during the development phase with a previous CDMO partner.
Powder characterization is an essential aspect of formulation development for solid oral dosage forms, as it provides insights into critical powder properties such as particle size distribution, morphology, density and flowability. In this case, information concerning the blend’s powder characterization originally revealed that during the development stage, static and flowability issues were observed, allowing the problem to be addressed during developmental transfer batches rather than further downstream; crucially, this straightforward solution was not shared with the CDMO. When manufacturing highly potent products, equipment containment needs can make it difficult to amend parameters during manufacture.
A thorough understanding of powder properties and their impact on processing performance is crucial for the successful development of high potent solid dosage forms. Techniques like particle size analysis, bulk and tapped density measurements, angle of repose and shear cell testing can be employed to assess the flow properties of a powder blend. With this information, formulation scientists can modify the blend composition or implement suitable processing techniques, such as granulation (wet or dry), to enhance the blend’s flowability and processing performance.
This is just one example of how withholding critical reports and information about the product or project strategy can prevent CDMO partners from analyzing the data themselves and planning accordingly. We don’t know what we don’t know, and lack of transparency can lead to issues that only surface when problems arise, making it difficult for a CDMO to address them effectively. It also means that the CDMO’s processes are generated based on secondhand information, increasing the risk of critical information being missed or misunderstood.
Another pitfall is the establishment of unrealistic or aggressive timelines, which can force the acceleration of development activities. This rushed approach may create problems during later stages of development and scale-up, potentially compromising the overall success of the project, as more formulation development may inevitably be required at a later, more time-critical stage. Limiting the amount of development activity prior to the clinical trial manufacturing stage can also create headaches by hindering the acquisition of robust process knowledge and design space. This may lead to issues further into the project, when making modifications is less tenable or feasible and potentially cause more work for both sponsor and CDMO.
Of course, sometimes limitations are baked in from the outset; more often than not, such constraints are fiscal. Here, the best course is open and honest discussion during proposal stages, so that a potential CDMO can advise what is possible within budget. In some cases, a limited supply of HPAPI results in compressing multiple trials into a single batch. This approach can reduce the usefulness of the data produced, making it challenging to draw meaningful conclusions from the results. While often beyond the sponsor’s control, this can nevertheless impact the quality of formulation development activities and, correspondingly, the data gleaned during those processes.
A Collaboration Checklist
Fortunately, there are several key strategies that sponsors can follow to help increase the success and efficiency of their formulation development projects. Firstly, it is essential to perform excipient compatibility and forced degradation studies upfront. These benchmarks help identify potential incompatibilities or stability issues early in the development process, allowing for timely adjustments and mitigations.
A clear definition of the work scope, along with a well-defined timeline, is crucial for the efficient execution of formulation development projects. Sufficient time should be allocated for reviewing and processing data and results before progressing to additional work. This approach ensures a methodical and thorough evaluation of each stage of the project, minimizing the risk of potential issues going unnoticed.
Effective communication and early notification of any changes in strategy are vital for maintaining a strong partnership between sponsor and CDMO. Open communication channels facilitate the sharing of technical expertise and promote a collaborative environment where both parties can fully contribute their knowledge and experience. Such a collaborative approach — as opposed to a guarded or even confrontational one — is critical for resolving issues and ensuring that the sponsor is an integral part of the problem solving process.
And again: if you know it, bestow it. Sponsors should share all available information and reports on the project’s development as early as possible, including any issues encountered during development. This transparency enables the development team to make informed decisions and address potential challenges proactively.
Lastly, it is important to consider the scale-up process during the development stage. This can be achieved by using equipment and processes that are transferable and compatible with large-scale manufacturing. By keeping the scale-up process in mind from the beginning, formulation development teams can design processes that are more easily scaled, reducing potential challenges and delays during the transition from early phase development to late stage clinical and commercial manufacturing.
Optimizing Your Chances of Success
The importance of formulation development to the life cycle of highly potent drug products cannot be overstated. A well-executed pharmaceutical formulation development process can significantly improve the efficiency and speed to market of a new drug product. By identifying the most suitable form, dosage, and delivery mechanism for the API, manufacturers can optimize drug absorption, bioavailability and stability, reducing the need for costly and time-consuming reformulations later down the line.
Establishing a strategic partnership with a CDMO is crucial for driving efficiencies and speeding up the drug development process. A truly global, integrated CDMO can provide end-to-end support, from early-stage formulation development through scale-up, clinical trials, commercial manufacturing and launch. By establishing a strong collaborative relationship during the development stage, sponsors give their drug products the best chances to achieve speed to patient, study, approval and commercial launch.
References
1. 2022 data: What percentage of drug compounds are highly potent? Affygility Solutions. July 2021.
2. Small Molecule Drug Discovery Market Size & Share Analysis – Growth Trends & Forecasts (2025 – 2030). Mordor Intelligence.
3. Cytotoxic Drugs and HPAPI Manufacturing Market: Industry Trends and Global Forecasts, 2022-2035. Roots Analysis.
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