The development and manufacture of drug products containing highly potent active pharmaceutical ingredients (HPAPIs) is in demand. Recent data suggest that between 2023 and 2030, the small molecule drug discovery market will register a compound annual growth rate (CAGR) of around 8%.¹ This is particularly relevant in the field of oncology, which accounts for around 35% percent of small molecule drug candidates, around half of which contain HPAPIs.

The development of targeted therapies and precision medicines has revolutionized cancer treatment, resulting in more effective and potentially less toxic therapeutic options for patients. Furthermore, regulatory agencies including the FDA have implemented accelerated approval pathways, fostering innovation and promoting faster commercialization of novel oncology drugs. In this dynamic landscape, the role of formulation development becomes even more critical, as it ensures the successful translation of these breakthrough discoveries into safe, effective, and accessible drug products for patients, whilst ensuring a greater speed to market for sponsor organizations.

Essential Attributes

Successful formulation development requires the engagement of highly experienced teams across a variety of disciplines, such as analytical, manufacturing, quality assurance and control and, of course, formulation development. These cross-functional teams would possess a comprehensive knowledge and understanding of their equipment and processes, and a strong awareness of alternative development and manufacturing methods. This would enable them to determine how various formulation attributes can impact the final drug product, both positively and negatively, and advise their sponsors accordingly throughout the process.

In terms of technology and manufacturing equipment, it is beneficial to work with a CDMO with facilities designed for small-scale operations while also offering in-house scalability for large-scale clinical and commercial manufacturing. This flexibility enables a CDMO to accommodate a wide array of product requirements and adapt to different formulation challenges. Access to an extensive range of equipment and processes ensures that various challenges can be addressed, and the most suitable solution for each unique project can be found.

QbD/DoE: A Growing Trend

A noticeable trend in the formulation development space is the use of a Design of Experiment (DoE)/Quality by Design (QbD) approach at an earlier stage of the product lifecycle. DoE is a systematic, statistical approach with the aim of optimizing the product and the process by understanding the relationship between various factors (input variables) and responses (output variables). This method helps identify the most influential factors, determine their optimal levels, and establish robust and efficient processes while minimizing the number of experimental runs.

During formulation development, multiple factors can influence the quality, safety, and efficacy of the final drug product, such as the choice of excipients, API concentration, processing conditions, and manufacturing equipment. Traditional trial-and-error methods can be time-consuming, resource-intensive, and may not identify the best combination of factors to produce a high-quality drug product.

DoE provides a deeper understanding of the interactions between factors and their impact on the final product, enabling the 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, which saves time and resources.

Through the identification of optimal factor settings and the establishment of a design space, DoE helps create robust and efficient processes, which can lead to improved product quality, reduced variability, and increased manufacturing efficiency. It also helps identify potential risks and sources of variability in the formulation and process, allowing for proactive mitigation strategies to minimize the impact of these risks on the final product.

Regulatory agencies, such as the FDA, encourage the use of Quality by Design (QbD) principles in pharmaceutical development, which includes the application of DoE to ensure a science-based and risk-based approach.

Challenges and Solutions

Formulation development is a dynamic and experimental process. However, certain challenges are presented to CDMO partners which add a layer of unnecessary pressure to the development process—some of which are avoidable.

For example, clients occasionally withhold critical reports and information about the product or project strategy, preventing their CDMO partner from analyzing the data themselves. This lack of transparency can lead to issues that surface when problems arise, making it difficult for the CDMO team to address them effectively. It also means that the CDMO’s processes are generated based on second-hand information, increasing the risk of critical information being missed by the CDMO.

Another challenge 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 (CTM) stage can also pose difficulties. Inadequate pre-CTM development hinders the acquisition of robust process knowledge, which may lead to issues further into the project when it is less feasible to make modifications. Limited development can be the result of a limited budget, however if open and honest discussions are held up front during the proposal stages, the CDMO partner will be able to advise what is possible within the sponsor’s proposed budget.

In some cases, a limited supply of active pharmaceutical ingredients (API) 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. This can often be beyond the client’s control, but it does have an impact on the quality of formulation development activities and the data gleaned during the process.

In addition to keeping these challenges in mind, 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 studies 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 the client and the development team. Open communication channels facilitate the sharing of technical expertise and promote a collaborative environment where both parties can contribute their knowledge and experience.

A collaborative approach, as opposed to a confrontational one, is critical for resolving issues and ensuring that the client is an integral part of the problem-solving process. Clients 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. Occasionally, clients may not heed the expert advice and experience shared by the CDMO teams. This disregard can lead to suboptimal decisions and negatively impact the project’s progress and outcome.

Lastly, it is important to consider the scale-up process during the development stage of the project. 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 development to commercial manufacturing.

Case Study

In this real-world case study, a specific challenge was encountered during the development for a film-coated tablet.

The client 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 PCI at the time.

The issue only came to light when the client requested that we incorporate debossed tooling on the tablets. During the scale-up of the project using the new tooling, tablet splitting issues were observed halfway through the production run. The investigation into the cause of tablet splitting led to the revelation that the client had experienced these issues during the development phase.

Powder characterization is an essential aspect of formulation development, as it provides insights into critical powder properties, such as particle size distribution, morphology, density, and flowability. In this case, powder characterization of the blend during the development stage could have identified the issue with static and flowability, allowing the problem to be addressed during development rather than at the scale-up phase.

A thorough understanding of powder properties and their impact on processing performance is crucial for the successful development of solid dosage forms, such as tablets. 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, to enhance the flowability and processing performance of the blend.

In Summary

The importance of formulation development to the product lifecycle 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, a CDMO 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 trusted 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 to scale-up, clinical trials, commercial manufacture, and launch. They will have a proven track record in developing successful drug formulations, a deep understanding of regulatory requirements, and state-of-the-art equipment and facilities.

However, it is important to remember that the right CDMO is there to help you achieve your clinical and commercial goals. They know their processes and equipment trains and have a vast amount of experience in their areas of expertise. By establishing a strong collaborative relationship during the development stage, sponsors can rest assured that their drug product will achieve speed to patient, study, approval, and commercial launch.

References
1. https://www.mordorintelligence.com/industry-reports/small-molecule-drug-discovery-market

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Louise Carpenter is the Head of Formulation Development at PCI Pharma Services’ Tredegar facility. Louise manages a strong technical team and provides oversight and support to her team and clients in the areas of Formulation Development, Technical Transfer and Scale-up of solid oral, oral liquid and semi-solid products for clinical trials and/or commercialization, including controlled substances and highly potent dosage forms.