EXECUTIVE INTERVIEW - PCI Pharma Services: A Consultative Approach to High Potency Formulation Development

Drug development is a very lengthy, expensive process. Reports indicate that for every single day a drug launch is delayed, millions of dollars in revenue can be lost, with estimates varying from $600,000 to $8 million per day.¹ Delays also lead to the suffering of patients who are unable to access the critical therapies in development to treat their condition. Ideally, this would not happen. But proper long-term due diligence on CDMO partners isn’t always performed, leading to a suboptimal development and manufacturing strategy. As such, not only are delays a possibility, they are inevitable. Drug Development & Delivery recently interviewed David O’Connell, Director of Scientific Affairs at PCI Pharma Services, about why it’s so important to choose the right CDMO partner to accompany you throughout the drug product lifecycle.

Q: What are the essential attributes of an industry-leading CDMO?

A: In terms of technology and manufacturing equipment, it’s incredibly beneficial to work with a CDMO able to conduct small-scale development and manufacture (D&M), while also offering in-house scalability for late-stage clinical and ultimately commercial supply. This flexibility, and access to an extensive range of equipment and processes, ensures various challenges can be addressed, and the most suitable solution for each unique project can be found. A major benefit of in-house scalability is that no additional tech transfers are required; switching CDMOs throughout the product’s lifecycle can be costly and introduces additional risk.

But equipment and facilities are only as good as their staff. Successful D&M requires strong cross-functional collaboration between highly experienced teams across a variety of disciplines, such as analytical, manufacturing, quality assurance and control and, of course, formulation development. A deep knowledge of their equipment and processes, and a strong awareness of alternative D&M methods, enables 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.

Understanding the CDMO’s containment strategy is vital when outsourcing highly potent OSD programs. You need to understand the containment measures in place, and the level of potency the facility is able to handle safely. Oncology dominates the formulation development market with a 25% share in 2022, and an estimated Compound Annual Growth Rate (CAGR) of 8.3% to 2030.² Around half of oncology drug candidates contain highly potent APIs, so along with scalability and development capabilities, safe handling of these dangerous substances is a key consideration.

Q: What are the main challenges facing CDMOs during D&M programs?

A: Clients occasionally withhold critical reports and information about the product or overall project strategy, preventing their CDMO partner from analysing the data themselves and being able to develop a longer-term strategy for their product. 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 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. Of course, limited development can be the result of a limited budget, but open and honest discussions during the proposals stages enables the CDMO partner to advise what is possible within the sponsor’s proposed budget.

Similarly, a limited supply of API can result in compressing multiple trials into a single batch. This reduces the usefulness of the data produced, making it challenging to draw meaningful conclusions from the results. Again, 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.

Q: What can sponsors do to maximize the efficiency of D&M programs?

A: Talk with your CDMO early to ensure the stability-indicating methods are optimized. CDMOs with the capability to develop methods in-house can work with you to execute multiple development activities in parallel. The more information you can share with the CDMO about your molecule, the quicker the development team can get your product to the clinic — and, of course, to commercial launch.

It’s also 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.

Considering the scale-up process during development stages is also important. Doing so enables the formulation team to design processes that are more easily scaled, reducing potential challenges and delays during the transition from development, through clinical to commercial manufacturing. Considering scale-up early, along with clearly defined scopes of work, improves the workflow between the formulation and manufacturing operations teams within the CDMO, and contributes to a strong collaborative relationship between the CDMO and their sponsor — a relationship based on effective communication and a deep understanding of the long-term program goals.

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.

Q: What trends have you noticed in the highly potent formulation development space?

A: A noticeable trend in the formulation development space is the use of a Design of Experiment (DoE)/Quality by Design (QbD) approach at earlier stages 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.

Q: Can you briefly describe a real-world case study in which D&M programs have been affected by poor strategy?

A: One customer had 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. It only came to light when the client requested we use 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 revealed the client had experienced these issues during the development phase.

Powder characterization is essential, as it provides insights into critical powder properties, such as particle size distribution, morphology, density, and flowability. In this particular 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. Techniques, including 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.

It’s important to remember 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 identifying the right CDMO and establishing a strong collaborative relationship during the development stage, sponsors can rest assured their drug product will achieve speed to patient, study, approval, and commercial launch.

References

1. https://mdgroup.com/blog/the-true-cost-of-patient-drop-outs-in clinicaltrials/#:~:text=Studies_have% 20shown_that_80,to_get_back_on_track.
2. Grand View Research (2023) Formulation Development Outsourcing Market Estimates and Trend Analysis from 2018 to 2030.